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Background: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. Patients and methods: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged

Aim: Anthracyclines are first line drugs against cancer, but produce a well-known cardiomyopathy through multiple mechanisms, which also include, among many, Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species (ROS and RNS), posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late INa, the target of Ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late INa blunts anthracyclines cardiotoxicity. Methods: To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by M/B mode echocardiography and radial and longitudinal strain (RS and LS) were measured using 2D speckle-tracking ecocardiography, in C57/BL6 mice, 2-4 mo old, at day 0, and after 2 and 7 days of daily administration of Doxorubicin (Doxo, 2.17 mg/kg/day, ip). These measurements were repeated after 5 days of RAN treatment (750 mg/kg/day, a dose comparable to the one used in humans) iniziated at the end of Doxo treatment. Results: In our in vivo studies, after 7 days with Doxo, FS decreased to 50.5 ± 8.4%, p Conclusions: RAN post-treatment blunts cardiotoxic effects due to anthracyclines, as demonstrated by the normalization of the values of FS, EF and RS. It remains to explain the persistent abnormality of the LS. Disclosure: All authors have declared no conflicts of interest.

Aim: ErbB2 is overexpressed in about 25% of breast cancers. It modulates myocardial development and function in the heart. Trastuzumab (T), an anti-ErbB2 inhibitor, has improved the prognosis of patients with breast cancer, but is related to an increased risk of asymptomatic left ventricular (LV) dysfunction (3–34%) and heart failure (2–4%). The mechanisms of T cardiotoxicity are not entirely known and can include changes in Ca2+ regulation related to blockade of ErbB2. Here, we aim at assessing whether ranolazine (RAN), diminishing intracellular Ca2+ through its inhibition of late Ina, blunts T cardiotoxicity in vivo. Methods: To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by echocardiography M-Mode in C57BL6 mice, 2-4 mo old, pretreated with RAN (750mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, alone and together with T (2.25 mg/kg/day ip), according to our well established protocol. Results: In our in vivo studies, after 7 days with T, FS decreased to 49 ± 1.5%, p < 0.01 vs 60 ± 0.5% (sham), and EF to 81 + 2%, p < 0.01 vs 91 ± 1% (sham). RAN alone did not change FS (59 ± 2%) nor EF 89 ± 1%. Interestingly, in mice treated with RAN and T, RAN prevents the reduction of EF and FS vs T alone (FS was 58 ± 1%, EF was 90 ± 1%, p = 0.01 and p < 0.01 respectively). Conclusions: In our mouse model, T produces LV dysfunction and RAN blunts T cardiotoxic effects. We plan to test RAN as a cardioprotective agent with other target-therapy drugs in our experimental models and to define the mechanisms of cardioprotection.

Background Doxorubicin (DOX) produces a well-known cardiomyopathy through multiple mechanisms, which include, among many, Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. DOX generates Reactive Oxygen and Nitrogen Species (ROS and RNS), posing the heart at increased demand for oxygen, setting the stage for metabolic ischemia that also activates late INa, target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) prevents DOX cardiotoxicity. Methods We measured left ventricular (LV) function with fractional shortening (FS) by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, alone and together with DOX (2.17mg/kg/day ip), according to our well established protocol. Hearts were then excised, mRNA expression was analyzed by qRT- PCR, interstitial fibrosis with picrosirius red staining. By Western blotting, we measured the activation of the apoptotic pathway. Results After 7 days with DOX, FS decreased to 50 ± 2%, p = .002 vs 60 ± 1% (sham). RAN alone did not change FS (59 ± 2%). Interestingly, in mice treated with RAN + DOX, the reduction in FS was milder: 57 ± 1%, p = 0.01 vs DOX alone. DOX-cardiotoxicity was accompanied by significant elevations in ANP (1000 folds), BNP (500 folds), CTGF (26 folds) and MMP2 (81 folds) mRNAs, while co-treatment with RAN significantly lowered these same genes compared to DOX. The alterations in extracellular matrix remodeling were confirmed by an increase of interstitial collagen with DOX (3.66%), p = .004 vs 2.19% (sham), which was normal in hearts co-treated with RAN (2.02%, p = .0002 vs DOX). Finally, the levels of PARP and pro-Caspase 3 were significantly decreased in DOX (indicating activation of apoptosis) but not in RAN + DOX. Conclusions In mice, RAN prevents DOX cardiotoxic effects. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in mice, and to better characterize the cardioprotective mechanisms of RAN in these settings. Disclosure All authors have declared no conflicts of interest.

Forty-five ovarian cancer patients were submitted to abdominopelvic computed tomography after intraperitoneal administration of soluble contrast in large fluid volumes (3 liters of normal saline) (IPC-CT), for a total of 66 exams. In all cases standard abdominopelvic CT scanning had previously missed the presence of disease. Peritoneal access was achieved by a temporary Teflon catheter inserted blindly. No major complications related to peritoneal access or fluid administration occurred. Laparotomy was performed in all cases to evaluate accuracy of this new diagnostic procedure. Overall, 32/66 exams showed no abnormal findings. In 9/32 cases persistence of disease was demonstrated by laparotomy. The remaining 34 exams were suggestive of persistence of tumor. In 19 cases CT scan showed nodular images or peritoneal thickness. Persistence of disease was confirmed by laparotomy in all instances. In 15 cases only an abnormal diffusion of soluble contrast into peritoneum (suprahepatic, anterior, or parietocolic region) was demonstrated. In 11/15 persistence of tumor was found at laparotomy. To summarize, IPC-CT revealed persistence of tumor in 30/39 cases (77% sensitivity). Positive results were predictive of persistence of disease in 30/34 cases (88% specificity). This new procedure was able to detect persistence of disease in most of our patients showing negative standard CT (30/39 vs 0/39; P10E-8) and its diagnostic accuracy was even better than standard CT+serum tumor markers (30/39 vs 16/39; P0.001). In conclusion, IPC-CT could be very effective in monitoring response to treatment and could markedly reduce the number of ovarian cancer patients requiring second-look laparotomy.

e11040 Background: Anti-ErbB2 therapies are associated with increased risk of left ventricular (LV) dysfunction. Trastuzumab increases the frequency of asymptomatic decrease in LV ejection fraction (LVEF) by 3-18%, and the risk of heart failure (HF) by 2-4%. The newer ErbB2 antibody rhuMAb 2C4 (pertuzumab) seems to affect ligand induced ErbB signaling in a more direct fashion, affecting EGFR/ErbB2 dimerization; yet, its cardiac side effects are only beginning to emerge. Here, we test whether the murine 2C4 induces cardiac dysfunction in normal mice. Methods: In vivo cardiac function was measured with LV fractional shortening (FS) by M-mode echocardiography in sedated C57BL/6 mice (2-4 mo. old) at day 0, and after 2 and 6 days of daily i.p. administration of 2C4 (2.25 μg/g/day) or doxorubicin (Doxo, 2.17 μg/g/day) as a positive control, and in sham animals. With Speckle Tracking echocardiography (ST) we also evaluated radial myocardial strain (%), a very sensitive parameter which can predict LV dysfunction...

e13612 Background: The mTOR inhibitor temsirolimus is being evaluated for anticancer efficacy in hundreds of clinical trials and is approved for treatment of advanced renal cell carcinoma. The PI3K...