Aim: To investigate the safety and efficacy of 52 weeks of dienogest treatment in patients with endometriosis. Methods: One hundred and thirty-five patients with endometriosis received 2 mg of dienogest orally each day for 52 weeks. Adverse drug reactions and bone density were evaluated. Global improvement was assessed based on the changes in severity categories of five subjective symptoms during non-menstruation (lower abdominal pain, lumbago, dyschezia, dyspareunia, and pain on vaginal examination) and two objective findings (induration involving the pouch of Douglas and limited uterine mobility). Results: The most common adverse drug reactions included metrorrhagia (71.9%), headaches (18.5%), and constipation (10.4%). No clinically significant changes were noted in the incidence or severity of reactions associated with the course of the treatment period (52 weeks). Changes from the baseline bone mineral density of the lumbar spine measured by dual-energy X-ray absorptiometry were -1.6 +/- 2.4% and -1.7 +/- 2.2%(mean +/- standard deviation) at 24 and 52 weeks, respectively, which were statistically significant decreases; however, there was no cumulative decrease. The proportions of patients assessed as marked or moderate improvement in terms of global improvement were 72.5%(95/131 cases) at 24 weeks and 90.6%(106/117 cases) at 52 weeks. Conclusion: The long-term effect of dienogest on bone mineral density was slight, whereas the efficacy increased cumulatively.

BACKGROUND Decreased susceptibility of endometrial tissue to apoptosis may contribute to the pathogenesis of endometriosis. We investigate the role of survivin in the pathophysiology of endometriosis through the ability of ectopic and eutopic endometrial stromal cells (ESCs) to resist apoptosis. METHODS Ectopic ESCs were obtained from ovarian chocolate cysts in patients undergoing laparoscopic surgery (n = 22). Eutopic ESCs were isolated from endometrial tissue of cyclic premenopausal women undergoing hysterectomy for fibroids (n = 22). Purified stromal cells were studied in vitro. The number of surviving cells and activation of caspases were assessed by WST-8 assay and immunoblotting. Expression of inhibitor of apoptosis proteins (IAP) family members: cIAP1 (birc2), cIAP2 (birc3), XIAP (birc4), survivin (birc5) were examined using cDNA array and real-time RT-PCR. Effects of gene silencing by small inhibitor RNAs (siRNA) were examined by WST-8-assay, Annexin-V staining and immunoblotting. RESULTS After staurosporine (SS) treatment, 55% of eutopic ESCs survived versus 70% of ectopic ESCs. Procaspase-3 or -7 was more intensely activated by SS treatment in eutopic than in ectopic ESCs (P < 0.01). mRNAs for IAP-family genes, such as cIAP-1, XIAP and survivin, were highly expressed in ectopic ESCs before SS treatment. The fold induction of survivin expression after SS treatment was higher in ectopic than eutopic ESCs (2.8 +/- 0.27 versus 0.69 +/- 0.07, respectively). Survivin gene silencing in SS-treated ectopic ESCs led to an increase of apoptotic cells (P < 0.05, versus control siRNA). CONCLUSIONS We demonstrated that survivin plays a critical role in susceptibility of ESCs to apoptosis. Our results indicate that a survivin inhibitor may be effective as a novel treatment for endometriosis.

Lipopolysaccharide-enhanced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production were compared in endometriotic stromal cells (ESCs) and eutopic endometrial stromal cells. Lipopolysaccharide promotes the proliferation and invasion of ESCs via up-regulation of COX-2 and PGE2 expression, suggesting that pelvic inflammation may promote the progression of endometriosis.

BACKGROUND: The obesity paradox has recently attracted considerable interest in the study of many diseases. In this investigation we examine the relationship between body mass index (BMI) and prognosis after left ventricular assist system (LVAS) implantation. METHODS: We measured the BMI of 64 patients 3 months after LVAS implantation for end-stage heart failure. The patients were classified according to BMI into Group A (BMI <16 kg/m(2)), Group B (BMI 16 to 18.4 kg/m(2)) or Group C (BMI > or =18.5 kg/m(2)). We compared the prognosis among these three groups after a mean follow-up period of 583 days. RESULTS: Seven patients were weaned from their LVAS, 24 received heart transplantation, 25 died on the transplant waiting list, and 8 remain on the list. Long-term (>1 year) mortality was significantly higher in Group A than in Groups B and C (59% vs 40% and 18%, respectively; p < 0.05). The incidence of sepsis was also significantly higher in Group A than in Groups B and C (68% vs 45% and 32%, respectively; p < 0.05). After multivariate adjustment, BMI <16 kg/m(2)(hazard ratio [HR] 14.9; 95% confidence interval [CI] 2.61 to 86.0; p < 0.01) and levels of C-reactive protein (HR 1.56; 95% CI 1.15 to 2.13; p < 0.01) were independent predictors of mortality. CONCLUSIONS: A lower BMI indicated a poor prognosis, as well as a higher incidence of a fatal complication, sepsis, after LVAS implantation. Control of BMI could be an effective way to improve management of patients with LVAS.

Endometriosis causes pelvic pain and infertility in women of reproductive age. We explored TNFalpha-induced specific signaling pathways and gene expressions in endometriotic stromal cells (ESCs). Based on the data of the pathway specific cDNA array, we analyzed the role of TAK1, which is believed to work as a common mediator for NFkappaB and MAPK pathways. Using the NFkappaB pathway array, we found that TNFalpha up-regulated ICAM3, IL-6, IL-8, TAK1, JNK2, RelA, and TLR4 expressions. TNFalpha augmented the phosphorylation of TAK1. By transfection of TAK1 siRNA, TNFalpha-induced phosphorylation of IkappaBalpha, JNK1/2, and p38MAPK, as well as IL-6 or IL-8 expression, were repressed. TAK1 silencing in TNFalpha-pretreated ESCs caused a decrease in the proportion of cells in S-phase, and reduced TNFalpha-promoted BrdU incorporation. We provide the first evidence that TNFalpha and its downstream TAK1, which are key mediators for NFkappaB and MAPK pathways, may be involved in the pathogenesis of endometriosis.

Problem We previously reported that lipopolysaccharide (LPS)-promoted endometriotic stromal cell (ESC) proliferation by inducing TNFalpha production. The aim of this study was to investigate the efficacy of TNFalpha gene silencing on LPS-treated ESCs. Method of study Endometriotic stromal cells (ESCs) and endometrial stromal cells (ESCs)(EMSCs) were obtained from ovarian chocolate cysts and uterine myoma, respectively. Using PCR array, LPS-induced gene expression profiling after transfection of TNFalpha siRNA into ESCs was performed. Down-regulated genes by TNFalpha silencing were examined using real-time RT-PCR. Effect of TNFalpha silencing was examined using ELISA and BrdU incorporation, respectively. Results In PCR array, TNFalpha silencing in ESCs repressed LPS-induced expression of cIAP2 and IL-8, NFkappaB pathway responsive genes. After adding LPS, the levels of cIAP2 and IL-8 expression in ESCs were higher compared with those in EMSCs. TNFalpha silencing attenuated the LPS-induced ESC proliferation. Conclusion Tumor necrosis factor alpha may be involved in cell proliferation of endometriotic tissues.

Resistance of ovarian mucinous adenocarcinoma to standard chemotherapy with paclitaxel and carboplatin is associated with poor prognosis, and an effective treatment is needed. The present study aimed to identify an effective chemotherapy for ovarian mucinous adenocarcinoma. Five human ovarian mucinous adenocarcinoma cell lines (MN-1, OMC-1, RMUG-L, RMUG-S, TU-OM-1) were used in this study. Sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and we assessed drug sensitivity by calculating the assay area under the curve for each agent. Protein expression was confirmed by Western blot analysis. We also examined the efficacy of combination chemotherapy on survival in a xenograft model of nude mice. The IC(50) to anticancer agents ranged widely. The assay area under the curve indicated that two of five cell lines (MN-1, TU-OM-1) were sensitive to oxaliplatin, 5-fluorouracil and etoposide, and only one (TU-OM-1) was sensitive to 7-ethyl-10-hydroxycamptothecin, which is an active metabolite of camptothecin. All cell lines were resistant to cisplatin and paclitaxel. The combination of oxaliplatin and 5-fluorouracil resulted in additive or synergistic effects on all cell lines. The combination of oxaliplatin and 5-fluorouracil significantly prolonged survival in a ovarian mucinous adenocarcinoma xenograft model of nude mice. Protein expression levels of the excision repair cross-complementation group 1 were lower in oxaliplatin sensitive cell lines. Exposure to 5-fluorouracil down-regulated cross-complementation group 1 expression in ovarian mucinous adenocarcinoma cells. We conclude that combination chemotherapy consisting of oxaliplatin and 5-fluorouracil was an effective treatment for ovarian mucinous adenocarcinoma and may be a pivotal candidate for a novel treatment strategy.(Cancer Sci 2009).

The present authors previously reported that a synthetic retinoid, CD437, induces endoplasmic reticulum stress-mediated apoptosis in ovarian adenocarcinoma cells in spite of no response to natural retinoids. However, the precise mechanism of its proapoptotic action has not been fully determined. The present study herein demonstrates that apoptosis induction of ovarian adenocarcinoma SKOV3 cells by CD437 involves the upregulation of thioredoxin-binding protein 2 (TBP2) by a mechanism that is dependent on the intracellular calcium concentration. TBP2 is known to bind to and suppress thioredoxin (TRX) activity whereas TRX has an anti-apoptotic effect by inhibiting apoptosis signal-regulating kinase 1 (ASK1). The activation of ASK1 and its downstream molecule, c-Jun N-terminal kinase, was observed after induction of TBP2 by CD437. Interestingly, CD437 induced the association of TBP2 with TRX and, in turn, facilitated the dissociation of ASK1 from TRX. Moreover, blockade of TBP2 induction by small interfering RNA (siRNA) significantly attenuated the cytotoxic effect of CD437. These results suggest that TBP2 plays a critical role in the mechanism by which CD437 exerts proapoptotic action against SKOV3 cells.(Cancer Sci 2008).

Malignant mixed müllerian tumors (MMMT) of the fallopian tube are extremely rare, and optimal therapy for them is unknown. A 71-year-old woman presented to us with symptoms of abdominal distension and nausea. A right salpingo-oophorectomy was performed. Pathological examination determined International Federation of Gynecology and Obstetrics (FIGO) stage IIIc MMMT of the right fallopian tube. Of note, multiple tumoral nodules were attached to the sigmoid colon. The patient received three courses of chemotherapy, consisting of 175 mg/m(2) paclitaxel and AUC = 5 carboplatin (TC therapy), administered at 3-week intervals. A second, debulking, surgery was then performed, consisting of total abdominal hysterectomy, left salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy. The tumor attached to the sigmoid colon had shrunk by 60% after chemotherapy. The patient received an additional five courses of adjuvant TC therapy. The patient is alive and free of disease 28 months after the debulking surgery. TC therapy may be effective for MMMT of the fallopian tube.