Intraluminal tumor cells and prognostic accuracy of endometrial cancer stage criteria: A multi-institution study.

OBJECTIVE: Endometrial cancer stage is a strong prognostic factor; however, the current stage classification does not incorporate transtubal spread as determined by intraluminal tumor cells (ILTCs). We examined relationships between ILTCs and survival outcomes according to histological subtype and stage and examined whether identification of ILTCs improves prognostic accuracy of endometrial cancer staging. METHODS: We conducted a retrospective cohort study of women diagnosed with endometrial cancer at five academic hospitals between 2007 and 2012. Pathologists determined ILTC presence (no vs. yes) and location (free in lumen vs. attached to epithelial surface) based on pathology review of hematoxylin and eosin-stained sections of fallopian tubes. Associations between ILTCs with time to recurrence (TTR) and overall survival (OS) were examined with Cox proportional hazards models adjusted for other prognostic factors. Model discrimination metrics were used to assess the addition of ILTCs to stage for prediction of 5-year TTR and OS. RESULTS: In the overall study population (N = 1303), ILTCs were not independently associated with TTR (HR = 0.95, 95% CI = 0.69-1.32) or OS (HR = 0.97, 95% CI = 0.72-1.31). Among 805 women with stage I disease, ILTCs were independently associated with worse TTR (HR = 2.31, 95% CI = 1.06-5.05) and OS (HR = 2.16, 95% CI = 1.14-4.11). Upstaging early-stage cases with ILTCs present did not increase model discrimination. CONCLUSION: While our data do not suggest that endometrial cancer staging guidelines should be revised to include ILTCs, associations between ILTCs and reduced survival observed among stage I cases suggest this tumor feature holds clinical relevance for subgroups of endometrial cancer patients.

Associations Between Intraluminal Tumor Cell Involvement in Serially Examined Fallopian Tubes and Endometrial Carcinoma Characteristics and Outcomes.

Approximately 12% of routinely examined fallopian tubes of endometrial carcinoma (EC) cases have intraluminal tumor cells (ILTCs). ILTC associations with EC characteristics and outcomes are understudied, and unknown in serially examined and embedded tubal fimbriae. Glass slides of serially examined and embedded tubal fimbriae for 371 EC cases were independently reviewed by 2 pathologists who recorded ILTC presence and characterized them as mucosal if involved and floating if not. Disagreements were reviewed by a third pathologist, and agreement between any 2 determined final ILTC status. Clinico-pathologic associations and ILTC presence were tested for significance ( P <0.05) by univariable analysis, and stage and histotype determinants were included in a multivariable analysis. The Kaplan-Meier estimates and log-rank tests compared overall and EC-specific survival, and Cox proportional regression estimated hazard ratios. ILTCs were present in 56 (15.1%) cases: 30 mucosal and 26 floating. FIGO stage 3/4, lymph-vascular space invasion, deep myometrial invasion, nonendometrioid histotype, and adjunctive chemotherapy were significantly associated with ILTC presence, and only stage was significant in the multivariable analysis. Overall, 61 women died: 30 of whom died of EC. ILTCs were nonsignificantly associated with higher overall and EC-specific mortality and mucosal ILTCs had the highest hazard ratios (1.64 and 1.89, respectively). Serially examined and embedded tubal fimbriae have a higher prevalence of ILTCs than routinely examined tubes, and high FIGO stage is an independent determinant. A prognostic effect was not found, but the higher trending hazard ratios suggest additional study is needed to determine whether ILTCs and in particular mucosal ILTCs adversely affect prognosis.

The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors.

Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.