Takuya Ayabe

Estrogen receptor-mediated effects of tamoxifen on human endometrial cancer cells.

Tamoxifen is an estrogen receptor (ER)-antagonist that is widely used for the treatment of breast cancer, although it increases the risk of endometrial cancer. The mechanism mediating the stimulatory effect of tamoxifen on endometrial cancer is presently unknown. In this study we examined the effects of tamoxifen on Ishikawa 3H-12 endometrial cancer cells and MCF-7 breast cancer cells. Ishikawa cell growth was stimulated by 4-hydroxytamoxifen and accompanied by increased transcriptional activity of the endogenous ER. These stimulatory effects did not occur in MCF-7 cells. The relative transcriptional activity of the activation function (AF) 1 domain of ERalpha compared with that of the AF2 domain was 4-fold higher in Ishikawa cells than in MCF-7 cells. Mitogen-activated protein (MAP) kinase, which stimulates the transcriptional activity of AF1, was constitutively activated in Ishikawa cells, but not in MCF-7 cells. These observations suggest that the constitutively activated MAP kinase-signaling pathway in Ishikawa cells enhances the transcriptional activity of ERalpha via the AF1 domain. This ERalpha activation pathway may be involved in the stimulatory effect of tamoxifen on the development and/or progression of endometrial cancer.

Severe 5-fluorouracil-induced toxicity due to decreased dihydropyrimidine dehydrogenase activity: report of a patient survival and urinary pyrimidine and dihydropyrimidine levels

Abstract We report a Japanese woman who survived severe 5-fluorouracil (5-FU) toxicity after receiving 5′-deoxy-5-fluoro-uridine (5′DFUR) for the treatment of breast cancer (pt2n1m1); the toxicity was due to decreased dihydropyrimidine dehydrogenase (DPD) activity. Pharmacokinetic investigation showed very high and prolonged plasma 5-FU concentrations after termination of the oral administration of 5′DFUR. The DPD activity in all plasma samples was below 30 pmol/min per mg protein. Her urinary thymine and uracil levels were high, and the ratios of urinary dihydrothymine/thymine and dihydrouracil/uracil were very low compared with the ratios in healthy people. These findings suggest that determination of urinary pyrimidine and dihydropyrimidine levels would be an appropriate urinary screening sytem that may be useful for evaluating DPD activity before 5-FU treatment is initiated.

Diagnostic usefulness of intraoperative ultrasonography in avoiding unnecessary para-aortic lymphadenectomy in women with endometrial carcinoma.

Objective: To evaluate the usefulness of intraoperative ultrasonography (IU) in reducing the number of unnecessary para-aortic lymphadenectomy in women with endometrial carcinoma. Methods: Computed tomography (CT) and IU were used to assess whether para-aortic lymph nodes were enlarged in 91 women with endometrial carcinoma. All women underwent hysterectomy and systematic pelvic and para-aortic lymphadenectomy. On the basis of the intrauterine pathological findings (IPF) of the removed uterus, the women were classified into low- and high-risk groups. It was assumed that para-aortic lymphadenectomy would be performed only when enlarged nodes were detected by CT or IU or only when women were classified into the high-risk group. The numbers of women who would have had missed metastases and who could have avoided para-aortic lymphadenectomy were calculated. Results: Eighteen women had pathological para-aortic node metastases. Theoretically, the number of women who would have had missed metastases on the basis of CT, IU, and IPF were 11, 2, and 2, respectively; more metastases were missed with CT than with the other 2 methods. The number of women who could have avoided para-aortic lymphadenectomy on the basis of CT, IU, and IPF were 84, 59, and 29, respectively; compared to IPF, IU helped avoid para-aortic lymphadenectomy in more women. Conclusions: Intraoperative ultrasonography is the most efficient method for avoiding both unnecessary para-aortic lymphadenectomy and missed para-aortic node metastases in women with endometrial carcinoma.

Case of minimal deviation adenocarcinoma: Possible clinical link to lobular endocervical glandular hyperplasia as its origin

Minimal deviation adenocarcinoma (MDA) is defined as an extremely well differentiated variant of endocervical adenocarcinoma. Several reports have stated that MDA associates with lobular endocervical glandular hyperplasia (LEGH). It is difficult to distinguish LEGH from MDA based on clinical and histologic similarities. There is no definite evidence proving that LEGH is a precursor lesion of MDA. A 45‐year‐old woman was admitted to our hospital for minute investigation of her neurological disorder. The multiple‐cystic lesion at the uterine cervix was identified by magnetic resonance imaging. Based on her normal histological findings and severe underlying conditions, a careful follow‐up strategy was adapted. Two years later, atypical glandular cells were observed and the multiple‐cystic lesion had increased. Pathological diagnosis of a conization specimen was MDA. Radical hysterectomy was carried out. Pathological examination revealed coexistence of LEGH and MDA. Her clinical course and histological findings suggested the possibility that LEGH might be a precursor lesion of MDA.

Loss of the cell polarity determinant human Discs-large is a novel molecular marker of nodal involvement and poor prognosis in endometrial cancer.

Background:Recent Drosophila studies showed that Discs-large (Dlg) is critical for regulation of cell polarity and tissue architecture. We investigated the possibility that loss of the human homologue of Drosophila Dlg (DLG1) is involved in endometrial carcinogenesis.Methods:We analysed DLG1 expression in 160 endometrial cancers by immunohistochemical staining. Its expression was confirmed by quantitative real-time PCR (RT–PCR). We investigated the roles of DLG1 in growth and invasion by knockdown experiment in endometrial cancer cell lines.Results:Human DLG1 localises at cellular membrane in normal endometrial tissues. Loss of DLG1 was observed in 37 cases (23.1%). Loss of DLG1 was observed in patients with advanced stage and high-grade histology. It was also observed in patients with nodal metastasis, deep myometrial invasion, and negative oestrogen and progesterone receptors. Patients with loss of DLG1 showed poorer overall survival (P=0.0019). Immunohistochemistry data correlated with RT–PCR data. Knockdown of Dlg1 in endometrial cancer cells resulted in accelerated tumour migration and invasion in vitro.Conclusions:Tissue polarity disturbance because of loss of DLG1 was shown to confer more aggressive characteristics to endometrial cancer cells. Our study revealed that DLG1 expression is a novel molecular biomarker of nodal metastasis, high-grade histology, and poor prognosis in endometrial cancer.

Erythematous and bullous rash strongly indicating toxic epidermal necrolysis associated with the use of intravenous ritodrine hydrochloride

Toxic epidermal necrolysis (TEN) is a very rare drug reaction associated with a high mortality rate. This condition warrants prompt recognition, diagnosis and treatment. Only one case report of TEN that was possibly induced by ritodrine hydrochloride, a tocolytic agent, was found in English literature. Here, we report the case of a 26‐year‐old pregnant woman who was suspected with TEN following the intravenous administration of ritodrine hydrochloride in the 35th week of gestation. An emergency cesarean section was performed because the labor pains caused systemic intolerable haphalgesia. After the surgery, intensive dermatological treatment commenced, which helped her recover from the serious condition. The result of the drug‐induced lymphocyte stimulation test for ritodrine hydrochloride was positive. When a skin eruption appears during the administration of ritodrine, we must consider the benefits as well as the risks of continuous use of tocolytic agents because there is a risk of Stevens–Johnson syndrome or TEN.

Postoperative concurrent chemoradiotherapy for the high-risk uterine cervical cancer.

Aim:  To determine whether concurrent chemoradiotherapy (CCRT) can improve the survival rate of high‐risk uterine cervical cancer.

Serous Endometrial Intraepithelial Carcinoma Involving Endometrial PolypDiagnosed by Transcervical Resection: A Case Report

Uterine serous carcinoma is a representative histological subtype of endometrial type II cancer. Uterine serous intraepithelial carcinoma is thought to be a precursor lesion of uterine serous carcinoma. Uterine serous intraepithelial carcinoma is frequently found to involve an endometrial polyp. Preoperative diagnosis of uterine serous intraepithelial carcinoma is difficult due to its localized occurrence in the endometrial cavity. We experienced a case of postmenopausal women with abnormal endometrial cytology. Endometrial biopsy suggested the possibility that she has a malignant uterine tumor, but it did not reached to the confirmative pathological diagnosis. Hysteroscopy revealed that she has an endometrial polyp. Pathological analysis of the resected endometrial polyp confirmed that her disease is uterine serous intraepithelial carcinoma involving endometrial polyp. She underwent hysterectomy, bilateral salpingo-oophorectomy, omentectomy and retroperitoneal lymphadenectomy. No extrauterine lesion was detected. Our case suggested the possibility that transcervical resection under the hysteroscope might be useful to detect serous endometrial intraepithelial carcinoma.

Spinal cord infarction in diabetic pregnancy: A case report

Spinal cord infarction (SCI) is uncommon as compared to cerebral stroke. Moreover, SCI during pregnancy is rare. Here, we report a case of SCI in diabetic pregnancy, properly diagnosed, promptly treated, and a good prognosis achieved. A 38‐year‐old, pregnant woman, para 1, with type 1 diabetes mellitus on insulin since 14 years of age, was admitted to our hospital for paresthesia and numbness in the lower left side of the body, with movement disturbances. On the basis of the temporal profile of the onset and the multiple resonance imaging scans, SCI was diagnosed. Steroid pulse therapy and low‐dose aspirin administration was initiated. Her symptoms were improved and discharged. A repeat cesarean section was performed at 37 weeks of gestation and her postoperative course was uneventful. Her daily activities were not hindered severely, though she experienced defecation discomfort.