ABSTRACT Background The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway is involved in growth regulation, proliferation control and metabolism in renal cell carcinoma (RCC). In our prospective pilot study, we determined whether common genetic variations in the AKT/ PI3K, FRAP1 (encoding mTOR) are associated with clinical outcomes in RCC patients who underwent palliative therapy with everolimus. Patients and methods Our pilot study was designed to assess everolimus efficacy in RCC patients relapsed after TKI inhibitors (sunitinib and/or sorafenib). Patients were treated with everolimus 10 mg daily orally until disease progression. The genomic DNA was extracted from formalin-fixed, paraffin-embedded primary tumor RCC tissues. 12 potentially functional SNPs in 4 key genes (AKT1, AKT2, FRAP1, PIK3CA) were determined using a real-time PCR genotyping assay and analyzed for association with response to therapy, progression free survival (PFS) and overall survival (OS). Results Median age of 45 enrolled patients was 62 years (range, 41–78). At a median follow-up duration of 8,6 months, the 6-month PFS rate was 53.3%. Partial response was observed in 4,4% (2/45) of the patients. Median PFS was significantly prolonged in the PIK3CA rs6443624 for the CC genotype in comparison to the AA/AC genotype (8.9 months versus 5.5 months, log rank, p= 0.0157). In the multivariate analysis elevated corrected serum calcium and PIK3CA rs6443624 for the AA/AC genotype were unfavorable predictors of PFS (HR 5.25; 95% CI, 1.75–15.75 and HR 3.48; 95%CI, 1.47–8.25, respectively, p Conclusion These results suggest that PIK3CA rs6443624 genetic variation in PI3K/AKT/mTOR pathway may modulate clinical outcomes in patients with RCC who undergo chemotherapy with everolimus. Further clinical studies are needed to confirm these findings. Disclosure All authors have declared no conflicts of interest.

ABSTRACT Background Qualification of patients with advanced ovarian cancer (AOC) to treatment with primary or interval debulking surgery (IDS) is the subject of controversy. The aim of this study was to assess the expressions of selected proteins of apoptosis to the effects of neoadjuvant chemotherapy (NAC) in patients with AOC. Material and methods We evaluated 60 consecutive patients with AOS (FIGO stage IIIC-IV) treated with NAC, retrospectively. Formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained for expression of p53 and survivin in patients given platinum-based NAC undergoing IDS. The expression of survivin was adopted dichotomization by the median expression of the protein found total score (TS) equals 2. For low expression of survivin was TS ≤ 2, while high total score TS> 2 The positive and negative expression of p53 were used to dichotomization study group. Results Median age of 60 patients was 60 years. The optimal IDS was achieved in 69.1% (38/55). We observed significant difference in the percentage of stained nuclei (PS, p = 0.0002), the intensity of staining (IS, p = 0.0003) and TS (p = 0.0001) by comparing the expression of survivin in tumor tissue taken before and after NAC. The expression of p53 in tumor tissue before and after NAC was observed and significant difference was in PS, (p = 0.0424). There were no statistically significant difference in IS and the TS. Expression of survivin and p53 was not related to the results of IDS. Survivin expression was a prognostic factor in AOC patients treated with NAC (p = 0.0484). Expression of survivin and p53 proteins was not a predictor factor in AOC patients. Adverse factors affecting the PFS for AOC patients treated with NAC were: lack of optimal IDS and the lack of an objective response by RECIST criteria (respectively HR was 3.93 (95% CI, 2.07-7.46, p Conclusions High expression of survivin is a useful prognostic factor in patients treated with neoadjuvant chemotherapy for advanced ovarian cancer. This effect is more significant in patients with positive expression of p53. Disclosure All authors have declared no conflicts of interest.

ABSTRACT Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.

The aim of the studies was to determine the effect of addition of feed antibiotic flavomycin (100 mg in 1 kg of 5% premix - group C) or prebiotic BIO-MOS (cell of Saccharomyces cerevisiae yeasts, strain 1026, 0.1% in the first growing period - group E) on production results, blood biochemical parameters, morphometric intestine properties and composition of intestinal microflora in fatteners. During slaughter of 32 crossbred pigs, blood samples were collected and the following biochemical indices were determined. Segments of small intestine were collected and morphometric analysis was carried out. Post-mortem quantitative and qualitative bacteriological tests and quantitative mycological tests on the determination of the contents of small and large intestine were carried out. The comparable results of fattening and slaughter evaluation of pigs in the groups were obtained. Significantly lower HDL (P≤0.01) and higher ALT (P≤0.05) content in blood serum of E fatteners was found as compared to the animals from C group. In group C, as compared to group E, significantly higher (P≤0.01) height of epithelial cells of crypts in duodenum and significantly lower one (P≤0.01) in jejunum was found; the results for ileum were comparable. Application of Saccharomyces cerevisiae yeasts feeding caused a favourable increase of the number of lactic acid bacteria in the contents of intestines and a decrease of the content of bacteria from Enterobacteriaceae family, including Proteus vulgaris and hypha fungi. The employment of BIO-MOS in feeding occurred to be favourable from the production and animal health point of view and seems to be a suitable alternative to feed antibiotics.