Impact of night shifts on laparoscopic skills and cognitive function among gynecologists.

OBJECTIVE: To assess whether gynecologists have impaired laparoscopic skills and/or reduced cognitive function after long on-call hours. DESIGN: Prospective cohort study. SETTING: Department of Gynecology and Obstetrics, Norway. POPULATION: 28 gynecologists working long shifts in a single department. METHODS: Pre-training of laparoscopic skills on a virtual reality simulator. Simulator- and cognitive testing on two different occasions; one in the morning after a normal nights' sleep at home and one in the morning directly after 17.5 h on call. The virtual reality simulator test consisted of three repetitive salpingectomies in an ectopic pregnancy module. The cognitive test consisted of a standardized cognitive test battery (Cambridge neuropsychological test automated battery). MAIN OUTCOME MEASURES: Simulated laparoscopic performance was assessed by time to perform the procedure, total length of instrument movement (tip trajectory) and blood loss. Cognitive function was assessed by reaction time, errors and total score. RESULTS: No significant impairment in laparoscopic skills was found after 17.5 h on call. Cognitive testing revealed a statistically significant increase in reaction time post-call. Construct validity for the metrics "time to perform procedure" and "tip trajectory" in the ectopic pregnancy module was established in a validation study prior to our main study. CONCLUSIONS: We were not able to detect impaired laparoscopic skills among gynecologists tested by a virtual reality procedural module after 17.5 h on call. We found a small increase in reaction time but no other signs of reduced cognitive function. The study adds information on surgical performance of sleep-deprived gynecologists.

Deoxyribonucleic acid ploidy in endometrial carcinoma: a reproducible and valid prognostic marker in a routine diagnostic setting.

OBJECTIVE: The objective of the study was to investigate the prognostic impact of deoxyribonucleic acid (DNA) ploidy in endometrial carcinoma in a routine diagnostic series as compared with a research series. STUDY DESIGN: We studied a population-based series of 363 endometrial carcinomas prospectively collected, with long and complete follow-up. The prognostic value of DNA ploidy was investigated in a routine diagnostic series (n=262) and compared with the results from a previous research series (n=101). RESULTS: The proportion of DNA aneuploid tumors was 21% in the research series and 25% in the routine diagnostic series (P=NS). In both series, DNA aneuploidy was significantly correlated to higher age at diagnosis, nonendometrioid subtype, and high histologic grade. Patients with DNA aneuploid tumors had significantly poorer survival, adjusted for established clinicopathologic prognostic factors. CONCLUSION: DNA ploidy estimation in endometrial carcinoma adds independent prognostic information in a routine diagnostic setting.

Biologic markers in endometrial cancer treatment.

With a lifetime risk among women of 2-3%, endometrial cancer is the most common pelvic gynecologic malignancy in industrialized countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis, accounts for the majority of cases and is associated with a low-stage, low-grade and endometrioid histology. In contrast, type II, associated with a poor prognosis, is characterized by a high-stage, high-grade and non-endometrioid histology. However, the prognostic value of this distinction is limited, as up to 20% of type I endometrial cancers recur, while half of type II cancers do not. We review the current literature on epidemiology, etiology, pathology, molecular alterations, staging, treatment and prognostic factors in endometrial cancer. Ongoing molecular-based clinical trials and newly reported molecular alterations with a potential for development of new targeted therapy are discussed.

GATA3 expression in estrogen receptor alpha-negative endometrial carcinomas identifies aggressive tumors with high proliferation and poor patient survival.

OBJECTIVE: The transcription factor GATA3 has recently been found to be involved in the carcinogenesis for numerous cancers. We investigated this marker in relation to clinicopathologic characteristics, hormone receptors, other biomarkers, and survival in endometrial carcinoma. STUDY DESIGN: A population-based study of 316 endometrial carcinomas with complete follow-up was studied for GATA3, estrogen receptor (ER)-alpha, ERbeta2, and progesterone receptor (PR) expression. RESULTS: Positive GATA3 expression in hysterectomy specimens significantly correlated to high International Federation of Gynecology and Obstetrics stage, serous papillary/clear cell subtypes, high histologic grade, loss of PR expression, aneuploidy, high proliferation, pathologic p53 and p16 expression, and poor prognosis (P = .003). Loss of hormone receptors significantly correlated with aggressive phenotype and poor prognosis. Pathologic expression of GATA3/ERalpha in combination added independent prognostic information. CONCLUSION: GATA3 expression is associated with an aggressive phenotype and adds independent prognostic information in addition to receptor status. Further studies of its value in tailored treatment protocols seem justified.

Drug-sensitive FGFR2 mutations in endometrial carcinoma.

Oncogenic activation of tyrosine kinases is a common mechanism of carcinogenesis and, given the druggable nature of these enzymes, an attractive target for anticancer therapy. Here, we show that somatic mutations of the fibroblast growth factor receptor 2 (FGFR2) tyrosine kinase gene, FGFR2, are present in 12% of endometrial carcinomas, with additional instances found in lung squamous cell carcinoma and cervical carcinoma. These FGFR2 mutations, many of which are identical to mutations associated with congenital craniofacial developmental disorders, are constitutively activated and oncogenic when ectopically expressed in NIH 3T3 cells. Inhibition of FGFR2 kinase activity in endometrial carcinoma cell lines bearing such FGFR2 mutations inhibits transformation and survival, implicating FGFR2 as a novel therapeutic target in endometrial carcinoma.

HER-2/neu expression is associated with high tumor cell proliferation and aggressive phenotype in a population based patient series of endometrial carcinomas.

Gene alterations and overexpression of various oncogenes and cell-cycle regulators are important in tumor development. In a population based series of 316 endometrial carcinomas with long and complete follow-up we investigated the distribution of HER-2/neu and EGFR expression and copy number alteration in endometrial cancers. HER-2/ neu, EGFR and Ki-67 expression in curettage and hysterectomy specimens were studied immunohistochemically for expression in relation to molecular markers and clinical phenotype. Fresh tumor samples (n=76) were studied by global characterization of genetic alterations by single nucleotide polymorphism (SNP) array for detection of high level amplification for HER-2/neu and EGFR. Pathological expression of HER-2/neu in curettage was detected in 23% which significantly correlated to high FIGO stage, non-endometrioid subtype, high grade and aneuploidy. In hysterectomy specimens, pathological HER-2/neu staining was seen in 13% which correlated significantly with high FIGO stage, non-endometrioid subtype, high proliferation and poor survival (p=0.009). Expression of EGFR was examined with three different antibodies, but none showed significant correlation with molecular markers or clinical phenotype. High level amplification of HER-2/neu or EGFR was seen in only one out of 76 samples, respectively. High proliferation estimated in tumors from hysterectomy specimens showed independent prognostic impact and was superior to estimation in curettage specimens as a prognostic marker. In conclusion, high level amplification of HER-2/neu or EGFR is infrequent in endometrial cancer. Pathological HER-2/neu staining identifies endometrial carcinomas with an aggressive phenotype, high proliferation and patients with poor survival in a population based setting. These results motivate further clinical trials with trastuzumab based on HER-2/neu status in endometrial carcinomas.

Pathologic expression of p53 or p16 in preoperative curettage specimens identifies high-risk endometrial carcinomas.

OBJECTIVE: The purpose of this study was to investigate the prognostic impact of p53 and p16 expression in curettage material from patients with endometrial carcinoma. STUDY DESIGN: Preoperative curettage material from a population-based series of 236 endometrial carcinomas from Norway with long and complete follow-up was studied immunohistochemically for p53 and p16 expression. RESULTS: Pathologic expression of p53 and p16 was seen in 24% and 25%, respectively, and was significantly correlated with high International Federation of Gynecology and Obstetrics (FIGO) stage and serous/clear cell histologic subtypes. Pathologic p53 expression showed significant correlation with postmenopausal status, high grade, high tumor cell proliferation, and aneuploidy. Patients with normal expression had 85% 5-year survival compared with 51% and 50% when pathologic expression of p53 and p16, respectively. Five-year survival for patients with 2 pathologic markers was 13%, compared with 67% and 91% for 1 or no pathologic markers, respectively. CONCLUSION: Pathologic expression of p53 and p16 in curettage material identifies high-risk endometrial carcinoma patients with poor prognosis.