Tomoharu Okubo

Atheroprotective effect of estriol and estrone sulfate on human vascular smooth muscle cells

In patients with atherosclerosis, fibrosclerotic focuses are induced by multiplication of vascular smooth muscle cells (VSMC), and they are regulated by cytokines and regulators. There have been few reports about the atheroprotective effect of estriol (E(3)). Estrone sulfate (E(1)-S) is the predominant estrogen of conjugated equiline estrogens, which is commonly used in hormone replacement therapy, but it should be hydrolyzed by steroid sulfatase (STS) to enter the cells of target tissues. The purpose of this study was to detect STS in VSMC and to investigate whether E(3) and E(1)-S have atheroprotective effects like E(2). First, we detected the presence of STS mRNA in VSMC by in situ hybridization. We then examined the changes in the expression of mRNAs of cytokines, namely, PDGF-A chain, IL-1, IL-6 and TGF-beta, in VSMC, in the presence and absence of E(3) and estrogens. As a result, the expression of PDGF-A chain, IL-1 and IL-6 mRNAs was suppressed by E(3) (P<0.05 vs control) significantly like E(1)-S and E(2), but that of TGF-beta mRNA was not significantly affected by any estrogen. These results indicate that E(1)-S can be hydrolyzed by STS in VSMC, and that E(3) may regulate the cytokines by suppressing the production of mRNAs. It is suggested that there is a possibility of E(1)-S and E(3) having a direct effect on vessels in atherogenesis.

Effects of estrogens on cholinergic neurons in the rat basal nucleus

Estrogen replacement in postmenopausal women may help prevent or delay development of Alzheimers disease. Because loss of basal forebrain cholinergic neurons with reductions in choline acetyltransferase (ChAT) concentration are associated with Alzheimers disease, we investigated the effect of estradiol (E(2)) and J 861, a non-feminizing estrogen, on cholinergic neurons in the basal forebrain. Ovariectomized rats received E(2), J 861 or vehicle, and basal forebrain sections through the substantia innominata, medial septum, and nucleus of the diagonal band were immunostained for ChAT. ChAT-immunoreactive cells in the basal forebrain were significantly reduced in the ovariectomized rats compared to intact rats, but those ovariectomized rats receiving estrogen replacement with E(2) and J 861 had near normal levels of ChAT-positive neurons. While retrograde tracing experiments with fluorogold injected into the prefrontal cortex showed no significant differences in the number of fluorogold-labeled cells among the groups, ChAT-immunoreactive cells and double-labeled cells were significantly lower in OVX rats than in intact and E(2) rats. Some substantia innominata cells in the J 861 rats were ChAT/estrogen receptor alpha-positive. These results suggest that E(2) and J 861 have positive effects on cholinergic neurons that project from the basal nucleus to the forebrain cortex.

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.

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.

Premature delivery due to intrauterine Candida infection that caused neonatal congenital cutaneous candidiasis: A case report

Congenital cutaneous candidiasis is a very rare disease with less than 100 cases published in the medical literature. Neonates having this disease present with systemic skin lesions caused by intrauterine Candida infections. We present a case of threatened premature delivery due to Candida chorioamnionitis, which caused both maternal postpartum endometritis and neonatal congenital cutaneous candidiasis. A 34‐year‐old woman who was admitted for fetal membrane bulging at 20 weeks of gestation underwent McDonald cervical cerclage. We diagnosed threatened premature delivery due to intrauterine infection; therefore, we terminated the gestation by cesarean section at 24 weeks of gestation. Fungi‐like yeast was detected in infantile gastric juice. Histopathological findings of the placenta revealed that Candida albicans mycelium invaded the placenta, chorioamniotic membrane and umbilical cord.

Prenatal Diagnosis of Agnathia-Otocephaly Using Sonography and Magnetic Resonance Imaging

Agnathia-otocephaly is a rare lethal malformation characterized by micrognathia/agnathia, microglossia/aglossia, microstomia, and several types of abnormally positioned ears. Most cases of agnathia-otocephaly are sporadic; however, our case was an extremely rare case of agnathiaotocephaly following a sibling case of micrognathia. In this case, 2-dimensional (2D) sonography, magnetic resonance imaging (MRI), and subsequent 3-dimensional (3D) sonography led us to a precise prenatal diagnosis of agnathia-otocephaly. The patient was a 40-year-old woman, gravida 3, para 3. She had histories of left anophthalmia, left sensorineural hearing loss, and infertility. Her husband had a history of right amblyopia. However, the cause had not been clear. Her first pregnancy resulted in dichorionic triamniotic triplets; 2 fetuses died in utero at 15 weeks’ gestation. A live female neonate was delivered vaginally at 38 weeks (weight, 2322 g; Apgar scores, 9 and 10 at 1 and 5 minutes, respectively); the 2 dead fetuses were delivered as fetuses papyraceus simultaneously. The female child was healthy and in good condition for 6 years after birth. In her second pregnancy, MRI findings at 31 weeks revealed a male fetus with mandibular hypoplasia. The neonate was delivered vaginally at 37 weeks (weight, 2287 g; Apgar scores, 1 and 1 at 1 and 5 minutes) and died of airway obstruction shortly after birth. The autopsy showed that the neonate had micrognathia without other abnormalities (Figure 1). In her third pregnancy, the amniotic fluid was abundant (amniotic fluid index, 26 cm) at 25 weeks. We collected the amniotic fluid to reduce the volume and to perform a karyotyping analysis. The results revealed a normal 46,XY karyotype. Two-dimensional sonography showed micrognathia, orbital hypotelorism, downward displacement of the orbits, proboscis, low-set ears, and a normal brain. Other minor abnormalities were not detected. Magnetic resonance imaging confirmed the 2D sonographic findings. At this time, we thought about the possibility of agnathia-otocephaly. Subsequent 3D sonography showed a total 3D craniofacial construction and extremely low-set ears adjacent to each other medially, which confirmed our diagnosis (Figure 2, A and B). We informed the parents of the diagnosis of agnathiaotocephaly, the poor prognosis, and the fact that all survivors require support to maintain airway patency, such as tracheostomy or ex utero intrapartum treatment. However, the parents did not agree to those treatments. A male neonate was delivered vaginally at 38 weeks (weight, 2454 g; Apgar scores, 1 and 1 at 1 and 5 minutes) and died of total airway obstruction shortly after birth. Externally, the neonate had agnathia, extremely low-set ears adjacent to each other medially, a proboscis with 2 nostrils, a small mouth cavity, and downward-slanting palpebral fissures. The subsequent internal autopsy revealed bilateral auditory meatus atresia, a hypoplastic palate, a rudimentary tongue, a small trachea-oropharynx connection, 2 nostrils connecting with an extremely small blind-ending duct, orbital hypotelorism, and normal-size orbits located laterally and caudally to the proboscis. The brain and other organs were normal. The skeletal structure showed total mandibular agenesis and a rudimentary maxillary bone (Figure 2C). Clinical Letters

Mature cystic teratoma coexisting with clear‐cell carcinoma in the ovary

Mature cystic teratoma (MCT) is the most common benign ovarian tumor; clear‐cell carcinoma (CCC) is a relatively common malignant ovarian tumor in Japan, but there are few reports on the coexistence of MCT and CCC. Here we report a case of simultaneous MCT and CCC in the ovary and review the relevant literature. The patient was a 49‐year‐old woman. A 5‐cm MCT was found in the left ovary on initial gynecological examination, and she was referred to hospital for treatment because it was expanding. Magnetic resonance imaging showed a multilocular cystic tumor 16 × 10 × 9.5 cm in the left ovary, and surgery was performed. The final pathological diagnosis was MCT, endometriotic cyst, clear‐cell adenofibroma, clear‐cell borderline tumor, and CCC in the left ovary.

Symptomatic deep venous thrombosis of the lower extremity in a pregnant woman successfully treated with endovascular procedures

We report a pregnant woman with symptomatic deep venous thrombosis of the lower extremity distributing in the left iliac, femoral, popliteal and calf veins. Systemic anticoagulation therapy failed; however, treatment was successful through a combination of various endovascular procedures, including catheter‐directed thrombolysis. During the therapies, an optional inferior vena cava filter was implanted to protect against the development of pulmonary embolism.

Retroperitoneal Endometriotic Cyst Infiltrated in the Iliopsoas Incidentally Found in a Patient with Acute Back Pain

We describe a rare case of retroperitoneal endometriotic cyst infiltrated in the iliopsoas incidentally found in a patient with acute back pain. Endometriosis at the pelvic peritoneum, including the Douglas pouch, has been reported often; there are few reports of cystic endometriosis in the retroperitoneal cavity. Today there are various theories regarding how endometriosis occurs. By pathological findings and lesion sites of the present case, we concluded that the endometrial tissues in the menstrual blood might metastasize lymphatically and implant and form the retroperitoneal cyst.