Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model.

PTEN mutations have been implicated in the development of endometrial hyperplasia and subsequent cancer. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists have demonstrated antineoplastic and chemopreventive effects. The purpose of this study was to evaluate the effects of the PPAR-gamma agonist rosiglitazone on both PTEN wild type and PTEN null cell lines and in the PTEN heterozygote((+/-)) murine model. Hec-1-A (PTEN wild type) and Ishikawa (PTEN null) cells were treated with rosiglitazone. Thirty-five female PTEN(+/-) mice were genotyped and placed into one of four groups for treatment for 18 weeks: A) PTEN wild type with 4 mg/kg rosiglitazone, B) PTEN(+/-) mice with vehicle, C) PTEN(+/-) mice with 4 mg/kg rosiglitazone, and D) PTEN(+/-) mice with 8 mg/kg rosiglitazone. Proliferation and apoptosis were measured by bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragmentation sites assay. Rosiglitazone caused cell growth inhibition in both Hec-1-A and Ishikawa in a dose-dependent manner (P < 0.02 and P < 0.03, respectively). Rosiglitazone also induced apoptosis in both Hec-1-A (P < .001) and Ishikawa (P < .001) cells in a dose-dependent manner. In the murine model, rosiglitazone decreased proliferation of the endometrial hyperplastic lesions (B vs C; 39.7% vs 9.3% and B vs D; 39.7% vs 4.2%; P < 0.0001) and increased apoptosis of glandular endometrial epithelial cells (B vs C; 2.8% vs 22.4%; P < 0.0001 and B vs D; 2.8% vs 30.2%; P = 0.003). PPAR-gamma agonist rosiglitazone inhibits proliferation and induces apoptosis in both PTEN intact and PTEN null cancer cell lines and in hyperplastic endometrial lesions in the PTEN(+/)(-)murine model.

Modified uterine manipulator and vaginal rings for total laparoscopic radical hysterectomy.

At present, there is no standard technique that allows surgeons performing total laparoscopic radical hysterectomy to complete the colpotomy and remove an adequate (2-cm) margin of upper vaginal tissue while maintaining adequate pneumoperitoneum. We evaluated the feasibility and safety of using a modified uterine manipulator for total laparoscopic radical hysterectomy in patients with cervical or endometrial cancer. A retrospective review was performed in all patients who underwent total laparoscopic radical hysterectomy using a modified uterine manipulator at our institution during the period April 2004 to December 2006. This analysis included 30 patients who underwent surgery with the modified uterine manipulator. There were no reports of difficulty with placement of the instrument, multiple attempts at placement, difficulty with uterine manipulation, or uterine perforation. In no patient was a vaginal incision or episiotomy required to fit the instrument through the introitus. In no case was there loss of pneumoperitoneum during colpotomy. Additional upper vaginal tissue had to be removed after intraoperative assessment of the adequacy of the surgical specimen in five (16.7%) of 30 patients. Use of the modified uterine manipulator according to our technique is safe and feasible, allowing for adequate vaginal resection and maintenance of pneumoperitoneum.

Loss of phosphatase and tensin homologue deleted on chromosome 10 and phosphorylation of mammalian target of rapamycin are associated with progesterone refractory endometrial hyperplasia.

The objective of our study was to evaluate the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p27, and mammalian target of rapamycin (mTOR) expressions in women with progesterone-responsive and refractory endometrial hyperplasia (EH) samples and to determine if these markers could be associated with response or used as potential targets for treatment. Thirty-eight matched pre- and posttreatment pairs of paraffin-embedded endometrial biopsies were obtained from patients with EH. Immunohistochemical analysis for PTEN, p27, and phospho-mTOR were performed on all samples. Median age at diagnosis was 49 years (20-79 years). Median treatment interval was 3 months (1-12 months). Sixteen patients (42.1%) had complete resolution of their hyperplasia (responders), and 22 (57.9%) had persistent hyperplasia (nonresponders) after treatment with progesterone. In the pretreatment samples, no markers were found to predict nonresponders. In posttreatment samples, loss of PTEN expression with phospho-mTOR expression was observed in more nonresponders than responders (40.9% vs 6.3%; P= 0.03). Phospho-mTOR overexpression was found in 63.6% of nonresponders. We found that persistent hyperplasia refractory to progesterone therapy was associated both with the loss of PTEN and with the loss of phosphorylation of mTOR. In select cases of non-responsive progesterone refractory EH, a rational target for treatment may involve the mTOR pathway.

Ethnic differences in socioeconomic status, diagnosis, treatment, and survival among older women with epithelial ovarian cancer.

The purpose of the study was to determine the ethnic disparities in socioeconomic status (SES) and in receiving definitive surgical treatment and adjuvant chemotherapy and to examine if these differences contribute to ethnic disparities in survival. We studied a population-based cohort of 5131 women diagnosed with epithelial ovarian cancer at age >or=65 between 1992 and 1999, identified from the Surveillance, Epidemiology and End Results-Medicare linked databases with up to 11 years of follow-up. The percentage of women diagnosed with epithelial ovarian cancer at advanced stage (stage III or IV) was 71.6% in Caucasians and 69.7% in African-Americans. Of these 4264 with stage IC-IV disease who are recommended for chemotherapy, fewer African-Americans received chemotherapy compared to Caucasians (50.2% versus 64.7%, P < 0.001). The risk of all-cause mortality in African-Americans was not significantly different from Caucasians (hazard ratio [HR] = 1.00, 95% CI = 0.88-1.13) after controlling for patient demographics, tumor characteristics, and comorbidity. The HR remained not significant in African-Americans compared to Caucasians after additionally adjusting for treatments (0.93, 0.82-1.06) or SES (0.94, 0.82-1.08) or both (0.88, 0.77-1.01). Women who underwent cancer-directed surgery and received adjuvant chemotherapy were 50% less likely to die than those who did not. The survival benefits from these therapies were similar in Caucasian and African-American women with ovarian cancer. There was no significant difference in survival between African-American and Caucasian women with ovarian cancer after adjusting for tumor characteristics, treatment, and sociodemographic factors. Although adjuvant chemotherapy was effective in prolonging survival, substantial numbers of women with ovarian cancer still did not receive chemotherapy.

Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma.

Cyclins D1 and D3 play key roles in cell cycle progression. The downregulation of cyclin D3 was associated with phosphatase and tensin homolog deleted on chromosome ten-(PTEN)-induced cell cycle arrest. We attempted to determine whether cyclin D1 and D3 overexpression is correlated with PTEN inactivation in endometrioid endometrial cancer (EEC). The expression of PTEN, cyclin D1, and cyclin D3 were determined by immunohistochemical analysis in 105 EEC specimens. Forty-three percent of the EEC demonstrated loss of PTEN expression. Cyclin D3 was overexpressed in only 18% of the EEC specimens and was not associated with tumor grade. Cyclin D1 was overexpressed in 64% of the specimens and was more common in moderate or high-grade tumors (P = 0.002 and P = 0.02, respectively). The overexpression of cyclin D3 was not correlated with loss of PTEN in the EEC. The overexpression of cyclin D1 was much higher in grade 1 tumors with negative PTEN than tumors with positive PTEN expression (67% vs 26%). The overexpression of cyclin D3 was neither frequent nor correlated with the loss of PTEN expression. The overexpression of cyclin D1 was higher in the low-grade tumors with negative PTEN expression than tumors with positive PTEN expression. Overexpression of cyclin D1 is frequent in moderate or high-grade EECs and likely results from multiple mechanisms.

Survey of Plant-parasitic Nematodes in Missouri Cotton Fields.

During September 1990, 30 cotton fields in each of three Missouri counties were surveyed for plant-parasitic nematodes. Soil samples for nematode analysis consisted of a composite of 20 cores collected in a zig-zag pattern within a 1-ha block in each field. Cores were taken from within weed-free cotton rows. Nine genera of plant-parasitic nematodes were found (Rotylenchulus, Helicotylenchus, Hoplolaimus, Meloidogyne, Paratylenchus, Pratylenchus, Tylenchorhynchus, Heterodera, and Trichodorus), and five species were identified: Meloidogyne incognita, Rotylenchulus reniformis, Hoplolaimus galeatus, Pratylenchus vulnus, and P. scribneri. This is the first report of R. reniformis, H. galeatus, P. vulnus, and P. scribneri in Missouri cotton fields and the first report of R. reniformis and P. vulnus in Missouri. The known cotton pathogens M. incognita, R. reniformis, and H. galeatus were found in 30%, 3%, and 2% of the fields sampled, respectively. The correlation between sand content of the soil sample and the number of vermiform M. incognita in the sample was not significant, with r(2) = 0.13. Select fields where H. galeatus and R. reniformis were found in 1990 were sampled more intensely in 1991. The 1-ha block sampled in 1990 was sampled in 1991, along with three other 1-ha blocks uniformly distributed within the field. In addition, a 1-ha block was sampled in each of eight nearby fields, within 2 km of the first field. The nine plant-parasitic nematode genera identified in the 1990 survey were observed again in 1991. Within-field distribution of M. incognita, R. reniformis, and H. galeatus was not uniform. When M. incognita, R. reniformis, or H. galeatus were present in a field, the same species was found in 38%, 25%, or 50% of nearby fields, respectively.