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Leiomyomas of the deep soft tissue are extremely rare. We report a case of a deep soft tissue leiomyoma that was difficult to differentiate from a uterine leiomyoma. A 48-year-old woman was diagnosed with a uterine leiomyoma, but surgical and pathological findings revealed a deep soft tissue leiomyoma and normal uterus.

We previously reported satisfactory therapeutic results when using cisplatin-based cyclic balloon-occluded arterial infusion chemotherapy as neoadjuvant chemotherapy (NAC), which enabled hysterectomy to be performed for patients with locally advanced cervical cancer. Mitotic arrest deficiency 2 (MAD2) is a key component of the mitotic spindle checkpoint pathway. The expression of MAD2 is associated with tumor progression and resistance to chemotherapy. Therefore, the aim of the present study was to examine whether the expression of MAD2 is related to the efficacy of NAC for locally advanced uterine cervical cancer. We reviewed 53 cases of locally advanced uterine cervical cancer (stage IIIa-IIIb; based on the International Federation of Gynecology and Obstetrics criteria). These patients were initially treated at Osaka City University Medical School Hospital, Japan, from 1995 to 2008 and were under 70 years old. Tumor samples were obtained by biopsy prior to NAC. Cases were divided into two groups: one group in which NAC was effective, surgery was possible and radiotherapy was performed (NAC+OP+R group; n=33), and another group in which NAC was ineffective and radiation therapy was performed (NAC+R group; n=20). MAD2 expression was examined in paraffin-embedded sections using the avidin-biotin peroxidase complex method. The results showed that MAD2 expression was significantly higher in the NAC+R group compared to the NAC+OP+R group (P

Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma (LMS) is extremely malignant, with high rates of recurrence and metastasis. We earlier reported that mice with a homozygous deficiency for LMP2, an interferon (IFN)-gamma-inducible factor, spontaneously develop uterine LMS. The IFN-gamma pathway is important for control of tumor growth and invasion and has been implicated in several cancers. In this study, experiments with human and mouse uterine tissues revealed a defective LMP2 expression in human uterine LMS that was traced to the IFN-gamma pathway and the specific effect of JAK-1 somatic mutations on the LMP2 transcriptional activation. Furthermore, analysis of a human uterine LMS cell line clarified the biological significance of LMP2 in malignant myometrium transformation and cell cycle, thus implicating LMP2 as an anti-tumorigenic candidate. This role of LMP2 as a tumor suppressor may lead to new therapeutic targets in human uterine LMS., Article, SCIENTIFIC REPORTS. 1:180 (2011)

Objective To determine correlations between shrinkage of uterine leiomyomas after treatment with GnRH agonists (GnRH-a) or menopause and expression levels of estrogen receptors (ER), progesterone receptors (PR), and vascular endothelial growth factor (VEGF). Design Cohort study. Setting University teaching hospital. Patient(s) A total of 26 women with uterine leiomyoma. Intervention(s) Ten women were treated with buserelin acetate injection (1.8 mg), four courses every 4 weeks, and 16 women went into menopause naturally. Main Outcome Measure(s) Tumor shrinkage rates determined from magnetic resonance images taken before and after GnRH-a therapy and before and after natural menopause; immunohistochemical analysis of ER, PR, and VEGF in uterine leiomyoma biopsy specimens taken before intervention or within 6 months before menopause. Result(s) Shrinkage rates of uterine leiomyomas were positively correlated with expression levels of ER in women treated with GnRH-a and in postmenopausal women managed conservatively, and with VEGF expression in women treated with GnRH-a. There were no significant correlations with PR expression levels in either group. Conclusion(s) Estrogen plays the predominant role in myoma shrinkage for women with GnRH-a therapy and naturally menopausal women.

The majority of smooth muscle tumors found in the uterus are benign, but uterine leiomyosarcomas (LMSs) are extremely malignant, with high rates of recurrence and metastasis. The development of gynecologic tumors is often correlated with female hormone secretion; however, the development of uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are not clearly understood. The presentation of antigenic peptides by major histocompatibility complex (MHC) class I molecules is important for tumor rejection by cytotoxic T-lymphocytes (CTLs). Such antigenic peptides are generated as a result of the degradation of intracellular proteins by the proteasome pathway, a process that is influenced by the interferon (IFN)-γ-inducible low molecular mass polypeptide-2 (LMP2) subunit of the 20S proteasome. Homozygous deficient mice for LMP2 are now known to spontaneously develop uterine LMS. LMP2 expression is reportedly absent in human uterine LMS, but present in human myometrium. Further studies revealed a few infiltrating CD56+ NK cells in human uterine LMS tissues. This review aims at summarizing recent insights into the regulation of NK cell function and the T cell-mediated immune system as tumor immune surveillance, first attempts to exploit NK cell activation to improve immunity to tumors.

The objective of this study was to assess the effects of an upstream estrogen response element (ERE) on exogenous p53 tumor suppressor gene with a codon 72 polymorphism about which there have been controversial reports in relation to cancer risk. The p53 gene (bases 166-1143 from start codon) with the codon 72 polymorphism, inserted into the pIRES-hrGFP II plasmid with or without upstream ERE, were transfected into HHUA endometrial cancer cells expressing the estrogen receptor. The ERE-linked p53 gene with the proline variant at codon 72 showed lower transfection rates than the gene without ERE or with the arginine variant at codon 72. p21 expression was significantly higher in HHUA cells transfected with the proline variant gene than in those transfected with the arginine variant gene. We consider that the presence of an upstream ERE promotes the transcriptional effects of the exogenous p53 gene with the proline variant, which strengthens the expression of p21, and results in lower transfection rates through cell cycle inhibition.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They have gain-of-function mutations of the c-kit receptor tyrosine kinase gene and have been suggested to originate from the interstitial cells of Cajal. A small percentage of GISTs form extragastrointestinal masses. We report a rare case of a GIST originating from the vulva. A 55-year-old woman presented with a vulvar tumor. The tumor was initially diagnosed as a leiomyosarcoma following the first resection. Following a second recurrence the patient was administered chemotherapy. A third recurrence occurred and the patient underwent a third resection. Histology revealed that a bundle of fibrous tumor cells had invaded the connected tissue and muscular coat, and some spindle-shaped and blunt-ended nuclei were detected. Furthermore, immunohistochemical evaluation revealed that the tumor cells exhibited strong and diffuse staining for c-kit and CD34. The recurrent tumor was diagnosed as a GIST and a reevaluation of the original specimens also revealed a GIST. The patient was treated with imatinib, and is currently healthy with no evidence of recurrence at 20 months after the last surgery.

Claudin-4, a component of the tight junction, plays an important role in tumorigenesis and metastasis of ovarian cancer, but its role in platinum resistance has not been elucidated.Claudin-4 expression in ovarian cancer cells was inhibited and the changes in cisplatin sensitivity were examined. Fluorescence-labeled cisplatin was used to examine whether inhibition of claudin-4 changed the cellular accumulation of cisplatin. Claudin-4 expression in ovarian cancer tissue resected from the patients surgically was evaluated immunohistochemically.Suppression of claudin-4 resulted in a significant increase of cisplatin sensitivity and cellular accumulation of fluorescence-labeled cisplatin. Claudin-4 expression was significantly greater in ovarian cancer tissue from chemoresistant patients compared to chemosensitive patients. The overall survival was significantly shorter for claudin-4-positive than claudin-4-negative cases.These data suggest that claudin-4 contributes to platinum resistance in ovarian cancer and may be a potential target in the treatment of platinum-resistant tumors.

Cirsoid aneurysm, an uncommon abnormal either congenital or acquired arteriovenous communication, is described. As massive life-threatening bleeding can be a consequence, diagnosis is very important. Earlier, angiography was the only imaging method available for visualizing vascular lesions and recent developments in imaging techniques have made diagnostic imaging of cirsoid aneurysms possible using ultrasonography, color flow mapping, magnetic resonance imaging and magnetic resonance angiography. In this report, a patient with intrapelvic cirsoid aneurysm posthysterectomy who died 8 h after she had been kicked in the abdomen is described and the results obtained by various imaging techniques are discussed.

Purpose The objective of this study was to assess clinical outcomes and fertility in patients treated conservatively for unilateral stage I invasive epithelial ovarian cancer (EOC). Patients and Methods A multi-institutional retrospective investigation was undertaken to identify patients with unilateral stage I EOC treated with fertility-sparing surgery. Favorable histology was defined as grade 1 or grade 2 adenocarcinoma, excluding clear cell histology. Results A total of 211 patients (stage IA, n = 126; stage IC, n = 85) were identified from 30 institutions. Median duration of follow-up was 78 months. Five-year overall survival and recurrence-free survival were 100% and 97.8% for stage IA and favorable histology (n = 108), 100% and 100% for stage IA and clear cell histology (n = 15), 100% and 33.3% for stage IA and grade 3 (n = 3), 96.9% and 92.1% for stage IC and favorable histology (n = 67), 93.3% and 66.0% for stage IC and clear cell histology (n = 15), and 66.7% and 66.7% for stage IC and grade 3 (n = 3). Forty-five (53.6%) of 84 patients who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 56 healthy children. Conclusion Our data confirm that fertility-sparing surgery is a safe treatment for stage IA patients with favorable histology and suggest that stage IA patients with clear cell histology and stage IC patients with favorable histology can be candidates for fertility-sparing surgery followed by adjuvant chemotherapy.

Aim: To clarify the effects on uterine arterial flow velocity waveforms of uterine contractions following oxytocin infusion and during spontaneous labor. Methods: Uterine arterial flow velocity waveforms were obtained by pulsed Doppler methods from 22 women during an oxytocin challenge test (OCT), 26 women during oxytocin-induced labor, and 40 women during spontaneous labor. Mean resistance index (RI) for bilateral arteries was used for analyses. After the onset of labor, flow velocity waveforms were assessed according to cervical dilatation. During OCT, Doppler flow velocimetry was performed when three uterine contractions occurred per 10-min period. Results: RI values did not differ significantly between induced and spontaneous labor during relaxations at any level of cervical dilatation. However, during contractions, RI was significantly higher for induced labor than for spontaneous labor. Absence or reversal of flow was more frequent in the OCT group than in the induced labor group (P

Aim: To explore parameters relating to shrinkage of submucosal myomas after microwave endometrial ablation. Methods: Fourteen patients underwent microwave endometrial ablation at 2.45 GHz using a curved microwave applicator to treat menorrhagia caused by a submucosal myoma. The size of myomas was measured on magnetic resonance images before, one month after, and six months after the operation. The average radius r was defined as half of the size of the myoma measured in three dimensions. The protrusion ratio α was defined as the ratio of the thickness of the protruding part of a myoma in the uterine cavity to the size of the myoma before the operation. The ratio of the directly necrotized volume by microwave irradiation to the total volume (RODNeV) of preoperative myomas was calculated using the following formula: (1) where d is the depth of myoma tissue directly necrotized by microwave irradiation. The relationships of preoperative α, r and RODNeV to postoperative shrinkage were then examined. Results: Two-dimensional plots showing shrinkage of submucosal myomas versus the RODNeV indicated that shrinkage at six months after microwave endometrial ablation depends on the RODNeV. Myomas with a RODNeV greater than 0.17 had shrunk more than 50% at six months after the operation. Conclusions: RODNeV is closely related to postoperative necrosis and shrinkage of the submucosal myoma after microwave endometrial ablation. Prediction of the shrinkage rate of submucous myomas appears to be possible by calculating the RODNeV preoperatively.

Doppler ultrasonography has been widely used for fetal estimation, but most of them were estimated by the resistance and pulsatility indices. Acceleration time is one of parameters of flow velocity waveforms, but only few reports had discussed acceleration time of fetal circulation.We analyzed Doppler flow velocity waveforms of fetal middle cerebral artery, descending aorta and abdominal umbilical artery obtained from 70 normal pregnant women between 18 and 40 weeks. Acceleration time was cross-sectionaly examined throughout pregnancy course.The acceleration times revealed no remarkable changes throughout pregnancy course in the middle cerebral artery, but significant increases were observed in the acceleration time of the descending aorta between 18-23 and 24-32 weeks. It also significantly decreased after 33 weeks compared to that of 18-32 weeks in the umbilical artery.The acceleration time in fetal descending aorta is significantly shorter than that in the abdominal umbilical artery between 18 and 32 weeks of gestation. The umbilical arterial acceleration time apparently decreases throughout pregnancy course. Its values are almost double for that in the descending aorta between 18 and 23 weeks, but it becomes to be equal to the aortic acceleration time. The continuous decrease of the umbilical arterial acceleration time might be a result of a relative increase of placental flow.

Uterine leiomyosarcomas (LMS) are difficult to distinguish from benign leiomyomas without surgery. In this study we performed transcervical needle biopsy on 475 patients, 8 LMS patients and 467 patients with non-sarcomas (non-LMS) in a high-risk group for LMS, and evaluated whether examinations performed with Ki-67 and CD34 immunohistochemical analyses in addition to the standard hematoxylin-eosin (HE)-stained sections would improve preoperative diagnostic precision of the uterine smooth muscle tumors. Histopathologic analysis included three factors: degree of cytologic atypia, mitotic index and coagulative tumor cell necrosis (CTCN). We also evaluated cell proliferation with Ki-67 expression. In cases of suspected CTCN, we examined CD34 expression and counted positive blood vessels in the necrotic area. Three of the 8 LMS cases satisfied the diagnostic criteria of LMS by histopathologic evaluation with HE-stained sections. We made a score list based on these analyses; scores for LMS specimens ranged from 6-14 points; non-LMS specimens scored 0-2 points. At the cut-off score of 6 points, the positive predictive value to distinguish LMS from non-LMS was 100%, showing that this scoring system, is a useful method for preoperative differentiation between LMS and non-LMS tumors.

Objective Measurement of the peak systolic velocity (PSV) in the inferior thyroid artery (ITA) before withdrawal of an anti-thyroid drug (ATD) is useful for predicting relapse of Graves’ disease (GD). We further investigated whether the ITA–PSV can be used for prediction of GD relapse after delivery in euthyroid women with GD who stopped ATD administration during mid- to late pregnancy. Patients and methods ITA–PSV was monitored monthly for three months after delivery in 42 women with GD aged from 24 to 45 years old (mean ± SE: 34.7 ± 0.92 years old) who met the above criteria. To confirm the stability of the measurement, ITA–PSV was also measured monthly in 32 age-matched non-pregnant normal women and for three months after delivery in 10 age-matched women. Results ITA–PSV and thyroid volume were higher in women with GD immediately after delivery compared to normal women, but the levels of TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) did not differ significantly between the two groups. Of the 42 patients, 23 had relapse of GD and the smoker/non-smoker ratio and thyroid volume in these patients immediately after delivery were significantly higher than those in the 19 patients who did not undergo relapse (10/23 vs. 0/19, p 3 , p = 0.046), while ITA–PSV, TRAb and TSAb did not differ between the two groups of patients. The ITA–PSV ratio was calculated by dividing each value in the follow-up period by that obtained immediately after delivery. A significant increase in the mean ITA–PSV ratio occurred at least one month before the time of relapse (1.00 ± 0.00 at –3 months before relapse vs. 1.46 ± 0.12 at –1 month, p = 0.010; 1.00 ± 0.00 at –3 months vs. 1.77 ± 0.13 at the time of relapse, p = 0.0048). In contrast, there were no significant changes in this ratio during the follow-up period in non-relapse patients. Conclusion Monthly measurement of ITA–PSV after delivery in remitted euthyroid women with GD may assist in early prediction of GD relapse.

A premenopausal woman with vaginal agenesis underwent surgery for leiomyomas in rudimentary uterine horns. Immunohistochemical study of surgical specimens revealed that progesterone receptors are distributed in the nuclei of a majority of the leiomyoma cells and in the nuclei of a minority of the myometrial cells. Estrogen receptors are not detected in the surgical specimens.

In cancer-bearing animals, we previously demonstrated that skeletal muscle apoptosis may be involved in muscle wasting and that Bax may play a role in skeletal muscle cell apoptosis at an early stage. In this study, we investigated the occurrence of apoptosis in the liver, kidney, spleen, lung and heart during cancer cachexia as well as the associations between apoptosis and the expression levels of Bcl-2, Bcl-xL and Bax proteins. We also examined the relationship between normal organ apoptosis in cancer cachexia and multiple organ failure. We further studied the changes in body weight, lean body mass (LBM), apoptotic index (AI), DNA laddering pattern and expression levels of Bax, Bcl-2 and Bcl-xL in the liver, kidney, spleen, lung and heart in VX2 carcinoma-bearing rabbits. In the early stage of tumor bearing (20 days after implantation), the LBM was significantly reduced by 19.06+/-1.02% in the tumor-bearing group compared to an increase of 1.66+/-0.83% in the control group. The apoptotic indices of the liver, kidney, lung and spleen in the tumor-bearing group increased by 14.2+/-1.8%, 34.4+/-2.0%, 66.7+/-6.0% and 24.8+/-3.8%, respectively and were significantly higher than the corresponding indices in the control group. DNA laddering patterns characteristic of DNA fragmentation were visible on day 50 in the liver, kidney, spleen and lung in the tumor-bearing group. The expression of Bax increased in the tumor-bearing group and coincided with the occurrence of apoptosis. However, no significant changes were noted in the expression levels of Bcl-2 and Bcl-xL. These findings suggest the possibility that normal organ cell apoptosis related to Bax not only causes body weight loss but also multiple organ failure in cancer cachexia.

Protein S is an antithrombotic cofactor for protein C that also has multifunctional anti-inflammatory, cellular protective, apoptotic and mitogenic properties. Protein S levels are thought to decrease during pregnancy, but the underlying mechanism remains unknown. We compared protein S concentrations throughout normal pregnancy with those of nonpregnant women and measured plasma C4b-binding protein levels in nonpregnant women and in pregnant women at the 40th gestational week. We also examined protein S and C4b-binding protein in the placenta by immunohistochemical staining at early (20th gestational week) and late (40th gestational week) stages of pregnancy. Plasma protein S activity and free protein S-antigen levels significantly decreased from the 10th gestational week and total protein S antigen decreased from the 20th. C4b-binding protein levels between pregnant and nonpregnant women did not significantly differ. The stainable portion of protein S was located at the fetomaternal interface, particularly at degenerative villi. C4b-binding protein was weakly stained at the same areas as protein S. Neither protein S nor C4b-binding protein were stained at normal villi. These results indicated that protein S can protect or restore damaged villi via a physiological effect in addition to its anticoagulation properties.

To better understand the molecular mechanisms of carcinogenesis induced in uterine endometrium by therapeutic anti-estrogenic Tamoxifen (TAM) exposure, 27 uterine tumors (4 benign endometrial polyps and 23 carcinomas) associated with TAM exposure were analyzed for the presence and spectrum of p53 and K-ras mutations. Although there was no significant difference between TAM-associated endometrial carcinomas and sporadic endometrial tumors in the frequency of these mutations, the spectrum of p53 mutations was characteristically unique to the TAM-associated tumors. The median duration of TAM exposure was significantly longer in patients with p53 mutations than those without p53 mutations (62 vs. 30 months, p=0.028). Our observation suggests that prolonged TAM exposure may directly inactivate the p53 gene by acting as a mutagen in a significant fraction of TAM-associated endometrial carcinomas.

HHUA, a rare endometrial cancer cell line expressing the estrogen receptor (ER), was adopted to investigate the expression of vascular endothelial growth factor (VEGF), erythropoietin (Epo), Bcl-2 and p53 under the administration of estradiol-17beta (E2). Based on quantitative real-time reverse transcription polymerase chain reaction assays, both VEGF and Bcl-2 mRNA levels decreased in a dose-dependent manner, although VEGF levels were increased in a time-dependent manner; no significant change was found for Epo and p53. An immunocytochemical study also showed the suppressed expression of VEGF and Bcl-2 under E2 induction. Both ERalpha and ERbeta mRNAs were detected in HHUA cells with ERbeta expression being predominantly higher than that of ERalpha, which is the converse of the pattern seen in normal endometria. The present study shows the E2-downregulated expression of VEGF and Bcl-2, and reveals a disrupted balance of ERalpha and ERbeta expression, which should be taken into consideration to understand the particularity of E2-regulated gene expression in HHUA cells.

HHUA, a rare endometrial cancer cell line expressing the estrogen receptor (ER), was adopted to investigate the expression of vascular endothelial growth factor (VEGF), erythropoietin (Epo), Bcl-2 and p53 under the administration of estradiol-17beta (E2). Based on quantitative real-time reverse transcription polymerase chain reaction assays, both VEGF and Bcl-2 mRNA levels decreased in a dose-dependent manner, although VEGF levels were increased in a time-dependent manner; no significant change was found for Epo and p53. An immunocytochemical study also showed the suppressed expression of VEGF and Bcl-2 under E2 induction. Both ERalpha and ERbeta mRNAs were detected in HHUA cells with ERbeta expression being predominantly higher than that of ERalpha, which is the converse of the pattern seen in normal endometria. The present study shows the E2-downregulated expression of VEGF and Bcl-2, and reveals a disrupted balance of ERalpha and ERbeta expression, which should be taken into consideration to understand the particularity of E2-regulated gene expression in HHUA cells.

Reproductive hormones exert their actions via receptors in diverse tissues. In this study, we examined the expression of estrogen receptors (ERalpha and ERbeta), progesterone receptor (PR), and follicle-stimulating hormone receptor (FSHR) in the adipose tissue and reproductive organs of mice following oral treatment with Dandelion T-1 extract (DT-1E) for 6 weeks. Quantitative assays by real-time reverse transcription polymerase chain reaction showed enhanced expression of ERalpha and ERbeta mRNA in the adipose tissue of mice fed a diet containing DT-1E compared with the control group fed a plain diet. Furthermore, following gonadotropin injection, higher mRNA expression of ERalpha, ERbeta and PR in the uterus and FSHR in the ovary was found in the DT-1E group compared with the control group. An immunohistochemical study also showed increased levels of the above-mentioned receptors in the DT-1E group. The present study shows that oral intake of DT-1E up-regulates ERalpha, ERbeta, PR and FSHR expression in mice, suggesting the potential application of DT-1E for the clinical treatment of reproductive hormone-related disturbances.

Recent changes in the lifestyle of young women have led to an increase in the rate of uterine cervical cancer. We investigated the clinicopathological characteristics of uterine cervical cancer in young women, and examined the expression of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Tumor samples from 439 patients with uterine cervical cancer, who were initially treated at Osaka City University Medical School Hospital, Japan between 1995 and 2004, were stained immunohistochemically. The patients were classified into two groups according to age at onset: group Y included women agedor =35 years, and group O included women agedor =36 years. Group Y had more cases of squamous cell carcinoma, while group O had more advanced cases (P0.05). Advanced cases (beyond stage Ib2) had a significantly worse prognosis in group Y than in group O (P0.05). There were no differences between the two groups in the expressions of VEGF, MMP-2 and COX-2. However, in advanced cases (beyond stage Ib2), the expression of VEGF, MMP-2 and COX-2 was significantly greater in group Y than in group O (P0.05). The above findings suggest that the expression of VEGF, MMPs and COX-2 is related to a worse prognosis for advanced uterine cervical cancer in young women.

We immunohistochemically examined the expression of the glucose transporters (GLUT)1, GLUT3 and GLUT4, in 154 tumor samples of epithelial ovarian carcinoma. In addition, we investigated the correlations between the expression of GLUTs and the vascular endothelial growth factor (VEGF), and microvessel count and clinical parameters. The rates of expression of GLUT1, GLUT3 and GLUT4 were 98.7%, 92.8% and 84.4%, respectively. GLUT1 and GLUT4 were both strongly expressed in serous adenocarcinoma, but weakly expressed in clear cell adenocarcinoma. The expressions of GLUT1 and GLUT4 correlated with the clinical disease stage. The expressions of GLUT1, GLUT3 and GLUT4 correlated positively with VEGF expression. The expression status for GLUT1, GLUT3, GLUT4 and VEGF did not represent a prognostic factor. These findings suggest that characteristic differences in the patterns of glucose uptake can exist according to the histological type and that GLUT1, GLUT3 and GLUT4 could be related to tumor angiogenesis in epithelial ovarian carcinoma.

The aim of this study was to evaluate the efficacy and toxicity of irinotecan and doxorubicin in the treatment of patients with early recurrent or platinum-refractory ovarian cancer. Nineteen woman from five different institutions were treated. Two patients had platinum-refractory cancer, 11 had platinum-resistant disease, and 6 had platinum-sensitive tumors. An intravenous infusion of Irinotecan (50mg/m2) was given on days 1, 8, and 15, while doxorubicin (40mg/m2) was administered as an intravenous bolus on day 3. This treatment schedule was repeated every 4 weeks. Among the 13 patients defined as having platinum-refractory/platinum-resistant disease, 4 patients achieved a clinical response (30.8%, 95% CI: 9.1–61.4), while only one of 6 patients defined as having platinum-sensitive disease achieved a clinical response (16.7%, 95% CI: 0.4–64.1). Leukopenia and neutropenia were the major dose- limiting toxicities. Grade 3 or 4 leukopenia and neutropenia were noted in 24 (48%) and 33 (66%) of the courses, while febrile neutropenia occurred in 2 courses. Five patients (26%) had grade 2 or worse diarrhea during 7 courses. Our data demonstrated that this regimen might be comparable to standard approved agents in patients with early recurrent or platinum refractory ovarian cancer.

Widespread use of fetal aortic blood flow velocity measurements for assessment of fetal circulatory status has been precluded by difficulties in achieving an adequate Doppler insonation angle at particular sampling points. The goal of this study was to evaluate the differences in resistance index (RI) and systolic peak velocity (Vmax) of fetal aortic blood flow velocity waveforms throughout gestation among various Doppler sampling points.A total of 551 normal women between 18-41 weeks of pregnancy participated in this study. Pulsed Doppler flow velocity waveforms were acquired from three different aortic sampling points (thoracic portion, beneath the diaphragm, and abdominal portion) of the fetal descending aorta. The Vmax and RI were calculated at the respective sampling points.The Vmax were significantly lower in abdominal portion than those in thoracic portion at every time point (from 69 +/- 11 cm/second in thoracic to 49 +/- 8 cm/second in abdominal portion at 18-19 gestational weeks, p0.0001), and RI were also lower (from 0.84 +/- 0.05 in thoracic portion to 0.76 +/- 0.05 in abdominal portion at 18-19 gestational weeks, p0.0001). Significant increase in the Vmax was seen until third trimester (from 58+/-10 cm/second at 18-19 gestational weeks to 113 +/- 13 cm/second at 38-39 gestational weeks beneath the diaphragm, p0.0001), while the RI remained stable (0.79 +/- 0.04 at 18-19 gestational weeks; 0.80 +/- 0.05 at 38-39 gestational weeks beneath the diaphragm).In measuring the fetal circulatory status, these data demonstrate that the sampling point should be considered when evaluating the maximum systolic velocity and the resistance index of the fetal descending aorta.

Objective To examine the effect of a low concentration of DHEAS on the expression of the androgen receptor, estrogen receptor α and β, progesterone receptor, aromatase, 3-β-hydroxysteroid dehydrogenase, and cyclooxygenase-2 in human preovulatory granulosa cells, and to measure their production of steroid hormones (estrone, estradiol, progesterone, androstenedione, and testosterone). Design Analysis of cultured primary human preovulatory granulosa cells by real-time reverse-transcriptase polymerase chain reaction and assays of hormone production. Setting Osaka City University Postgraduate School of Medicine. Intervention(s) Preovulatory granulosa cells were collected from follicular fluid obtained from patients undergoing transvaginal oocyte retrieval with ultrasound guidance. The cells were cultured in the absence or presence of a low concentration of DHEAS. Real-time reverse-transcriptase polymerase chain reaction was performed to quantify the RNA expression of the investigated genes, and steroid hormone (estrone, estradiol, progesterone, androstenedione, and testosterone) levels were measured in the culture medium. Main Outcome Measure(s) Changes in [1] the levels of mRNAs encoding androgen receptor, estrogen receptor α, estrogen receptor β, progesterone receptor, aromatase, 3-β-hydroxysteroid dehydrogenase, and cyclooxygenase-2; and [2] the levels of steroid hormones (estrone, estradiol, progesterone, androstenedione, and testosterone) in the culture medium. Result(s) Treatment of granulosa cells with 20 ng/mL DHEAS increased the expression of androgen receptor, aromatase, 3-β-hydroxysteroid dehydrogenase, and cyclooxygenase-2, reduced the expression of estrogen receptor β, and increased estrone and estradiol levels, but had no effect on progesterone, androstenedione, or testosterone levels. Conclusion(s) DHEAS may be an essential trigger of ovulation.

Complex endometrial hyperplasia with atypia (CEHA) often precedes an endometrial carcinoma. A nulli-gradiva woman at high risk due to various complications underwent microwave endometrial ablation (MEA) at a frequency of 2.45 GHz for treatment of CEHA as an alternative to hysterectomy. The endometrium near the internal orifice was conserved to avoid hematometra. Endometrial biopsy specimen from the neighborhood of the internal orifice did not show any signs of endometrial hyperplasia postoperatively. Two years after the operation, endometrial biopsy revealed recurrence. The second MEA was performed. MRI one month after the second operation revealed that the uterine lining was completely replaced by avascular area without signs of regrowing endometrium or endocevix. Eighteen months have passed without recurrence.

AIM We investigated microwave power and duration of use, which does not affect extrauterine organs, in order to treat organic menorrhagia caused by myomas or adenomyosis. METHODS Electric fields around a microwave applicator at a frequency of 2.45 GHz were calculated using the finite element method with commercially available software for analysis of electromagnetic fields. Transient temperature distributions around the applicator were obtained by numerically solving the bioheat transfer equation during microwave irradiation for 120 s in the human uterus and swine liver. We compared areas enclosed by the 60 degrees C isotherm obtained using numerical simulations and necrosis areas after microwave irradiation. Postoperative avascular areas in a Gd-enhanced MRI of a uterus enlarged by adenomyosis after clinical microwave endomyometrial ablation were compared with numerical simulations. RESULTS There was good agreement between the calculated results and the experiments. At 40 W of output power for 50 s of duration and 64.5 W for 100 s, the depth of the necrotized uterine wall did not increase beyond 7 mm and 11 mm, respectively, either in the calculations or the experiments. Generally, the 50 degrees C isotherm was located approximately 2 mm external to the 60 degrees C isotherm in temperature distributions. The Gd-enhanced MRI after the operation depicted avascular areas, which agreed with the results of numerical simulations. CONCLUSIONS The myometrial portion of a uterine wall > or = 13 mm throughout the uterus irradiated for < or = 64.5 W for 100 s is sufficient to avoid thermal damage of the extrauterine organs during microwave endomyometrial ablation.

Matrix metalloproteinases (MMPs) are associated with invasion and metastasis of several human malignant tumors, in particular MMP-7, which is mainly produced by the cancer cell itself. We examined the expression of MMP-2, 7 and 9, and tissue inhibitors of metalloproteinase (TIMP)-1 and 2 in uterine endometrial carcinoma, and compared the expression with clinicopathological characteristics in uterine endometrial carcinoma (UEC). A group of 256 patients with UEC received surgery at the Osaka City University Medical School Hospital, and 196 tumor samples were immunohistochemically stained to examine the expression of MMP-2, 7 and 9, and TIMP-1 and 2. Additionally, the invasion ability of cell stain established from UEC was examined using an in vitro invasion assay. The expression of MMP-2, 7 and 9, and TIMP-1 and 2 was observed in the cytoplasm, and the expression of MMP-2 and 7, and TIMP-1 and 2 was observed in stromal cells around the tumor cells. The expression of MMP-7 was significantly stronger in higher-grade than lower-grade tumors (P0.05). The invasion assay showed that the invasion of cells derived from UECs was significantly inhibited by TIMP-1 and 2. The disease-free interval was significantly shorter when MMP-7 expression was intense. This increased expression of MMP-7 in high grade UECs may be associated with tumor invasion and metastasis, and MMP-7 could serve as a prognostic maker in UEC.

Adenomyosis can cause severe menorrhagia, which is a common indicator of the need for hysterectomy. None of the ablative techniques developed over the last two decades are of use in treating menorrhagia in a uterus enlarged by deep adenomyosis. Using a curved microwave applicator specifically developed for enlarged uterine cavities, microwave endometrial ablation at a frequency of 2.45 GHz was successfully applied in the treatment of menorrhagia in a patient with adenomyosis and an enlarged uterine cavity 12 cm in length. Two weeks after the operation, the patient experienced a menstrual period of ten days with no flooding. Menstrual duration gradually decreased to six days over the following six months. The quality of life score recovered to within the normal range six months after the operation. The post-operative sub-endometrial low signal intensity zone on the T2-weighted magnetic resonance images, which corresponds to the region of necrotic tissue, vanished 12 months after the operation. Although microwave endometrial ablation using the curved applicator could not treat bleeding from deep adenomyosis lesions, it improved menorrhagia in the uterus, which would conventionally require a hysterectomy.

We previously reported satisfactory therapeutic results of cisplatin-based cyclic balloon-occluded arterial infusion chemotherapy (BOAI) as neoadjuvant chemotherapy, which enabled treatment by hysterectomy in patients with advanced cervical cancer. We also reported expression of apoptosis among these patients and determined that the bax gene is related to this apoptosis. In the present study, we investigated the relationship between the effectiveness of BOAI therapy and expression of apoptosis regulatory genes and proteins in these cases. The subjects were 27 women with advanced cervical cancer classified as FIGO (International Federation of Gynecology and Obstetrics) stage III or higher who were admitted to the Department of Gynecology, Osaka City University Medical School Hospital between 2000 and 2003. All patients were treated by BOAI, and expression of cancer cell apoptosis was examined by the TUNEL method, expression of bax, bcl-2 and bcl-xL proteins were examined by immunohistochemistry, and expression of bax, bcl-2 and bcl-xL mRNA was examined by quantitative RT-PCR before and 3 days after BOAI. The effectiveness of BOAI therapy was thus determined. The 20 patients in whom BOAI was effective showed significantly higher expression of the bax protein and gene after BOAI, and cancer cell apoptosis was accelerated. On the other hand, the 7 patients in whom BOAI was ineffective showed significantly higher expression of the bcl-xL protein and gene after BOAI. These results suggest that bax/bcl-xL expression can be used as an indicator of the effectiveness of BOAI therapy.

Whether the human papillomavirus (HPV) status of the tumor affects the sensitivity to neoadjuvant chemotherapy, and the prognosis in advanced uterine cervical cancer (FIGO stage III or higher) remains unknown. We examined the HPV status of 43 patients who had received CDDP therapy by balloon-occluded arterial infusion (BOAI), as neoadjuvant chemotherapy for advanced uterine cervical cancer (squamous cell carcinoma) stage III or higher. DNA was extracted from formalin-fixed, paraffin-embedded tumor samples obtained by punch biopsy before the neoadjuvant chemotherapy. The detection of HPV and its typing were analyzed by a polymerase chain reaction (PCR)-based assay using consensus primers for the L1 consensus regions. HPV DNA was detected in all 43 patients (100%): 29 cases with HPV 16 (67.4%), 5 cases with HPV 33 (11.6%), 4 cases with HPV 31 (9.3%), 3 cases with HPV 35 (7.0%), 1 case with HPV 18 (2.3%) and 1 case with HPV 58 (2.3%). The HPV types were divided into 3 groups, HPV 16, HPV 33 and other HPV types (HPV 18, 31, 35, 58), and comparisons and examinations were performed among the 3 groups. Although the rates of tumor reduction and operation accomplishment after 3 courses of BOAI showed no significant differences among the 3 groups, there were significant differences in the survival rates. The survival rate of advanced uterine cervical cancer patients with HPV 33 infection was the highest, followed by that of patients with HPV 16 infection. The survival rates of patients with the other types of HPV infection were the worst among the 3 groups and significantly lower than those of patients with HPV 16 or HPV 33 infection. The differences in the curative effect after BOAI may depend on the different characters of the HPV types.

The mechanism of rebound body weight-gain after a restricted-diet state is unclear. We investigated the expression of angiogenic factors in human adipocytes with a changing nutritional state in culture medium, and attempted to ascertain the mechanisms involved in rebound weight-gain. Adipocytes were divided into three groups; the first group (control group) was cultured in medium with 10% fetal calf serum (FCS), the second (DR3% group) was cultured in medium with 3% FCS, and the third (DR6% group) was cultured in medium with 6% FCS. After being cultured for 48 h, each was next cultured with 12% FCS for a further 48 h. When made to change from a low nutrition state to a higher one, adipocytes changed from hypotrophic to hypertrophic. Simultaneously, vascular endothelial growth factor (VEGF) in the culture medium increased significantly. When investigated immuno-histochemically, the expression of VEGF was similarly shown in the cytoplasm of adipocytes. The same tendency with the same quantity of mRNA was shown by RT-PCR. These results show that VEGF produced and secreted from adipocytes increases, when the cultivation state of adipocytes is changed from a low nutritional state to a higher one. VEGF produced and secreted from adipocytes may be related to rebound weight-gain.

Prostaglandins play important roles for oocyte maturation and follicular rupture. Cyclooxygenase-2 (COX-2), an inducible isoform of a prostaglandin metabolic enzyme, is essential for the timed production of prostaglandins in the ovary. The aim of the present study is to examine expression and distribution of COX-2 in human ovarian follicles at each of the maturation stages. Immunohistochemical staining shows that COX-2 is expressed in the granulosa cell layer of secondary and developing follicles, but is not detected in primary and Graafian follicles. Western blotting analysis revealed the existence of COX-2 in periovulatory follicular fluid at a mean concentration of 5.6 +/- 0.6 ng/ml. COX-2 might begin to be produced at the secondary follicle stage, and once a follicle reaches the Graafian follicle stage, the production of this enzyme is stopped. After exposure to luteinizing hormone (LH) surge, follicles might resume production of COX-2, and this is secreted into the follicular fluid.

Tetrahydrobiopterin (BH 4 ) is an essential co-factor for nitric oxide (NO) synthase (NOS) and regulates the production of NO, or endothelium derived relaxation factor. Although NOS is highly expressed in the placenta and NO plays a critical role in the regulation of feto-placental circulation, the mechanism maintaining the level of BH 4 is not known. To investigate the de novo synthesis of BH 4 in the human placenta, the activity of guanosine triphosphate cyclo-hydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR) in the chorionic tissue during the first, second and third trimester of pregnancy was analyzed. GTPCH activity was the lowest of the three enzymes and became negligible after the second trimester. There was no significant change in PTPS activity throughout pregnancy. Although SR activity decreased significantly after the second trimester, the levels remained abundant throughout pregnancy. These results showed that GTPCH is a rate-limiting enzyme and the total activity of the de novo synthesis of BH 4 is negligible in the mature placenta after the second trimester when fetal growth is accelerated. The present study suggests that the level of BH 4 in the placenta depends principally on the system other than de novo synthesis. The salvage pathway is considered the most potent system, which is formed by the transfer of the substrates from the fetus and their enzymatic conversion to BH 4 in the placenta.

To evaluate 2 methods of processing testicular tissue for the retrieval of viable sperm from men with nonobstructive azoospermia.Fresh testicular tissue was obtained from nonobstructive azoospermia patients using a biopsy needle. The specimens were divided into 2 fractions. All specimens were minced and immersed in human tubal fluid (HTF). The first fraction was filtered through a nylon filter and incubated for 3 hours. The supernatant was centrifuged, resuspended in HTF and analyzed. The second fraction was immediately vortexed for 5 minutes and filtered through a nylon filter. The supernatant was centrifuged, resuspended in HTF and analyzed.Spermatozoa were obtained in 13 of 24 cases (54.2%) using the vortex method and in 5 of 24 cases (20.8%) with the nylon filter method.The vortex mixing method may be a better option than the conventional method for processing testicular tissue for sperm collection.

CD45 (leukocyte common) antigen is a hemopoietic cell-specific tyrosine phosphatase essential for antigen receptor-mediated signaling in lymphocytes. The molecule undergoes complex alternative splicing in the extracellular domain, and different patterns of CD45 splicing are associated with distinct functions. Lack of CD45 leads to severe combined immunodeficiency, and alterations of CD45 splicing, because of a polymorphism in exon 4, have been associated with altered immune function. Here we describe a polymorphism in exon 6 (A138G) of the gene encoding CD45 that interferes with alternative splicing. The polymorphism results in an amino acid substitution of Thr-47 to Ala in exon 6, a potential O- and N-linked glycosylation site. This exon 6 A138G variant is present at a frequency of 23.7% in the Japanese population but is absent in Caucasoids. Peripheral blood T cells from individuals carrying the A138G variant show a significant decrease in the proportion of cells expressing the A, B, and C CD45 isoforms and a high frequency of CD45R0+ cells. These phenotypic alterations in the A138G carriers may lead to changes in ligand binding, homodimerization of CD45, and altered immune responses, suggesting the involvement of natural selection in controlling the A138G carrier frequency.

Matrix metalloproteinases (MMPs) are associated with invasion and metastasis of several malignant tumors in human. Especially so MMP-7, as it is mainly produced by the cancer cell itself. However, the expression of MMP-7 in renal cell carcinoma (RCC) has not been investigated. We examined expressions of MMP-7 and MMP-2 in RCC, and compared them with the clinicopathological characteristics in RCC. Tumor samples from 20 patients with RCC, who had surgery performed at Osaka City University Medical School Hospital, were immunohistochemically stained. Expression of MMP-2 was significantly stronger in advanced stage and in high grade tumors than in low stage and low grade tumors. MMP-7 was also expressed in RCCs, with its expression especially and significantly stronger in high grade than in low grade tumors (p=0.004). However, there was no significant difference of MMP-7 expression between advanced and low stages (p=0.1859). This increased expression of MMP-7 in high grade RCC might be associated with tumor invasion and metastasis.

Matrix metalloproteinases (MMPs) are associated with invasion and metastasis of several human malignant tumors. Especially so MMP-7, as it is mainly produced by the actual cancer cells. However, the expression of MMP-7 in transitional cell carcinoma (TCC) of the urinary bladder has not been previously investigated. We examined expressions of MMP-7 and MMP-2 in TCC, and compared them with clinicopathological characteristics in TCCs. Tumor samples from 20 patients with TCC of the urinary bladder who had surgery performed at the Osaka City University Medical School Hospital were immunohistochemically stained. Expression of MMP-2 was significantly stronger in advanced stage and high grade tumors than in low stage and low grade tumors. MMP-7 was also expressed in TCC, having a tendency to be more strongly expressed in high than in low grade tumors. However, there was no significant difference of MMP-7 expression between advanced and low stages. This increased expression of MMP-7 in high grade TCC of the urinary bladder may be associated with tumor invasion and metastasis.

Leukemia inhibitory factor (LIF) is produced locally in decidual tissues, but its direct effects on endometrial stromal cells have not been well characterized. In this study, we examined the direct effects of LIF on normal human endometrial stromal cells using an in vitro decidualization assay system with 8-Br-cAMP, a decidualization inducer. We found no effects of LIF on cell viability and prolactin secretion of unstimulated endometrial stromal cells. LIF dose-dependently enhanced cell viability, but not prolactin secretion of 8-Br-cAMP-stimulated cells. LIF dose-dependently enhanced the viability of stromal cells co-stimulated with 8-Br-cAMP and LIF without any significant effect on PRL secretion from the cells. Further, the extracellular matrix did not affect these stimulatory effects of LIF on cell viability of 8-Br-cAMP-stimulated endometrial stromal cells. These results indicate that LIF enhances the cell viability of PRL-non-secreting 8-Br-cAMP-stimulated stromal cells, and that the cell survival signals generated by LIF are independent of those generated by the extracellular matrix. LIF produced locally in decidual tissues may enhance cell viability in certain activated endometrial stromal cells in an autocrine or paracrine manner, and possibly protect against cell damage during embryo implantation and trophoblastic invasion.

We evaluated the parameters of preoperative pressure-flow for predicting the postoperative voiding difficulties in women with stress urinary incontinence. The preoperative urodynamic study records of 14 women treated using the tension-free vaginal tape (TVT) procedure were retrospectively analyzed. Of the patients treated with the TVT procedure, urinary retention occurred in one patient, and three had a residual urine volume of more than 30 ml. All patients became completely free of stress urinary incontinence postoperatively. The lowest Pdet max (5 cmH(2)O) in the preoperative pressure-flow study was found in a patient with a remarkable postoperative residual urine volume of more than 50 ml. The second lowest Pdet max value (8 cmH(2)O) was seen in a patient with postoperative urinary retention, whose residual urine volume, however, decreased to almost zero 1 year after the operation. The preoperative Pdet max x Qave values were remarkably low for these three patients, including the one with the lowest Pdet max, with a post-void residual urine volume of more than 30 ml. The plots of Pdet max x Qave versus the age of patients show that the Pdet max x Qave values tend to decrease with aging. The preoperative Pdet max x Qave value can be an important parameter for predicting increased residual urine after TVT sling surgery.

Granulated metrial gland (GMG) cells are a major immune cell population in the murine pregnant uterus, and contribute to the maintenance of pregnancy by functioning as uterus-specific natural killer (NK) cells. In order to reveal their kinetics, activation, and functional roles in pregnancy, we conducted quantitative and immunohistochemical analyses in normal and immuno-modulator-treated mice. Under a light microscope, GMG cells were identified by red cytoplasmic granules in periodic-acid-Schiff (PAS)-stained sections. They progressively increased in number and size with the peak at day 12-14 of pregnancy in the decidua and metrial gland. New vessel formation was most prominent around day 8, and the total vascular area reached the peak at day 13. GMG cells were often located near the blood vessels, and expressed vascular endothelial growth factor (VEGF), suggesting their possible inducing role in angiogenesis during the development of decidua/metrial gland. While blood vessels in the non-pregnant uterus were negative for vascular cell adhesion molecule (VCAM)-1, those in the pregnant one were positive. Treatment with neutralizing antibody against VCAM-1, however, did not decrease the number of GMG cells. On the other hand, mitosis of GMG cells was frequently observed. These data suggest that the increment of GMG cells during pregnancy may largely result from local proliferation in the uterus rather than an increased influx of precursor cells. Although we attempted to induce in vivo activation of GMG cells by administration of interleukin-12 (IL-12) or alpha-galactosylceramide, a potent activator for natural killer-T (NK-T) cells, the number of GMG cells did not appreciably increase. The present study has demonstrated that GMG cells locally proliferate in the pregnant uterus, not being related to VCAM-1 expression by the uterine vasculature or systemic activation of NK cells and NK-T cells, and seem to be involved in angiogenesis in the pregnant uterus through VEGF production.

Cervical cancer can be classified into two histological types: squamous cell carcinoma (SCA) and adenocarcinoma (ACA). Reportedly ACA has poorer prognoses, metastasizes more easily to lymph nodes, and is more resistant to radiotherapy than SCA. To clarify the cause of characteristic differences between these histological types, we examined the expressions of apoptosis inhibiting and tumor-invasion related factors in both histological types. We reviewed the 34 cases of cervical cancer (17 ACA, 17 SCA) that had surgery as their initial treatment at Osaka City University Medical School Hospital between 1996 and 2001. The differences of survivin, and matrix metalloproteinase (MMP-2, and MMP-7) expressions between both histological types were immunohistochemically assayed, and the correlation between the expression of each protein and clinicopathological characteristics was analyzed. Survivin was expressed significantly stronger in ACA cases (p=0.035). The number of patients who expressed MMP-2 and MMP-7 simultaneously was significantly higher in SCA cases (p=0.039). MMP-2 and MMP-7 had tendencies to be expressed stronger in SCA (p=0.057 and p=0.084, respectively). These results suggest that the differences of the expression of survivin (an apoptosis inhibiting factor), MMP-2, and MMP-7 (tumor-invasion related factors) between ACA and SCA were causes of the characteristic differences between the two histological types.

Malignant transformation of a mature cystic teratoma of the ovary is rare, that of an adenocarcinoma is extremely rare. A 32-year-old woman was suspected as having a malignant transformation of her mature cystic teratoma of the ovary because the preoperative level of carcinoembryonic antigen (CEA) was extremely high. Resections of her ovarian cysts were performed, and this particular tumor was histopathologically diagnosed as an adenocarcinoma arising from a mature cystic teratoma of the left ovary. Because adenocarcinomas arising from mature cystic teratomas of the ovary are extremely rare, we report this case with a review of some of the literature.