Drug absorption, sufficient and reproducible bioavailability and/or pharmacokinetic profile in humans are recognized today as one of the major challenges in oral delivery of new drug substances. The ...issue arose especially when drug discovery and medicinal chemistry moved from wet chemistry to combinatorial chemistry and high throughput screening in the mid-1990s. Taking into account the drug product development times of 8–12 years, the apparent R&D productivity gap as determined by the number of products in late stage clinical development today, is the result of the drug discovery and formulation development in the late 1990s, which were the early and enthusiastic times of the combinatorial chemistry and high throughput screening. In parallel to implementation of these new technologies, tremendous knowledge has been accumulated on biological factors like transporters, metabolizing enzymes and efflux systems as well as on the physicochemical characteristics of the drug substances like crystal structures and salt formation impacting oral bioavailability. Research tools and technologies have been, are and will be developed to assess the impact of these factors on drug absorption for the new chemical entities.
The conference focused specifically on the impact of compounds with poor solubility on analytical evaluation, prediction of oral absorption, substance selection, material and formulation strategies and development. The existing tools and technologies, their potential utilization throughout the drug development process and the directions for further research to overcome existing gaps and influence these drug characteristics were discussed in detail.
Objectives To develop a risk prediction model to preoperatively discriminate between benign, borderline, stage I invasive, stage II-IV invasive, and secondary metastatic ovarian tumours.Design ...Observational diagnostic study using prospectively collected clinical and ultrasound data.Setting 24 ultrasound centres in 10 countries.Participants Women with an ovarian (including para-ovarian and tubal) mass and who underwent a standardised ultrasound examination before surgery. The model was developed on 3506 patients recruited between 1999 and 2007, temporally validated on 2403 patients recruited between 2009 and 2012, and then updated on all 5909 patients.Main outcome measures Histological classification and surgical staging of the mass.Results The Assessment of Different NEoplasias in the adneXa (ADNEX) model contains three clinical and six ultrasound predictors: age, serum CA-125 level, type of centre (oncology centres v other hospitals), maximum diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites. The area under the receiver operating characteristic curve (AUC) for the classic discrimination between benign and malignant tumours was 0.94 (0.93 to 0.95) on temporal validation. The AUC was 0.85 for benign versus borderline, 0.92 for benign versus stage I cancer, 0.99 for benign versus stage II-IV cancer, and 0.95 for benign versus secondary metastatic. AUCs between malignant subtypes varied between 0.71 and 0.95, with an AUC of 0.75 for borderline versus stage I cancer and 0.82 for stage II-IV versus secondary metastatic. Calibration curves showed that the estimated risks were accurate.Conclusions The ADNEX model discriminates well between benign and malignant tumours and offers fair to excellent discrimination between four types of ovarian malignancy. The use of ADNEX has the potential to improve triage and management decisions and so reduce morbidity and mortality associated with adnexal pathology.
To assess the long-term oncological outcome and the fertility of young women with early-stage epithelial ovarian cancer (ES/EOC) treated with fertility-sparing surgery (FSS).
All patients treated ...with FSS for ES/EOC in two Italian centers were considered for this analysis. Univariate and multivariate analyses were used to test demographic characteristics and clinical features for the association with overall survival (OS), recurrence-free survival (RFS) and fertility.
From 1982 to 2010, 240 patients with malignant ES/EOC were treated with FSS in two tertiary centers in Italy. At a median follow-up of 9 years, 27 patients had relapsed (11%) and 11 (5%) had died of progressive disease. Multivariate analysis found only grade 3 negatively affected the prognosis of patients hazard ratio (HR) for recurrence: 4.2, 95% confidence interval (CI): 1.5–11.7, P=0.0067; HR for death: 7.6, 95% CI: 2.0–29.3, P=0.0032. Grade 3 was also significantly associated with extra-ovarian relapse (P=0.006). Of the 105 patients (45%) who tried to become pregnant, 84 (80%) were successful.
Conservative treatment can be proposed to all young patients when tumor is limited to the ovaries, as ovarian recurrences can always be managed successfully. Patients with G3 tumors are more likely to have distant recurrences and should be closely monitored.
To test the efficacy of levonorgestrel-release intrauterine device (LNG-IUD) plus gonadotropin-releasing hormone (GnRH) for treating women aged <40 years with atypical endometrial hyperplasia (AEH) ...or presumed International Federation of Gynecology and Obstetrics stage IA limited to the endometrium, well differentiated (G1), endometrioid endometrial cancer (EC), who wish to preserve their fertility.
A prospective observational study was conducted. Treatment consisted on the insertion of an LNG-IUD for 1 year plus GnRH analogue for 6 months.
From January 1996 to June 2009, 20 and 14 patients with AEH and EC, respectively, were studied. Complete response rate was 95% in patients with AEH and 57.1% in women with EC-G1. A progression of the disease was observed in one (5%) and in four patients (28%) with AEH and EC, respectively. Four of 20 patients with AEH and 2 of 14 with EC-G1 experienced recurrences. The average relapse time was 36 months (range: 16–62 months). All of them were alive without evidence of disease at the last follow-up, mean: 29 months (range: 4–102 months). Nine women achieved 11 spontaneous pregnancies.
The combined treatment showed effectiveness in a substantial proportion of patients with AEH and EC. Close follow-up during and after treatment is crucial.
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