Is neonatal uterine bleeding responsible for early-onset endometriosis?

BACKGROUND: It has been hypothesized that the origin of early-onset endometriosis could be from endometrial mesenchymal stem cells (eMSCs) in neonatal uterine blood (NUB). There is no information on the possible mechanistic basis linking an association between NUB/neonatal endometrium and development of early-onset endometriosis. In this study we performed a series of experiments to clarify the mechanistic link between NUB and/or neonatal endometrium and development of early-onset endometriosis. METHODS: We retrospectively collected postmortem neonatal endometria (n = 15) and prospectively collected NUB (n = 18) of female babies for the analysis of different biological markers including eMSCs. Immunohistochemical analysis of neonatal endometria was performed to examine the expression patterns of ovarian steroid receptors (ER/PGR), decidualization (prolactin, IGFBP1), pre-decidualization (Glycodelin A, α-SMA), proliferation (Ki-67 index), vascularity (CD31 + cells), immunocompetent CD68+, CD45+, CD56 + cells and some putative markers of eMSCs. Cell transfer method and immunocytochemistry were used to investigate the eMSCs and/or endometrial cells in NUB. RESULTS: Immunohistochemical analysis of postmortem neonatal endometria revealed variable staining response to ER/PGR, decidual markers, and substantial proliferative and angiogenic activity. A moderate to strong immunoexpression of Glycodelin-A was found in both neonatal and adult endometria. The tissue infiltration of CD56+, CD45 + and CD68 + immunocompetent cells was significantly low in neonatal endometria than that in adult endometria (p = 0.0003, p < 0.0001, p = 0.034, respectively). No eMSCs or even endometrial cells were detected in NUB. However, a variable expression of some phenotypes of eMSCs (CD90/CD105) was found in neonatal endometria. CONCLUSIONS: Based on our serial experiments we did not find any supporting evidence for the role of NUB in early-onset endometriosis. Neonatal endometria showed variable expression of ovarian steroid receptors, decidualization, and a substantial amount of proliferative and angiogenic activity. As an alternative mechanism, a significantly less tissue accumulation of immunocompetent cells in neonatal endometria may explain the survival of ER + and PGR + cells should they make entry into the pelvis and consequent development of early endometriosis with the onset of ovarian function. Future study with large sample size and application of modified technological tools is warranted to test the NUB hypothesis and to clarify their biological or clinical significance. TRIAL REGISTRATION: not applicable.

Multi-institutional phase II study of neoadjuvant irinotecan and nedaplatin followed by radical hysterectomy and the adjuvant chemotherapy for locally advanced, bulky uterine cervical cancer: A Kansai Clinical Oncology Group study (KCOG-G1201).

AIM: A multi-institutional phase II trial was conducted to determine the efficacy and toxicity of neoadjuvant chemotherapy with irinotecan and nedaplatin followed by radical hysterectomy and adjuvant chemotherapy for locally advanced, bulky stage IB2-IIB cervical cancer. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB2-II, bulky type (>4 cm in diameter) squamous cell carcinoma of the uterine cervix were enrolled. Irinotecan (60 mg/m2 ) was administered intravenously on days 1 and 8 and nedaplatin (80 mg/m2 ) was also administered on day 1 of every 21-day cycle. After two cycles of chemotherapy, a radical hysterectomy was performed. Until 6 weeks after the surgery, three to five cycles of the regimen were added as adjuvant chemotherapy. The primary endpoint was the 2-year relapse-free survival rate. The response rates and toxicities were evaluated as secondary endpoints. RESULTS: Thirty-two patients from seven institutions were enrolled in this study. The median age was 48 years (range 25-75 years). The average follow-up period was 37.8 months (15-71 months). Twenty-three patients completed the regimen as planned. The objective response rate (complete response + partial response) for the neoadjuvant chemotherapy regimen was 81.2%. The 2-year and 5-year relapse-free-survival rates were 87.5% and 78.8%, respectively. The incidence of grade 3/4 neutropenia was 6.3% and 34.4% during neoadjuvant and adjuvant treatment, respectively. All other toxicities were well tolerated. CONCLUSION: Our treatment showed efficacy and tolerability for patients with locally advanced, bulky stage IB2-IIB cervical cancer. This suggests that treatment has the potential to improve the prognosis compared to concurrent chemo-radiotherapy.

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.

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.

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.

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/m) and carboplatin (area under the curve, 2-an area under the time-concentration curve of 2 mg x 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.

Effects of estrogens on cholinergic neurons in the rat basal nucleus.

Estrogen replacement in postmenopausal women may help prevent or delay development of Alzheimer's disease. Because loss of basal forebrain cholinergic neurons with reductions in choline acetyltransferase (ChAT) concentration are associated with Alzheimer's 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.

Post-ovulatory rise of endometrial CD16(-) natural killer cells: in situ proliferation of residual cells or selective recruitment from circulating peripheral blood?

In the human endometrium, unique endometrial CD16(-) NK cells acutely increase in number after ovulation. Endometrial CD16(-) NK cells are thought to play a role in uterus-specific events, such as pregnancy or menstruation, because these NK cells are a minor leukocyte subset in circulating peripheral blood and other organs. The mechanism underlying the post-ovulatory rise of endometrial CD16(-) NK cells is largely unknown. By analogy with other organ systems, two potential mechanisms are proposed: one is in situ proliferation of residual cells and the other is selective recruitment from circulating peripheral blood. Our recent studies focus on the expression and function of potential molecules (including cytokines, chemokines and adhesion molecules) involved in these mechanisms in the human endometrium, and the regulation of these molecules by ovarian steroids. Based upon our findings, we discuss the possibility and relevance of these two potential mechanisms.

Fluctuation of 6Ckine expression in human endometrium during the menstrual cycle.

OBJECTIVE: To clarify the expression of 6Ckine, a potential chemoattractant for endometrial natural killer (NK) cells, in the human endometrium. DESIGN: Experimental study. SETTING: Department of obstetrics and gynecology at a medical university. PATIENT(S): Fifty-seven fertile women 25 to 52 years of age who had regular menstrual cycles and normal endometrium and were undergoing hysterectomy. INTERVENTION(S): Endometrium was obtained from operative samples. MAIN OUTCOME MEASURE(S): Tissue was immunostained to determine the localization of 6Ckine in the endometrium throughout the menstrual cycle. The number of NK cells was counted in 10 nonoverlapping stromal areas. The concentration of 6Ckine in homogenized endometrium was determined by enzyme-linked immunosorbent assay. RESULT(S): Endometrial surface, glandular epithelial cells, and perivascular stromal cells were immunoreactive for 6Ckine throughout the menstrual cycle with some fluctuation. In addition, some T cells, NK cells, and macrophages in the stroma were immunoreactive for 6Ckine. The 6Ckine concentration was low in the proliferative phase but elevated in the secretory phase. It showed a moderate positive correlation with the number of endometrial NK cells. CONCLUSION(S): 6Ckine may be a potential chemoattractant for endometrial NK cells.

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.

Expression of macrophage inflammatory protein-1beta in human endometrium: its role in endometrial recruitment of natural killer cells.

Human endometrium is infiltrated by natural killer (NK) cells throughout the menstrual cycle. The number of endometrial NK cells is low in the proliferative phase, but acutely increases after ovulation, and reaches a peak in the late secretory phase, suggesting that endometrium recruits these leukocytes selectively from circulating peripheral blood. We investigated the expression of macrophage inflammatory protein (MIP)-1beta, a potential chemoattractant for NK cells, in the endometrium. RT-PCR and ELISA revealed that MIP-1beta is expressed in the endometrium throughout the menstrual cycle at both the message and protein levels. MIP-1beta expression is stronger in the secretory phase endometrium than in the proliferative phase endometrium. Immunohistochemistry revealed that MIP-1beta is localized in the surface epithelial cells, glandular epithelial cells, and perivascular stromal cells throughout the menstrual cycle. Stromal cells in a wider perivascular area became immunoreactive in the secretory phase. There was a strong correlation between the endometrial MIP-1beta concentration and the number of endometrial NK cells. Progesterone significantly induced MIP-1beta secretion from cultured endometrial stromal cells, whereas 17beta-estradiol had a weak effect. These results suggest that endometrial MIP-1beta may be involved in the recruitment of NK cells from circulating peripheral blood.

Prevention and treatment of breast cancer by suppressing aromatase activity and expression.

Estrogen promotes the proliferation of breast cancer cells. Aromatase is the enzyme that converts androgen to estrogen. In tumors, expression of aromatase is upregulated compared to that of surrounding noncancerous tissue. Tumor aromatase is thought to stimulate breast cancer growth in both an autocrine and a paracrine manner. A treatment strategy for breast cancer is to abolish in situ estrogen formation with aromatase inhibitors. In addition, aromatase suppression in postmenapausal women is being evaluated as a potential chemopreventive modality against breast cancer. One area of aromatase research in this laboratory is the identification of foods and dietary compounds that can suppress aromatase activity. In vitro and in vivo studies have found that grapes and mushrooms contain chemicals that can inhibit aromatase. Therefore, a diet that includes grapes and mushrooms would be considered preventative against breast cancer. Another area of our aromatase research is the elucidation of the regulatory mechanism of aromatase expression in breast cancer tissue. Increased aromatase expression in breast tumors is attributed to changes in the transcriptional control of aromatase expression. Whereas promoter I.4 is the main promoter that controls aromatase expression in noncancerous breast tissue, promoters II and I.3 are the dominant promoters that drive aromatase expression in breast cancer tissue. Our recent gene regulation studies revealed that in cancerous versus normal tissue, several positive regulatory proteins (e.g., nuclear receptors and CREB1) are present at higher levels and several negative regulatory proteins (e.g., snail and slug proteins) are present at lower levels. This may explain why the activity of promoters II and I.3 is upregulated in cancerous tissue. In addition, our in vitro transcription/translation analysis using plasmids containing T7 promoter and the human snail gene as a reporter capped with different untranslated exon Is revealed that exon PII-containing transcripts were translated more effectively than were exon I.3-containing transcripts. An understanding of the molecular mechanisms of aromatase expression between noncancerous and cancerous breast tissue, at both transcriptional and translational levels, may help in the design of a therapy based on suppressing aromatase expression in breast cancer tissue.