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compared with 7.3 months (IQR 4.5–9.2) for FOLFIRINOX (p = 0.02). Median overall survival was 4.9 months (IQR 2.3–9.5) for first-line gemcitabine-based treatment and 10.5 months (IQR 7.0– 13.2) for first-line FOLFIRINOX therapy (p = 0.002). Patients who received FOLFIRINOX had better survival across all subgroups. Inpatient admissions and dose reductions were more frequent with FOLFIRINOX, but the difference between the two regimens was not statistically significant. FOLFIRINOX was successfully administered as outpatient therapy for some patients. Interpretation: FOLFIRINOX remains a suitable first-line option in patients with metastatic pancreatic cancer and good performance status, even in a resource-poor country where diagnostic and supportivecare facilities may be suboptimum and cost is a limitation. http://dx.doi.org/10.1016/j.ejca.2014.03.262
P0221 THE NEGATIVE REGULATORY ROLE OF PGC-1A IN PATHOGENESIS OF HEPATOCELLULAR CARCINOMA R. Liu a,*, C. Zhang c, K. Zeng b, C. Zhang b, Y. Ba a. a Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China, b School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China, c Department of Biochemistry, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, China Background: Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a) plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to energy metabolism in various tumours. We investigated the regulatory role of PGC-1a in the pathogenesis of hepatocellular carcinoma (HCC). Methods: Differences in PGC-1a mRNA levels between normal human liver and HCC tissue were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Knockdown of PGC-1a was done by RNA interference (RNAi) in the human liver cell line L02, and overexpression of PGC-1a was done by transfecting the human hepatocarcinoma cell line HepG2 with adenovirus encoding PGC-1a cDNA (Ad-PGC-1a). Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, expression levels of 21,400 genes were detected by microarray. Findings: PGC-1a expression was significantly lower in HCC compared with normal liver tissues. After knockdown of PGC-1a expression in L02 cells, cells reverted to an immature and de-differentiated morphology exhibiting cancerous tendency. Apoptosis occurred in HepG2 cells after being transfected with Ad-PGC-1a. Microarray analysis showed consistent results. Interpretation: These results suggest that PGC-1a plays an important role in the formation and development of HCC, and that PGC1a may be a potential therapeutic target for HCC. http://dx.doi.org/10.1016/j.ejca.2014.03.265
P0222 STEM CELL MARKERS RADIORESISTANCE
PREDICT
ORAL
CANCER
H.-Y. Lin a,c, S.-K. Hung a,c, M.-S. Lee a,c, W.-Y. Chiou a,c, W.-L. Hsu b,c, D.-W. Liu b,c, M.W.-Y. Chan d,e,f,* . a Department of
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Radiation Oncology, Buddhist Dalin Tzu Chi Hospital, Taiwan, Department of Radiation Oncology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan, c School of Medicine, Tzu Chi University, Hualien, Taiwan, d Institute of Molecular Biology, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, e Department of Life Science, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan, f Human Epigenomics Center, National Chung Cheng University, Min-Hsiung, Chia-Yi, Taiwan b
Background: Radiotherapy is an important modality in treating head and neck cancers. Clinically, predicting radiation response is essential. Stem-like cancer cells have been reported as having a high degree of radiation resistance. However, whether stem cell markers, such as OCT4 and NANOG, can predict clinical outcomes in patients with resected-then-irradiated oral cancer is still unknown. Methods: We established a radioresistant cell subline, OML1_R, from OML-1 oral cancer cells by using sequent 5-Gy irradiations, with a total dose of 50 Gy. Between each irradiation, cancer cells were allowed to regrow for 5–7 days, then PCR was used to detect mRNA expression of stem cell markers. Paraffin-embedded human tissue sections were used for validation of the role of stem cell markers in predicting post-resection, post-irradiation clinical outcomes. Findings: A 10-Gy radiation stress test confirmed the radioresistance of OML1_R. PCR showed upregulation of OCT4 (4-fold) and NANOG (6-fold) in OML1_R cells compared with their parent OML-1 cells. In 44 patients with resected-but-close-margined oral cancer, higher locoregional control was observed in the low OCT4/ NANOG expression group compared with the high OCT4/NANOG expression group (92% versus 62%, p = 0.03). Multivariate analysis confirmed that this stem cell marker is an independent factor in predicting locoregional control (adjusted hazard ratio 6.76; 95% confidence interval 1.87–24.43; p = 0.04). Interpretation: Our data showed that stem cell markers OCT4 and NANOG are potential bio-predictors in patients with resected-thenirradiated oral cancer. http://dx.doi.org/10.1016/j.ejca.2014.03.266
P0223 CYP3A4*18 AND CYP3A5*3 GENE POLYMORPHISMS AND IMATINIB RESISTANCE IN MALAYSIAN PATIENTS WITH CHRONIC MYELOID LEUKAEMIA R. Ankathil a,*, A.A. Zian a, Z.M. Nizam a, H. Azlan a, A.A. Baba b. a Human Genome Center, Universiti Sains Malaysia, Kota Bharu, Kelantan, Malaysia, b International Medical University, Kuala Lumpur, Malaysia Background: Although imatinib mesylate (IM) has shown excellent efficacy as first-line therapy for treatment of chronic myeloid leukaemia (CML), resistance to IM has emerged as a daunting clinical problem. Enhanced drug metabolism has been proposed as a hostdependent mechanism of drug resistance. IM is a substrate of CYP3A4 and CYP3A5 metabolism enzymes. CYP3A4*18 and CYP3A5*3 polymorphisms exhibit inter-individual differences in mRNA expression levels; however, the clinical significance of these polymorphisms on IM resistance remains unclear. We investigated the association between CYP3A4*18 and CYP3A5*3 polymorphisms in mediating IM response in Malaysian patients with CML. Methods: One hundred and one CML patients (48 IM good response, 53 IM resistant) initially treated with 400 mg IM daily for a minimum of 18 months were enrolled in this case–control study. Response criteria were based on European Leukemia Net recommendations. Genotyping was carried out for CYP3A4*18 (rs28371759) and
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CYP3A5*3 (rs776746) polymorphisms by polymerase chain reaction– restriction fragment-length polymorphisms (PCR–RFLP). Logistic regression analysis was done to calculate risk association using EpiInfo 7.0 software. Findings: The distribution of CYP3A5*3 genotype was 41.5% (GG), 37.7% (GA), and 20.8% (AA) among the IM-resistant group, compared with 45.8% (GG), 33.3% (GA), and 20.9% (AA) among the IM-good-response group. There was no significant difference in genotype frequencies between the two groups (p = 0.91). On evaluating the risk of IM resistance, the frequencies of homozygous TT genotype and heterozygous TC variant of CYP3A4*18 were insignificantly associated with IM response (p = 0.25). Odds ratio was 0.34 (95% confidence interval [CI] 0.062–1.827, p = 0.19) for the CYP3A4*18 heterozygous variant, 1.25 (95% CI 0.516–3.026, p = 0.69) for the CYP3A5*3 heterozygous variant, and 1.10 (95% CI 0.389–3.114, p = 0.86) for the CYP3A5*3 homozygous variant. Interpretation: Our preliminary results suggest a lack of association between CYP3A4*18 and CYP3A5*3 gene polymorphisms and IM resistance. This study is being continued with a larger number of patients.
http://dx.doi.org/10.1016/j.ejca.2014.03.267
P0224 A NOVEL, SMALL MOLECULE INHIBITOR, MSU-1001, IN ANDROGEN-SENSITIVE PROSTATE CANCER CELL LINES P.K. Bhavar a,*, M.R. Yadav a, S.S. Dinavahi b, S. Nyayapathy b. Department of Pharmacy, M.S. University of Baroda, Gujarat, India, b Biological Research Lab, Incozen Therapeutics, Andrapradesh, India a
Introduction: Prostate cancer is one of the leading causes of cancerrelated death in men worldwide. Current treatment options are limited to traditional chemotherapy, surgery, radiation, or hormone therapy, which often have unwanted side effects. There is a need to develop safer molecules that attenuate tumour progression without adversely affecting the overall quality of life. We report the in vitro activity of a novel, synthetic, small molecule, with potential to be a lead candidate for the treatment of prostate cancer. Methods: A library of novel small molecule inhibitors was developed through rational drug design. A pyrrolo-pyrimidine derivative (MSU-1001) was identified as a potential lead molecule. Prostate and colon cancer cell lines (LNCap, HT-29, and HCT-8) were obtained from the American Type Culture Collection (ATCC). Cells were incubated with various concentrations of MSU-1001 for 72 h. Growth inhibition was determined colorimetrically on a plate-reader using a 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Findings: Colon cancer cell lines HCT-8 and HT-29 were used in conjunction with the androgen-sensitive human prostate adenocarcinoma cell line, LNCaP, to investigate the specificity of MSU-1001 on tumour type. Among the library of compounds tested, MSU-1001 was pursued based on its anti-proliferative activity in LNCaP cells. Addition of MSU-1001 to LNCaP cells resulted in a dose-dependent inhibition of proliferation (GI50 = 161 nM) with a near-complete inhibition of cell growth noted at 10 lM. By contrast, GI50 of gemcitabine was more than 6-fold higher (GI50 = 1.21 lM) in LNCaP cells. Additionally, GI50 of MSU-1001 in HCT-8 and HT-29 was 1.8 and 8.7 lM, respectively, indicating relative specificity of MSU-1001 against prostate cancer. Interpretation: These data show the therapeutic potential of MSU-1001 in prostate cancer. Combination studies of MSU-1001 with
testosterone, 17b-estradiol, and dehydroepiandro-stenone in androgen-sensitive and insensitive prostate cancer cell lines are currently ongoing.
http://dx.doi.org/10.1016/j.ejca.2014.03.268
P0225 TELEMEDICINE: A NOVEL APPROACH OF BRINGING ONCOLOGY CARE CLOSER TO THE PATIENT D.M. Poprawski *, J. Adams, A. Bassal. Country Health South Australia Local Health Network (CHSALHN), Elizabeth Vale, SA, Australia Background: In Australia, long distances have motivated oncologists to try innovations in the provision of oncology care to improve cost efficiency, access, and compliance. This study aimed to demonstrate the use of telemedicine, a novel approach of bringing oncology care to regional centres, and its applicability across Asia and Oceania. Methods: A retrospective review of telemedicine clinic use was conducted for two South Australian regional sites (Whyalla and Mount Gambier) over a 12-month period. Findings: Between February 2013 and January 2014, 380 patients were reviewed in oncology telemedicine clinics (n = 152 in Whyalla, n = 228 in Mount Gambier). The average number of patients reviewed per month was 31 (n = 12, n = 19). As oncologists grew comfortable with the consultation technique, the types of consultations conducted by telemedicine were expanded. Numbers by consultation type were: pre-chemotherapy review, n = 285 (n = 135, n = 150); restaging, n = 39 (n = 15, n = 24); and first consultation, n = 6 (n = 2, n = 4). Both men and women were reviewed, age range was 24–87 years, and ethnicities included Indigenous, Australian, European, and Asian. A teleconferencing unit was used in the regional clinic and a computermounted camera at the oncologist’s clinic. The costs to run a telemedicine clinic will be compared to travel costs in a metropolitan-based approach. Interpretation: Telemedicine allows specialists to review patients on a regular basis during chemotherapy, without the need for travel to a major metropolitan centre. Uniformity and simplicity of approach makes telemedicine user-friendly and cost effective for patients and health services. Telemedicine provides a novel technique for safe and efficient oncology care closer to the patient’s home. The technique has clear savings by minimising travel and burden on metropolitan clinic budgets. This approach can be easily adapted to most countries in Asia and Oceania.
http://dx.doi.org/10.1016/j.ejca.2014.03.269
P0226 PATTERNS OF RECURRENCE IN LOCALLY ADVANCED SQUAMOUS CELL CARCINOMAS OF THE HEAD AND NECK AFTER THREE-DIMENSIONAL CONFORMAL RADIOTHERAPY: AN INSTITUTIONAL EXPERIENCE A. Singh *, D.J. Fernandes, M.S. Vidyasagar, S.A. Reddy. Department of Radiotherapy and Oncology, Shirdi Sai Baba Cancer Hospital, Kasturba Medical College, Manipal, India