Effect of surgery on ovarian reserve in women with endometriomas, endometriosis and controls.

BACKGROUND: Many women who experience endometriosis and endometriomas also encounter problems with fertility. OBJECTIVE: The purpose of this study was to determine the impact of surgical excision of endometriosis and endometriomas compared with control subjects on ovarian reserve. STUDY DESIGN: This was a prospective cohort study of 116 women aged 18-43 years with pelvic pain and/or infertility who underwent surgical treatment of suspected endometriosis (n=58) or endometriomas (n=58). Based on surgical findings, the suspected endometriosis group was further separated into those with evidence of peritoneal disease (n=29) and those with no evidence of endometriosis (n=29). Ovarian reserve was measured by anti-Müllerian hormone and compared before surgery and at 1 month and 6 months after surgery. RESULTS: Baseline anti-Müllerian hormone values were significantly lower in the endometrioma vs negative laparoscopy group (1.8 ng/mL [95% confidence interval, 1.2-2.4 ng/mL] vs 3.2 ng/mL [95% confidence interval, 2.0-4.4 ng/mL]; P<.02), but the peritoneal endometriosis group was not significantly different than either of these groups. Only patients with endometriomas had a significant decline in ovarian reserve at 1 month (-48%; 95% confidence interval, -54 to -18%; P<.01; mean anti-Müllerian hormone baseline value, 1.77-1.12 ng/mL at 1 month). Six months after surgery, anti-Müllerian hormone values continued to be depressed from baseline but were no longer significantly different. The rate of anti-Müllerian hormone decline was correlated positively with baseline preoperative anti-Müllerian hormone values and the size of endometrioma that was removed. Those with bilateral endometriomas (n=19) had a significantly greater rate of decline (53.0% [95% confidence interval, 35.4-70.5%] vs 17.5% [95% confidence interval, 3.2-31.8%]; P=.002). CONCLUSION: At baseline, patients with endometriomas had significantly lower anti-Müllerian hormone values compared with women without endometriosis. Surgical excision of endometriomas appears to have temporary detrimental effects on ovarian reserve.

Mammalian target of rapamycin complex 2 (mTORC2) is a critical determinant of bladder cancer invasion.

Bladder cancer is the fourth most common cause of cancer in males in the United States. Invasive behavior is a major determinant of prognosis. In this study, we identified mammalian target of rapamycin complex 2 (mTORC2) as a central regulator of bladder cancer cell migration and invasion. mTORC2 activity was assessed by the extent of phosphorylation of Ser473 in AKT and determined to be approximately 5-fold higher in specimens of invasive human bladder cancer as opposed to non-invasive human bladder cancer. The immortalized malignant bladder cell lines, UMUC-3, J82 and T24 demonstrated higher baseline mTORC2 activity relative to the benign bladder papilloma-derived cell line RT4 and the normal urothelial cell line HU1. The malignant bladder cancer cells also demonstrated increased migration in transwell and denudation assays, increased invasion of matrigel, and increased capacity to invade human bladder specimens. Gene silencing of rictor, a critical component of mTORC2, substantially inhibited bladder cancer cell migration and invasion. This was accompanied by a significant decrease in Rac1 activation and paxillin phosphorylation. These studies identify mTORC2 as a major target for neutralizing bladder cancer invasion.

Mammalian target of rapamycin (mTOR) regulates cellular proliferation and tumor growth in urothelial carcinoma.

Mammalian target of rapamycin (mTOR) signaling has been associated with aggressive tumor growth in many cancer models, although its role in urothelial carcinoma (UCC) has not been extensively explored. Expression of phosphorylated mTOR (P-mTOR) and a downstream target, ribosomal S6 protein (P-S6), was identified in 74% (90/121) and 55% (66/121) of muscle-invasive UCCs, respectively. P-mTOR intensity and %positive cells were associated with reduced disease-specific survival (P = 0.04, P = 0.08, respectively). Moreover, P-mTOR intensity corresponded to increased pathological stage (P < 0.01), and mTOR activity was associated with cell migration in vitro. In addition, mTOR inhibition via rapamycin administration reduced cell proliferation in UCC cell lines RT4, T24, J82, and UMUC3 in a dose-dependent manner to 6% of control levels and was significant at 1 nmol/L in J82, T24, and RT4 cells (P < 0.01, P < 0.01, P = 0.03, respectively) and at 10 nmol/L in UMUC3 cells (P = 0.03). Reduced proliferation corresponded with reduced P-S6 levels by Western blot, and effects were ablated by pretreatment of cells with mTOR-specific siRNA. No effects of rapamycin on apoptosis were identified by TUNEL labeling or PARP cleavage. Administration of rapamycin to T24-xenografted mice resulted in a 55% reduction in tumor volume (P = 0.03) and a 40% reduction in proliferation (P < 0.01) compared with vehicle-injected mice. These findings indicate that mTOR pathway activation frequently occurs in UCC and that mTOR inhibition may be a potential means to reduce UCC growth.