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Despite progress in primary treatment of patients with advanced ovarian cancer, the majority develop recurrence of the disease. A platinum salt treatment, either as monotherapy or in combination with another cytostatic agent, is indicated for patients who have relapsed 6 or more months after primary treatment and thus have platinum-sensitive relapse. Because repeated use of paclitaxel treatment may lead to substantial neurotoxicity, the combination of gemcitabine with carboplatin represents a suitable treatment option, which is widely used in common clinical practice in the Czech Republic and Slovakia. This non-interventional, prospective study observed the effectiveness and tolerability of second-line treatment with gemcitabine and carboplatin in patients with platinum-sensitive relapse of ovarian cancer in routine clinical practice. The primary endpoint was to evaluate the survival and secondary endpoints were to evaluate time to disease progression, objective tumor response rate, and treatment toxicity. Patients were enrolled to planned second-line treatment with gemcitabine and carboplatin (gemcitabine 1000 mg/m2 and carboplatin AUC 5 on Day 1, and gemcitabine 1000 mg/m2 on Day 8 of a 21-day cycle) for platinum-sensitive relapse of ovarian cancer as a part of routine clinical practice and followed for 12 months. The events (death, tumor progression), tumor response, and maximal grades of toxicity were recorded according to common clinical practice. Survival time (using Kaplan-Meier analysis) and objective tumor response rate were calculated using data forms, and a subgroup analysis was performed using log rank tests for time-to-event endpoints; p-values were also calculated. Response rates were calculated for the whole population; for the subgroups, the Fisher's exact test was performed and only p-values were calculated. Between January 2004 and June 2005, 53 patients were enrolled in the study. The median age was 57 years and 96% of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and 1 at baseline. Approximately 91% of patients were originally diagnosed with stage III or IV; 60% of patients had disease free intervals (DFIs) of 12 or more months from previous therapy, and the additional 40% less than 12 months. The 1-year survival rate was 83%. Median survival time was not determined within the 12-month period following the start of the treatment study due to the limited duration of follow-up. Objective tumour response rate was 67.3%. Most common reasons for discontinuation of therapy were "Planned treatment completed" (53%) and "Tumor progression" (11%). Most common toxicities were leukopenia, anaemia, neutropenia, and thrombocytopenia; grades 3 and 4 of these toxicity types did not exceed 30%. Febrile neutropenia was recorded in two patients. Most common non-haematological toxicities were nausea and vomiting, fatigue, and neuropathy; grades 3 and 4 of these were below 6%. Results on time to disease progression are not published due to inconsistent statistical analysis of reported data. Based on this observation from routine clinical practice, which corresponds with previously published results from controlled clinical trials, the gemcitabine and carboplatin combination seems to be a suitable therapeutic option for patients with platinum-sensitive relapse of ovarian cancer.

e15525 Background: Platinum-based chemotherapy led to stimulation of primarily damaged antioxidant defence system and lipid peroxidation reduction in MUC patients as we published before. The aim of...

e15567 Background: TGCTs represent a highly curable disease, however, a small proportion of patients develop disease recurrence. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homol...

e15558 Background: Accumulating data suggest that the plasma levels of some cytokines might reflect the activity of the immune system against the tumor and correlate to prognosis. Cytokines may inf...

9611 Background: Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development. SN-38 is excreted in glucuronidated form into...

e15599 Background: We investigated cytokines and angiogenic factors (CAFs) in patients with testicular germ cell tumors (TGCTs). We aimed to link the CAF profile to type of response to chemotherapy and select candidate prognostic and predictive markers for further study. Methods: In the presented study, plasma from 99 patients (pt) with TGCTs treated with first line (95 pt) or salvage (4 pt) chemotherapy was collected. The concentrations of 51 plasma CAFs were measured pre-treatment (n = 80) and on day 22 (n = 60) using multiplex bead arrays (Human Group I and II cytokine panels and TGF beta by Bio-Plex 200 system (Bio-Rad Laboratories, Hercules, CA). We used unsupervised clustering with self-organizing map (SOM) and k-means clustering to analyze CAF expression profiles. Results: Unsupervised clustering with self-organizing maps and k-means identified characteristic plasma cytokine profiles in different subgroups of patients according to response to chemotherapy and other clinical variables. Several cytokines were differentially expressed in patients with favourable and unfavorable response in serum before chemotherapy including IL-1b, IL-15, M-CSF, IL-4, IL-5, b-NGF, IL-10, MCP-3, FGF basic, IL-6, MIP-1a, GM-CSF, IL-17, IL-13, MIP1b, IL-8, SCF, IFN alfa, SCGFb, IL-2RA, IP-10, IL-16, TGFb-3. Similarly, following cytokines were differentially expressed in serum after 1st cycle of chemotherapy IL-1b, TGFb-3, LIF, TGFb-2, IL-16, IL-18, IL-2RA, MCP-3, IFN alfa, HGF, IL1a, MIF, SCF, IL-3, SCGFb, b-NGF, MIG, CTACK. Conclusions: CAF profiling with unsupervised clustering revealed clinically relevant differences in subgroups of TGCTs patients. We suggest that this platform may provide valuable insights into TGCTs biology, and could help to identify plasma cytokine signature for predicting treatment resistance.

4556 Background: CTCs are prognostic in several types of tumors and are easily accessible for repeat examination. TGCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. We investigated expression profiling of PB enriched for CTCs in TGCTs aimed to identify expression signature associated with treatment resistance. Methods: This prospective study included 30 patients (pt) treated with first line (27 pt) or salvage (3 pt) chemotherapy. CD45- peripheral mononuclear cells (PBMCs) were isolated from 10mL of PB on day 1 and on day 22 of first cycle of chemotherapy. Isolated PBMC were depleted of cells of hematopoietic origin (CD45+) using RossetteSep kit negative selection with anti-CD45 antibody. CD45-depleted PBMC represent compartment enriched for CTCs, as showed previously. RNA was extracted from CD45-PBMCs and the expression profiles were obtained using Roche NimbleGen microarrays. Data analysis was processed in R using a limma package followed by GO analysis and MetaCore pathway analysis. Results: Six patients achieved unfavorable response to chemotherapy (other than CR or PR with negative serum markers). We identified 1,506 and 211 genes that were expressed at significantly different levels (FDR

Background: There is an unmet need for noninvasive markers to identify patients with TGCTs most likely to benefit from treatment and to measure the effects of therapies. Cytokines can be easily identified and they have an important role on tumor initiation, growth, and progression. Prognostic and predictive values of 52 plasma CAFs in patients with metastatic renal cell carcinoma were recently investigated. Our endpoint was to find out relationship between established tumor markers beta-human choriogonadrotropin (HCG) and alphafetoprotein (AFP) with CAFs. Methods: We enrolled 47 patients with TGCTs treated by 1st line platinum based systemic chemotherapy. All patients received G-CSF support after chemotherapy (44 patients pegfilgrastim, 3 patients filgrastim). Fifty one plasma CAFs were analyzed before the 1st (47 patients) and before the 2nd cycle of chemotherapy (22 patients) using multiplex bead arrays (Human Group I and II cytokine panels and TGF beta by Bio-Plex 200 system, Bio-Rad Laboratories, Hercules, CA). HCG and AFP were measured by enhanced chemiluminescence immunoassay. CAFs were correlated to pretreatment serum levels of HCG and AFP. Spearman's correlation test was used to analyze the relationship between CAFs and tumor markers. We considered p Results: Median pretreatment AFP and HCG were 2.6 U/ml (range 0.9-13936.0 U/ml) and 5.5 mIU/ml (range 0.0-564261.0 mIU/ml), respectively. By the correlation analyses 4 from 51 pretreatment plasma CAFs were negatively and one positively correlated to pretreatment AFP. Negatively correlated CAFs were TGF-b1 (p=0.041), TGF-b3 (p=0.040), IL-7 (p=0.039) and G-CSF (p=0.016), positive correlation between pretreatment MIF (p=0.005) and pretreatment values of AFP was observed. We investigated, that pretreatment HCG had positive correlation to IL-2Ra (p=0.031), MIG (p=0.015), SCGF-b (p=0.045) and b-NGF (p=0.017), there was no negative elevation of pretreatment CAFs in correlation with pretreatment HCG. Additionally, we calculated ratio between pretreatment and postreatment values of CAFs. We investigated, that pretreatment HCG positively correlated to ratio values of several CAFs (IL-2Ra, p=0.009; IL-16, p=0.046; IL-18, p=0.014; SCGF-b, p=0.018; CTACK, p=0.004) and pretreatment AFP to RANTES (p=0.035), no negative relationships were observed. Conclusions: Several serum CAFs with significant correlation to pretreatment AFP and HCG were identified in this study. We suppose that this finding may be useful for further investigations, biological and clinical consequences of this correlation have to be find out. This work was supported by the Slovak Research and Development Agency under the contract No. APVV-0016-11. Citation Format: Daniela Svetlovska, Michal Mego, Dana Cholujova, Paulina Gronesova, Patrik Palacka, Usakova Vanda, Vera Miskovska, Bibiana Vetrakova-Krakovska, Jan Luha, Jozef Mardiak. Correlation between serum cytokine/angiogenic factors (CAFs) and tumor markers in testicular germ cell tumor patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4704. doi:10.1158/1538-7445.AM2013-4704

281 Background: The role of oxidative stress inpatients with MUC treated with GC is unknown. The objective of this ongoing study is to determinate plasma antioxidants, lipid peroxidation, and lipids in pts. with MUC before and after GC treatment, and to compare them with control. Methods: From May 2010 – January 2012, 42 MUC patients were enrolled into this study. The median of age was 65 years (range 44–81), median of metastasis sites was 2 (range 1–7). All patients were treated with gemcitabine 1000 mg/m2 i.v. days 1 and 8 with cisplatin 75 mg/m2 i.v. day 1, the new cycle of treatment started on day 22. Plasma samples were collected before and after 3 cycles of chemotherapy with GC. The control consisted of 22 subjects without cancer with age median 61 years (range 39–66). Results: In MUC patients, plasma γ-tocopherol before treatment were significantly lower (1.77±0.70 vs 2.13±0.70 μmol/L, P10-TOTAL (0.43±0.15 vs 0.56±0.16 μmol/L, P=0.003). TBARS concentrations were significantly decreased (5.76±1.32 vs 4.85±1.08 μmol/L, P=0.01). The concentrations of plasma lipids after GC were increased: Cholesterol (4.61±0.99 vs 5.47±1.21 mmol/L, P

Background GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients (pts) develop disease recurrence. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive GCTs. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these pts would have greater benefit from mTOR inhibition. Methods In December 2011, National Cancer Institute of Slovakia launched a one arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of Everolimus (E) in pts with refractory GCTs. The primary objective is to determine the efficacy of E in pts with refractory GCTs. The pts with radiological and/or serological proof of relapsed GCTs, who were not amenable to be cured by chemotherapy or surgery and who failed at least two platinum-based regimens or one platinum regimen in case of platinum-refractory disease or primary mediastinal non-seminomatous GCTs have been eligible. E has been administered at a dose of 10mg daily until progression or unacceptable toxicity. Results From December 2011, 4 patients have been enrolled. Median age of patients is 28 years. All patients were pretreated with at least 3 cisplatin-based therapy, three patients were absolute cisplatin refractory, progressed directly on cisplatin-based therapy. We observed no unexpected toxicity. One patient experienced pneumonitis grade 3, and dose reduction was needed. One patient progressed early, while three patients are still on treatment for 1 + , 3+ and 5+ months. Conclusion Our preliminary data suggests that, Everolimus is safe and well tolerated drug in patients with GCT. Efficacy data is warranted. Disclosure All authors have declared no conflicts of interest.

TPS4677 Background: GCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients (pts) develop disease recurrence. Because of insufficient results in the treatment of relapsed GCTs, evaluation of new treatments is a priority. Loss of the tumor suppressor gene PTEN (phosphatase and tensin homolog) marks the transition from intratubular germ cell neoplasias (ITGCN) to invasive GCTs. In the testis, PTEN was abundantly expressed in germ cells whereas it was virtually absent from 56% of seminomas as well as from 86% of embryonal carcinomas and virtually all teratomas. On the contrary, ITGCN intensely expressed PTEN, indicating that loss of PTEN expression is not in early event in GCTs development, but is associated with disease progression. PTEN inactivation is associated with dysregulation of PI3K/Akt pathway and increased mTOR signalling. We hypothesize that dysregulation of PI3K/Akt pathway due to PTEN inactivation in GCTs suggests that these pts could have greater benefit from mTOR inhibition. Methods: In December 2011, National Cancer Institute of Slovakia launched an one arm, two-staged phase II study aimed to evaluate the efficacy and toxicity of E in pts with refractory GCTs. The primary objective is to determine the efficacy of E in patients with refractory GCTs. Secondary objectives includes favourable response rate, time to progression and safety. The pts with radiological and/or serological proof of relapsed GCTs, who were not amenable to be cured by chemotherapy or surgery and who failed at least two platinum-based regimens or one platinum regimen in case of platinum-refractory disease or primary mediastinal non-seminomatous GCTs were eligible. All other standard inclusion and exclusion criteria for study of salvage treatment in refractory GCTs pts were applied. E will be administered at a dose of 10mg daily until progression or unacceptable toxicity. Assuming a response rate of clinical interest of ≥40%, a minimal response rate of 20%, a probability of 5% for rejecting an active drug, and a probability of 20% to further evaluate an ineffective drug, 18 pts will be enrolled into the first cohort. If

e15027 Background: Testicular germ-cell tumours (TGCTs) represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. PARP inhibitors represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate poly(ADP-ribose)polymerase-1 (PARP1) expression in TGCTs and to correlate expression patterns with clinico-pathological variables. Methods: In this translational study, tumor specimens from 124 patients with GCTs were identified. PARP1 expression was detected by immunohistochemistry using monoclonal antibody, scored by the multiplicative quickscore (QS) method and compared to PARP1 expression in testicular tissue of normal testis. The QS was calculated by multiplying the percentage score by the staining intensity score to yield a minimum value of 0 and a maximum value of 18. Based on the QS nuclear PARP1 expression was graded as low (0–9) or high (10–18). Results: We observed higher expression of PARP1 in testicular tumors compared to normal tissue of testis (mean QS = 10.04 vs. 3.60, p < 0.0000001). Mean QS ± SD for each histological subtype was following: intratubular germ cell neoplasia (ITGCN) = 18.00 ± 0.00, embryonal carcinoma = 9.62 ± 5.64, seminoma = 9.74 ± 6.51, yolc sac tumor = 7.8 ± 7.20, teratoma = 5.87 ± 5.34, and choriocarcinoma = 4.50 ± 8.33. The PARP1 overexpression (QS > 9) was most often detected in ITGCN (100% of specimen with PARP1 overexpression), seminona (52.6%), embryonal carcinoma (47.0%), yolc sac tumor (33.3%), teratoma (26.7%), and choriocarcinoma (25.0%), compared to 1.9% of normal testicular tissue specimen. There was no association between PARP1 expression and clinical variables. Conclusions: PARP1 overexpression is an early event in the development of TGCTs. We suggest that PARP1 could represent a novel treatment target in TGCTs and the assessment of PARP1 expression in tumor samples may lead to the consideration of TGCTs patients for PARP inhibitor therapy.

e15017 Background: Patients (pts) with platinum-refractory germ cell tumors (GCT) have very poor prognosis. Induction of angiogenesis is essential for tumor growth and metastasis. Vascular endothel...