Patterns of Recurrence, Long-term Survival and Toxicity Analysis of Endometrial Adenocarcinoma Patients Reclassified Under the Recent ESMO-ESGO-ESTRO Stratification: Seven-Year Results From a Single Institution.

AIM: The aim of this study was to report the patterns of recurrence, locoregional control, and survival of patients diagnosed with endometrial adenocarcinomas over a 7-year period after reclassifying them under the recent ESMO-ESGO-ESTRO (European Society of Medical Oncology/European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology) consensus classification. METHODS: Archives of a single institution from 2008 to 2014 were studied and patients with stages I-II endometrial adenocarcinoma were reclassified as per the new classification for uniformity. On magnetic resonance imaging, if found to be stage I, total abdominal hysterectomy with bilateral salpingo-oophorectomy alone was performed. The indications for adjuvant external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) were based on standard recommendations. Survival was calculated from Kaplan-Meier curves, and toxicity was recorded using Common Terminology Criteria for Adverse Events version 3. RESULTS: Of the 132 patients registered, 101 patients were included for analysis. A total of 18 patients have died, and information on outcome is available for 84% of patients. Five patients were metastatic at presentation. Five patients received definitive EBRT + intracavitary brachytherapy because of surgical inoperability, four of whom are disease-free locoregionally with median overall survival of 33.8 months. Of the 91 patients operated on, the incidence of low, intermediate, high-intermediate, and high risk was 34%, 29%, 2%, and 19%, whereas 16% were stage III. The overall recurrence rates were 10%, 15%, and 23% for low, intermediate, and high risk, respectively. With median follow-up of 32 months (range, 2-93 months), the disease-free survival for low, intermediate, and high risk and stage III were 92%, 81%, and 64% and 55%, whereas the mean survival for the same groups were 53, 44, and 34 and 22 months, respectively (P = 0.047). External beam radiotherapy resulted in significantly higher proctitis than VBT alone (P = 0.02). The median time to cystitis, proctitis, and enteritis were 27, 19, and 28 months, respectively. CONCLUSIONS: Recurrence rates, survival rates, and the patterns of recurrence are comparable with published literature and partly validates the ESMO-ESGO-ESTRO consensus statement. Addition of EBRT significantly increases risk of late proctitis as compared with VBT alone.

Ellagic acid inhibits PDGF-BB-induced vascular smooth muscle cell proliferation and prevents atheroma formation in streptozotocin-induced diabetic rats.

Plant-derived polyphenolic compounds have beneficial health effects. In the present study, we determined the ability of ellagic acid (EA) to prevent platelet-derived growth factor-BB (PDGF-BB)-induced proliferation of primary cultures of rat aortic smooth muscle cells (RASMCs). We also determined the ability of EA to prevent atherosclerosis in streptozotocin-induced diabetic rats. Proliferation of cells was measured via Alamar Blue assay and through propidium iodide-based cell cycle analysis in flow cytometer. Reactive oxygen species (ROS) were measured via 2',7'-dichlorofluorescin diacetate and Amplex red methods. Expression of proliferation markers and activation of kinases were assessed by immunoblot analysis. Cotreatment of primary cultures of RASMCs with 25 µmol/L of EA significantly reduced PDGF-BB (20 ng/ml)-induced proliferation by blocking S-phase entry. EA effectively blocked PDGF receptor-ß (PDGFR-ß) tyrosine phosphorylation, generation of intracellular ROS and downstream activation of extracellular signal-regulated kinase 1/2. It also blocked PDGF-BB-induced expression of cyclin D1. Computational molecular docking of EA with the PDGFR-ß-PDGF-BB complex revealed two putative inhibitor binding sites which showed similar binding energies with the known PDGFR-ß inhibitor AG1295. In diabetic rats, supplementation of diet with 2% EA significantly blocked diabetes-induced medial thickness, and lipid and collagen deposition in the arch of aorta. These were assessed through haematoxylin and eosin, Oil Red O and Masson's trichome staining, respectively. EA treatment also blocked cyclin D1 expression in medial smooth muscle cells in experimental animals. Thus, EA is effective in reducing atherosclerotic process by blocking proliferation of vascular smooth muscle cells.