Makoto Emoto

Differences in the Angiogenesis of Benign and Malignant Ovarian Tumors, Demonstrated by Analyses of Color Doppler Ultrasound, Immunohistochemistry, and Microvessel Density

To clarify the differences in angiogenesis between benign and malignant ovarian tumors, the authors examined the immunohistochemical characteristics and the density of tumor vessels in both tumor groups. Intratumoral vascularization was observed preoperatively by transvaginal color Doppler ultrasound.

Characteristics of cloned cells of mixed müllerian tumor of the human uterus carcinoma cells showing myogenic differentiation in vitro

Background. To elucidate the relationship between the epithelial and mesenchymal elements of malignant mixed Müllerian tumors (MMMT), the authors examined the biologic properties of two clones of different cell types (designated as FU‐MMT‐2‐C1 and FU‐MMT‐2‐S1) established from a uterine MMMT cell line (FU‐MMT‐2), which they previously have reported.

Two cell lines established from mixed Müllerian tumors of the uterus morphologic, immunocytochemical, and cytogenetic analyses

To clarify the cellular origin and characteristics of malignant mixed müllerian tumor (MMMT), the authors investigated two cell lines (designated as FU‐MMT‐1 and FU‐MMT‐2) established from two patients with heterologous MMMT of the uterus. Both cell lines propagated continuously for 83 and 55 serial passages over 1.5 years, respectively. Morphologically, FU‐MMT‐2 was a mixture of carcinoma cells and sarcoma cells with predominance of carcinoma cells; FU‐MMT‐1 only had a sarcomatous element with distinct rhabdomyoblastic differentiation. Immunocytochemically, the sarcoma cells of each cell line expressed, not only myogenic and mesenchymal antigens (desmin, myoglobin, and vimentin), but also epithelial antigens, including epithelial membrane antigen and keratin. The carcinoma cells in FU‐MMT‐2 were positive for the epithelial antigens and vimentin and negative for desmin and myoglobin. Both lines had abnormal karyotypes; the modal chromosome numbers of FU‐MMT‐1 and FU‐MMT‐2 were 47 and 80, respectively. In addition, FU‐MMT‐1 had trisomy 8, and FU‐MMT‐2 had complex structural abnormalities. When transplanted into nude mice, FU‐MMT‐1 reproduced and maintained the characteristics of the original tumor. These cell lines and xenografts appear to provide a useful system for studying the biologic behavior, cytogenetic features, and histogenesis of MMMT. In conclusion, the presence of epithelial antigens in the sarcomatous and carcinomatous elements seemed to support the hypothesis that both elements are derived from a common stem cell.

The grading of lymphovascular space invasion in endometrial carcinoma

This study was conducted to elucidate the prognostic significance of a three‐grade system for lymphovascular space invasion (LVSI).

Angiogenesis in carcinosarcomas of the uterus : Differences in the microvessel density and expression of vascular endothelial growth factor between the epithelial and mesenchymal elements

Carcinosarcoma of the uterus is a highly aggressive neoplasm. However, the angiogenesis of this neoplasm is still unknown. This is the first study to examine the differences in angiogenesis between the epithelial and mesenchymal elements of this biphasic neoplasm. Surgical specimens from 21 primary uterine carcinosarcomas were histopathologically evaluated, and then immunohistochemically analyzed for tumor angiogenesis, using an anti-vascular endothelial growth factor (VEGF) antibody. The microvessel density (MVD) was also measured in each element of these neoplasms, using anti-CD34 monoclonal antibody. The MVD in the epithelial element was found to be higher than that of the mesenchymal element in 20 of 21 (95.2%) primary tumors. The epithelial elements showed a higher MVD (mean, 81.6 +/- 41.1) than the mesenchymal elements (mean, 36.7 +/- 23.8) in these primary tumors (P < .0001). Moreover, the epithelial elements showed a higher VEGF expression (mean, 0.78 +/- 0.23) than the mesenchymal elements (mean, 0.37 +/- 0.20) (P < .0001). The tumors with lymph-vascular invasion showed a higher VEGF expression (n = 17; mean, 0.85 +/- 0.17) than the tumors without lymph-vascular invasion (n = 4, mean, 0.47 +/- 0.12) (P < .01). Microscopically, neither lymph-vascular space invasion nor metastatic tumors consisted of sarcoma alone in this series. In addition, a decrease in the VEGF expression was found in the transitional areas between carcinomatous and sarcomatous elements in all 10 homologous and 4 heterologous tumors evaluated. These results suggest that the tumor angiogenesis in the epithelial element may be more active than that of the mesenchymal element and also substantiated the high metastatic potential of the epithelial element in uterine carcinosarcoma. Based on these findings, carcinoma cells thus may play a key role in the angiogenesis of this biphasic neoplasm.

Metronomic doxifluridine chemotherapy combined with the anti-angiogenic agent TNP-470 inhibits the growth of human uterine carcinosarcoma xenografts

Uterine carcinosarcoma is a highly aggressive gynecological neoplasm that responds poorly to conventional chemotherapy and radiotherapy. Metronomic chemotherapy is accepted as a new approach for cancer treatment, and its underlying mechanism seems to involve the suppression of angiogenesis. However, the efficacy of metronomic and anti‐angiogenic therapies against uterine carcinosarcoma is unknown. The anti‐angiogenic effect of doxifluridine was assessed in vitro using human umbilical vein endothelial cells (HUVEC) co‐cultured with FU‐MMT‐1 human uterine carcinosarcoma cells. The antitumor and anti‐angiogenic effects of metronomic doxifluridine (delivered via oral gavage) in combination with TNP‐470 were evaluated in vivo. Tumor vascularity was assessed by contrast‐enhanced color Doppler ultrasound, laser Doppler and microvessel density staining. Doxifluridine suppressed tube formation of HUVEC and vascular endothelial growth factor production by FU‐MMT‐1 cells. Metronomic doxifluridine alone significantly suppressed tumor growth compared with the untreated (control) group, while metronomic doxifluridine in combination with TNP‐470 significantly inhibited tumor growth compared with each treatment alone. A significant reduction of intratumoral vascularity was observed in FU‐MMT‐1 xenografts following treatment with metronomic doxifluridine in combination with TNP‐470, as compared with each treatment alone. Intestinal bleeding was only observed when the maximum tolerated dose of doxifluridine was administered in combination with TNP‐470. Metronomic doxifluridine chemotherapy in combination with TNP‐470 might be effective for uterine carcinosarcoma without marked toxicity, possibly acting via its potent anti‐angiogenic effects. Clinical studies are needed to evaluate the safety and efficacy of this treatment in humans. (Cancer Sci 2011; 102: 1545–1552)

Transvaginal color Doppler ultrasonic characterization of benign and malignant ovarian cystic teratomas and comparison with serum squamous cell carcinoma antigen.

The preoperative diagnosis of squamous cell carcinoma (SCC) arising in mature cystic teratoma of the ovary remains difficult. The purpose of this study is to examine the usefulness of transvaginal color Doppler ultrasound (TV‐CDU) in differentiating malignant (SCC) from benign cystic teratoma of the ovary.

K‐ras mutation in tamoxifen‐related endometrial polyps

K‐ras mutation is thought to occur at an early stage of neoplastic progression in the endometrium. The authors investigated mutations in codon 12 of K‐ras in tamoxifen (TAM)‐related endometrial polyps.

Evidence-based guidelines for treatment of uterine body neoplasm in Japan: Japan Society of Gynecologic Oncology (JSGO) 2009 edition

Endometrial carcinoma is one of the most common gynecologic malignancies in Japan and its incidence has increased recently. Although surgery is the cornerstone of the management of patients with endometrial cancer, there is significant variation in Japan with regard to the type of hysterectomy employed. Additionally, it remains controversial whether full nodal staging is required in all patients. Furthermore, adjuvant therapy differs between Japan and Western countries. To delineate clearly the standard of care for endometrial cancer treatment in Japan, the guidelines for the treatment of endometrial cancer were published in 2006 and revised in 2009. The 2009 edition included topics not addressed in the previous edition including the treatment of mesenchymal tumors, for example leiomyosarcoma, and sections covering the treatment of serous and clear-cell adenocarcinoma. These guidelines are composed of nine chapters and include nine algorithms. The guidelines also contain fifty-one clinical questions (CQs) and each CQ consists of recommendations, background, explanations, and references. The treatment recommendations herein are tailored to reflect current Japanese clinical practice and ensure equitable care for all Japanese women diagnosed with endometrial cancer.

Expression of steroid receptors, Ki-67, and epidermal growth factor receptor in tamoxifen-treated endometrium.

Endometrial specimens of 34 (25 premenopausal and 9 postmenopausal) breast cancer patients receiving tamoxifen were immunohistochemically examined using estrogen receptor (ER), progesterone receptor (PR), Ki-67, and epidermal growth factor receptor (EGFR) antibodies. Proliferative (n = 6), secretory (n = 9), and postmenopausal (n = 6) endometria served as controls. The ER and PR expressions of the glandular cells in tamoxifen-treated patients did not differ from those of the glandular cells in the control women regardless of menopausal status. The Ki-67 index of glandular cells in tamoxifen-induced amenorrheic women was found to be lower than that of the proliferative glandular cells in the control women (p < 0.03), whereas the Ki-67 index of glandular cells in the tamoxifen-treated postmenopausal patients was higher than that of the glandular cells in the control women (p < 0.02). No EGFR overexpression was found in the glandular cells of the tamoxifen-treated premenopausal patients, but expression of EGFR was high in glandular cells of the tamoxifen-treated postmenopausal patients associated with a high Ki-67 index. In competition with ovarian estrogen secretion, tamoxifen may have an antiestrogenic effect on the endometrium, but tamoxifen probably has an estrogenic effect in the absence of ovarian estrogen secretion. This estrogenic effect of tamoxifen may be associated with an EGFR autocrine system.