Labour is associated with decreased expression of the PGF2alpha receptor (PTGFR) and a novel PTGFR splice variant in human myometrium but not decidua.

The prostaglandin F(2α) receptor (PTGFR) is believed to play a role in the process of parturition. The main support for this comes from animal studies; however, in humans, the evidence is less clear. The gene coding for PTGFR may be subject to alternative splicing to generate alternate variants with different signalling pathways. We have determined regional (upper versus lower segment) and labour-associated expression of PTGFR mRNA and a recently identified splice variant of PTGFR in human myometrium and decidua. We also examined the effect of the inflammatory cytokine interleukin-1ß (IL-1ß) on PTGFR mRNA expression in a model of cultured human myometrial smooth muscle cells. We identified a PTGFR transcript variant 2 (PTGFR-v2) generated by alternate splicing in human myometrium and decidua. The PTGFR-v2 contains an additional 71 base pair exon, which results in a truncated protein at 297 amino acids compared with the PTGFR transcript variant 1 (PTGFR-v1) at 359 amino acids. In contrast to our hypothesis, we demonstrate that PTGFR-v1 and PTGFR-v2 mRNA expression is not significantly higher in upper segment compared with lower segment paired samples. We also show a labour-associated decrease in PTGFR-v1 and PTGFR-v2 mRNA expression in lower segment myometrial samples. IL-1ß-stimulated mRNA expression of both PTGFR variants in a distinct time-dependent manner in myometrial cell cultures. We suggest that the role of the PTGFR in the human uterus requires further validation prior to pursuing it as a target for the treatment of preterm labour. In addition, the presence of distinct variants suggests further levels of gene regulation within the pregnant uterus.

Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 Trial.

PURPOSE: Studies indicate that ovarian cancer patients who have been optimally debulked survive longer. Although chemotherapy has been variable, they have defined standards of care. Additionally, it is suggested that patients from the United Kingdom (UK) have inferior survival compared with some other countries. We explored this within the context of a large, international, prospective, randomized trial of first-line chemotherapy in advanced ovarian cancer (docetaxel-carboplatin v paclitaxel-carboplatin; SCOTROC-1). The Scottish Randomised Trial in Ovarian Cancer surgical study is a prospective observational study examining the impact on progression-free survival (PFS) of cytoreductive surgery and international variations in surgical practice. PATIENTS AND METHODS: One thousand seventy-seven patients were recruited (UK, n = 689; Europe, United States, and Australasia, n = 388). Surgical data were available for 889 patients. These data were analyzed within a Cox model. RESULTS: There were three main observations. First, more extensive surgery was performed in non-UK patients, who were more likely to be optimally debulked (< or = 2 cm residual disease) than UK patients [corrected] (71.3% v 58.4%, respectively; P < .001). Second, optimal debulking was associated with increased PFS mainly for patients with less extensive disease at the outset (test for interaction, P = .003). Third, UK patients with no visible residual disease had a less favorable PFS compared with patients recruited from non-UK centers who were similarly debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). This observation seems to be related to surgical practice, primarily lymphadenectomy. CONCLUSION: Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.

Letter and category fluency in children with fetal alcohol syndrome from a community in South Africa.

OBJECTIVE: This study investigated whether there were differential effects of substantial prenatal alcohol exposure on letter and category fluency in children. Given that children with prenatal alcohol exposure are often impaired in executive functioning and that letter fluency taxes executive processes more than category fluency, it was expected that children with fetal alcohol syndrome (FAS) would be more impaired in letter than in category fluency. A second objective of the study was to examine the developmental trends in the two types of fluency in children with prenatal alcohol exposure. It was hypothesized that between the ages of 6 and 9 years, these FAS children would show age-related changes in category fluency but not in letter fluency. METHOD: As part of a neuropsychological test battery designed for an international collaborative study of FAS in South Africa, tests of letter and category fluency were administered in Afrikaans. The participants were 62 children with FAS and 61 controls matched with respect to age, gender (58 boys and 65 girls), ethnicity, and socioeconomic status. RESULTS: Results showed that the FAS group had relatively greater difficulty with letter fluency than with category fluency and that the FAS group generated fewer words in both fluency conditions. Contrary to the expectation, however, alcohol-affected children demonstrated age-related linear trends in both letter and category fluency. CONCLUSIONS: This is the first study of verbal fluency involving a large sample of well-diagnosed children with FAS conducted in a nonwestern environment. The results are nonetheless consistent with those obtained in western countries in studies of children with various levels of prenatal alcohol exposure and various levels of fetal alcohol spectrum disorder. This study suggests that at least some aspects of the cognitive profile associated with prenatal alcohol exposure may be generalizable across cultural and ethnic boundaries.

Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma.

BACKGROUND: Chemotherapy with a platinum agent and a taxane (paclitaxel) is considered the standard of care for treatment of ovarian carcinoma. We compared the combination of docetaxel-carboplatin with the combination of paclitaxel-carboplatin as first-line chemotherapy for stage Ic-IV epithelial ovarian or primary peritoneal cancer. METHODS: We randomly assigned 1077 patients to receive docetaxel at 75 mg/m2 of body surface area (1-hour intravenous infusion) or paclitaxel at 175 mg/m2 (3-hour intravenous infusion). Both treatments then were followed by carboplatin to an area under the plasma concentration-time curve of 5. The treatments were repeated every 3 weeks for six cycles; in responding patients, an additional three cycles of single-agent carboplatin was permitted. Survival curves were calculated by the Kaplan-Meier method, and hazard ratios were estimated with the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 23 months, both groups had similar progression-free survival (medians of 15.0 months for docetaxel-carboplatin and 14.8 months for paclitaxel-carboplatin; hazard ratio [HR] docetaxel-paclitaxel = 0.97, 95% confidence interval [CI] = 0.83 to 1.13; P = .707), overall survival rates at 2 years (64.2% and 68.9%, respectively; HR = 1.13, 95% CI = 0.92 to 1.39; P = .238), and objective tumor (58.7% and 59.5%, respectively; difference between docetaxel and paclitaxel = -0.8%, 95% CI = -8.6% to 7.1%; P = .868) and CA-125 (75.8% and 76.8%, respectively; difference docetaxel-paclitaxel = -1.0%, 95% CI = -7.2% to 5.1%; P = .794) response rates. However, docetaxel-carboplatin was associated with substantially less overall and grade 2 or higher neurotoxicity than paclitaxel-carboplatin (grade > or =2 neurosensory toxicity in 11% versus 30%, difference = 19%, 95% CI = 15% to 24%; P<.001; grade > or =2 neuromotor toxicity in 3% versus 7%, difference = 4%, 95% CI = 1% to 7%; P<.001). Treatment with docetaxel-carboplatin was associated with statistically significantly more grade 3-4 neutropenia (94% versus 84%, difference = 11%, 95% CI = 7% to 14%; P<.001) and neutropenic complications than treatment with paclitaxel-carboplatin, although myelosuppression did not influence dose delivery or patient safety. Global quality of life was similar in both arms, but substantive differences in many symptom scores favored docetaxel. CONCLUSIONS: Docetaxel-carboplatin appears to be similar to paclitaxel-carboplatin in terms of progression-free survival and response, although longer follow-up is required for a definitive statement on survival. Thus, docetaxel-carboplatin represents an alternative first-line chemotherapy regimen for patients with newly diagnosed ovarian cancer.