Radiological Toxicity Research Articles

Analysis of mRNA Expression Patterns in Peripheral Blood Cells of 3 Patients With Cancer After the First Fraction of 2 Gy Irradiation: An Integrated Case Report and Systematic Review.

Background:Radiation therapy induces acute and chronic radiological toxicity, in particular hematological toxicity (HT). This study aimed to explore the mechanistic clue and potential predictors at the messenger RNA (mRNA) level.Materials and Methods:Peripheral blood was collected from 3 patients with cervical cancer (CC), nasopharynx cancer (NC), and tongue cancer (TC) after the first 2 Gy fraction of radiotherapy (RT). High-throughput sequencing was used to assess mRNA profiles.Results:Eleven genes, such as ALAS2(5-aminolevulinate synthase), SLC4A1(solute carrier family 4 member 1), HBG2(hemoglobin subunit gamma 2), TNFAIP3 (TNF α-induced protein 3), PER1 (period circadian clock 1), CCDC136 (coiled-coil domain containing 136), C9orf84 (chromosome 9 open reading frame 84), IL1B (interleukin 1β), FOSB (FosB protooncogene), NR4A2 (nuclear receptor subfamily 4), PARP15 (polymerase family member 15), had overlapping expression changes in all 3 cancers of which 3 (ALAS2, FOSB, and HBG2) are suggested as potential predictors for the early diagnosis of HT after RT.Conclusions: ALAS2, FOSB, and HBG2 may be useful predictors of HT in patients after RT. Eleven overlapping expression mRNAs among 3 cancers might be potential predictors for early diagnosis of radiation toxicity in patients.

Uranium record from a 3 m snow pit at Dome Argus, East Antarctica.

Understanding the distribution and transport of Uranium is important because it can lead to both chemical and radiological toxicity. This study presents the Uranium concentrations time series from 1964 to 2009 obtained from a 3 m deep snow pit at Dome Argus, East Antarctic Plateau. The data shows that Uranium concentrations vary from 0.0067 pg g-1 to 0.12 pg g-1, with a mean concentration of 0.044 pg g-1. Its mean concentration is 2–3 folds lower than at West Antarctica study sites, such as the Antarctic Peninsula (mean 0.12 pg g-1), IC-6 (Ice Core-6) (mean 0.11 pg g-1) and a suite of ice cores from the US ITASE traverse. Before the mid-1980s, the varieties of Uranium concentrations are relatively stable, with a very low mean concentration of 0.016 pg g-1and its main source is sea salt deposition, while a small number of anthropogenic sources are likely to be caused by Uranium mining operations in South Africa. A remarkable increase of Uranium concentrations has occurred since the mid-1980s (by a factor of ~ 9) compared with the amount before the mid-1980s. This increase coincides with the Uranium records at IC-6 and Antarctic Peninsula (DP-07-01) during the same period, and are mostly attributed to Uranium mining operations in Australia as a potential primary anthropogenic Uranium source. Our observations suggest that Uranium pollution in the atmosphere might have already become a global phenomenon.

Rotundic acid enhances the impact of radiological toxicity on MCF-7 cells through the ATM/p53 pathway

Although radiation therapy is a powerful anticancer modality, radiation- induced stress response and gene expression with adaptive resistance may severely compromise the effectiveness of radiation. The function of rotundic acid (RA) on inducing apoptosis in the human breast cancer cell line MCF-7 has been investigated in a previous study. In the present study, the combined effect of chemotherapy and radiotherapy on reducing side effects was examined. The results of an MTT assay revealed that radiation (0.5, 2 and 10Gy) effectively inhibit MCF-7 cell viability in a dose-dependent manner, consistent with the effects of RA (2, 5 and 12.5µM). Interestingly, a lower dose of radiation (1Gy) combined with RA (5µM) exhibited a greater inhibition efficiency compared with a high dose of radiation alone. Flow cytometry revealed that radiation combined with RA induced the apoptosis of MCF-7 cells. Using western blotting, it was demonstrated that radiation induced the expression of ataxia-telangiectasia mutated (ATM) and p53 protein, and that RA enhanced this effect. On examining the potential underlying mechanism, it was revealed that radiation and RA combined induce Bcl-2-associated X protein expression and cell apoptosis in MCF-7 cells. An ATM inhibitor was able to restore the effect of radiation and RA on inducing MCF-7 cell apoptosis. These results suggest that the ATM/p53 pathway directly participates in radiation and RA-induced apoptosis in MCF-7 cells. RA has the potential for development as a novel drug for the treatment of human breast cancer combined with radiation therapy, given that the combined side effects are reduced.

Spatial distribution of uranium and basic water quality parameter in the capital of Bihar and consequent ingestion dose.

Investigation of presence ofUranium (U) in groundwater/drinking water is an active are of research due to itschemical and radiological toxicity as well as long-term health effects. The current study had the objective of estimating U as a naturally occurring radioactive element in groundwater samples and assessment of ingestion dose, when groundwater is the source of drinking water. The random sampling method was chosen for the collection of samples based on population density. The estimation of U was done using LED fluorimeter. Statistical tools were applied to analyze the data and its spatial distribution. The U concentrations in three blocks of urban Patna were well below the permissible limits suggested by different health agencies of the world. A correlation test was performed to analyze the association of U with other physiochemical parameters of water samples. It was found that the sulfate, chloride, calcium, hardness, alkalinity, TDS, salinity, and ORP were positively correlated, whereas fluoride, phosphate, magnesium, dissolved oxygen, and pH were negatively correlated with U concentrations. The ingestion dose due to U, occurring in groundwater, was found to vary from 0.2-27.0μSvy-1 with a mean of 4.2μSvy-1, which was well below the recommended limit of 0.1mSv (WHO WHO Chron 38:104-108, 2012).Therefore, the water in this region is fit for drinking purposes.

Does leaching of naturally occurring radionuclides from roadway pavements stabilised with coal fly ash have negative impacts on groundwater quality and human health?

We assessed the potential impact of using coal fly ash to stabilise roadway pavements on groundwater quality and human health. The leaching potential of naturally occurring radionuclides (NORs) typically present in the fly ash was assessed with the HYDRUS-1D code and data representative of a segment of the Wisconsin State Trunk Highway 60 as a case study.Our assessment suggests that the impact would be mainly from the chemical toxicity of uranium (U). In our particular case study, U concentration in the leachate exceeded the maximum contaminant level for this element (MCL = 30 μg L−1) in almost all the scenarios. In the groundwater, the MCL was only exceeded under conditions of high leaching and low dilution in the aquifer. The radiological toxicity from the consumption of the contaminated groundwater by a hypothetical adult, however, was at maximum 43% of the individual dose criterion (IDC = 0.1 mSv y−1).The results also highlight the need to consider site-specific conditions such as climate and hydrogeology when assessing the environmental impacts of utilising fly ash in roadway construction applications since they could have profound effects on the assessment findings. There is also a pressing need for reliable and representative data to support realistic assessments.

Radiological toxicity of some fish and meat tissues consumed in southwestern Nigeria

ABSTRACTThe activity concentrations of natural radionuclides in 30 fish tissues and 30 meat organs have been determined using high purity germanium (HPGe) detector. For the fish tissues, the mean activity concentrations of 238U and 232Th were highest in Catfish (Clarias gariepinus) with values of 5.31 ± 1.30 and 6.09 ± 0.91 Bq/kg, respectively. The lowest mean activity concentrations of 238U and 232Th were seen in Titus (Scomberomorus tritor) and Croaker (Micropogonias undulatus), Croaker with values of 1.51 ± 2.08 and 64.42 ± 6.33 Bq/kg, respectively. The mean activity concentration of 40K was highest in Micropogonias undulatus and lowest in Tilapia (Oreohronis niloticus) with values of 64.42 ± 6.33 and 6.53 ± 0.98 Bq/kg. For the meat organs, the highest mean activity concentration of 238U, 232Th, and 40K was highest in kidney, liver, and heart, respectively with values of 2.82 ± 0.47, 4.57 ± 0.69, and 52.07 ± 7.81 Bq/kg. Small intestine had the lowest mean activity concentrations of 238U and 232Th with values of 1.14 ± 0.16 and 0.89 ± 0.08 Bq/kg, respectively. Beef had the lowest mean activity concentration of 40K with a value of 17.61 ± 2.14 Bq/kg.

Inhibitory effect of uranyl nitrate on DNA double-strand break repair by depression of a set of proteins in the homologous recombination pathway.

Occupational and environmental exposure to uranium has been confirmed to cause tissue injury and carcinogenesis. As a heavy metal from actinide series, the chemical and radiological toxicities of uranium jointly induce the detrimental effects. However, the mutual action and mechanism of both forms of toxicities still need to be further elucidated. DNA double-strand break (DSB) is a fundamental cause of cell death or genomic instability induced by ionizing radiation. Herein, we investigate the effect of uranyl nitrate on the cellular function of DNA damage response and intrinsic DSB repair on the aspect of chemical toxicity. The results indicated that uranyl ion increased the accumulation of nuclear DNA DSBs in a dose-dependent manner. Both homologous recombination (HR) and non-homologous end joining (NHEJ) pathways of DSB repair were affected by the uranyl ion. The inhibition of DSB repair efficiency is attributed to the depression of a set of critical repair proteins, particularly those for the HR pathway such as ATM, BRCA1, RPA80 and EXO1. The available data enable us to imagine that the chemical toxicity of uranium leads to inhibition of cellular DNA repair capability, which can further aggravate its radiological toxicity.

Polyethyleneimine methylphosphonate: towards the design of a new class of macromolecular actinide chelating agents in the case of human exposition.

The use of uranium and to a minor extent plutonium as fuel for nuclear energy production or as components in military applications is under increasing public pressure. Uranium is weakly radioactive in its natural isotopy but its chemical toxicity, combined with its large scale industrial utilization, makes it a source of concern in terms of health impact for workers and possibly the general population. Plutonium is an artificial element that exhibits both chemical and radiological toxicities. So far, uranium (under its form uranyl, U(vi)) or plutonium (as Pu(iv)) decorporation or protecting strategies based on molecular design have been of limited efficiency to remove the actinide once incorporated after human exposure. In all cases, after human exposure, plutonium and uranium are retained in main target organs (liver, kidneys) as well as skeleton although they exhibit differences in their biodistribution. Polymers could represent an alternative strategy as their tropism for specific target organs has been reported. We recently reported on the complexation properties of methylcarboxylated polyethyleneimine (PEI-MC) with uranyl. In this report we extend our work to methylphosphonated polyethyleneimine (PEI-MP) and to the comparison between actinide oxidation states +IV (thorium) and +VI (uranyl). As a first step, thorium (Th(iv)) was used as a chemical surrogate of plutonium because of the difficulty in handling the latter in the laboratory. For both cations, U(vi) and Th(iv), the uptake curve of PEI-MP was recorded. The functionalized PEI-MP exhibits a maximum loading capacity comprised of between 0.56 and 0.80 mg of uranium (elemental) and 0.15-0.20 mg of thorium (elemental) per milligram of PEI-MP. Complexation sites of U(vi) and Th(iv) under model conditions close to physiological pH were then characterized with a combination of Fourier transform Infra Red (FT-IR) and Extended X-Ray Absorption Fine Structure (EXAFS). Although both cations exhibit different coordination modes, similar structural parameters with phosphonate functions were obtained. For example, the coordination sites are composed of fully monodentate phosphonate functions of the polymer chains. These physical chemical data represent a necessary basic chemistry approach before envisioning further biological evaluations of PEI-MP polymers towards U(vi) and Pu/Th(iv) contamination.

First mortality analysis in the French cohort of uranium millers, period 1968-2012.

Introduction: Uranium is a heavy metal naturally omnipresent in the environment known to have chemical and radiological toxicities. To better characterize potential health effects of uranium, studying the population of uranium millers (workers processing uranium ore) is highly pertinent. Compared to miners, they experienced much lower levels of radon exposure, so that uranium exposure contributes a larger percentage of their total radiation exposure. A new retrospective cohort of millers was set-up in France to assess the risk of cancer and non-cancer mortality related to uranium exposure. Methods: The cohort includes permanent contract workers employed during at least 6 months between 1955 and 2001 as uranium millers by SIMO (Societé Industrielle des Minerais de l’Ouest) and SMJ (Société des Mines de Jouac). Personal files and employment records were obtained from AREVA archives. Vital status and causes of death were obtained from French national registries between 1968 and 2012, in order to perform comparisons with French national and local mortality rates by computing standardized mortality ratios. Results: The cohort includes 1291 workers (8.6% women) with a median year of birth of 1941. The average duration of employment was 14.5 years and the mean age at the beginning of follow-up was 34.1 years old. At the end of follow-up (31/12/2012), 434 millers were deceased and 14 were lost to follow-up. Detailed mortality analyses using French national mortality rates as reference will be presented. Conclusions: This is the first cohort of uranium millers ever set-up in France. Those mortality analyses will help to improve current knowledge on the health effects of uranium and contribute to the validation or evolution of international radiation protection standards. In the future, undertaking combined analyses of cohorts of uranium millers, but also of miners and other uranium fuel cycle workers should help further refine risk estimates for uranium exposure.

Recent increase in Antarctic Peninsula ice core uranium concentrations

Understanding the distribution of airborne uranium is important because it can result in both chemical and radiological toxicity. Ice cores offer the most robust reconstruction of past atmospheric levels of toxic substances. Here we present the first sub-annually dated, continuously sampled ice core documenting change in U levels in the Southern Hemisphere. The ice core was recovered from the Detroit Plateau, northern Antarctic Peninsula, in 2007 by a joint Brazilian-Chilean-US team. It displays a significant increase in U concentration that coincides with reported mining activities in the Southern Hemisphere, notably Australia. Raw U concentrations in the Detroit Plateau ice core increased by as much as 102 between the 1980s and 2000s accompanied by increased variability in recent years. Decadal mean U concentrations increased by a factor of ∼3 from 1980 to 2007, reaching a mean of 205 pg/L from 2000 to 2007. The fact that other terrestrial source dust elements such as Ce, La, Pr, and Ti do not show a similar increase and that the increased U concentrations are enriched above natural crustal levels, supports an anthropogenic source for the U as opposed to a change in atmospheric circulation.

Chemical and radiological toxicity of uranium compounds

Studies into the effects from environmental pollution by uranium compounds have been overviewed. Analysis of the impact of uranium oxides resulted from military operations using armor-piercing shells made of depleted uranium shows a predominance of chemical toxicity caused by the strong oxidizing power of uranyl ions. They induce oxidative stress through the generation of reactive oxygen species. As a result, oxidative damage to biomolecules and disruption of metabolic processes occur. Oxidative DNA damage causes long-term genotoxic effects in the form of mutagenesis, carcinogenesis, and other pathologies. The necessity of prohibiting the use of depleted uranium shells as chemical weapons of mass destruction has been substantiated.

Abstract OT3-01-02: A phase I-II trial of dasatinib in combination with trastuzumab (T) and paclitaxel in the first line treatment of HER2 positive metastatic breast cancer (MBC) patients: GEICAM/2010-04

Abstract Background: Resistance to targeted-therapies is a current problem in our clinical practice. In HER2 overexpressing tumors, resistance to trastuzumab-based therapies is widely observed. Expression of SRC has been pre-clinically linked to trastuzumab resistance and the addition of the multi-tyrosine kinase inhibitor dasatinib to trastuzumab increases its antitumor activity (Seoane S, et al. J Natl Cancer Inst. 2010). On previous studies, Dasatinib showed a good toxicity profile, with low grade 3-4 toxicity rates (E. Mayer, et al. J Clin Oncol 2009). We have designed a phase I-II trial combining dasatinib with standard trastuzumab/paclitaxel. (ClinicalTrials.gov Identifier: NCT01306942). In this abstract we report the description of the phase II part of the trial which is ongoing. Trial Design: Eligible patients must be HER2+ (evaluated by central laboratory and assessed by immunohistochemistry and fluorescent in-situ hybridization) MBC and candidates for trastuzumab + chemotherapy as first line treatment. Taxanes and trastuzumab administered in the adjuvant setting are permitted if given >12 months before the inclusion. Patients with CNS involvement are eligible if treated and clinically stable without medication. Treatment consists of trastuzumab 2 mg/kg weekly (following a loading dose of 4 mg/kg in cycle 1), weekly paclitaxel (80 mg/m2, 3 weeks on-one week off) and dasatinib 100 mg once daily (based on the recommended phase II dose from the phase I part, Gil-Martin M, et al. European Breast Cancer Conference 2014, P-041) in a 28-days cycle. Patients are treated until radiologic or symptomatic progression or unacceptable toxicity. The primary objective for this phase II is efficacy, measured by Objective Response Rate (ORR according to RECIST 1.1). Secondary objectives are: Safety (evaluated using NCI-CTCAE v 4.03), Clinical Benefit Rate, Time to Progression, Progression Free Survival and Response Duration. Pharmacodynamic biomarkers include pAKT, pS6, pSRC, pErk1/2 in tumor tissue samples, mononuclear cells in blood samples and in skin tissue. An additional exploratory objective is to evaluate the correlation between the early presence of lymphocytosis and efficacy. The study will be considered positive if ORR increases 25% from a 50% ORR observed in previous studies with paclitaxel + trastuzumab. We need to include 28 evaluable patients to demonstrate this hypothesis (with an alpha error of 0.05 and a statistical power of 80%), assuming a 10% drop-out rate. Twenty one patients have already been included. Recruitment is expected to finish by the end of 2015. Citation Format: Ocaña A, Ruiz Borrego M, Gil-Martín M, Antolín S, Guerrero Á, Vidal Boixader L, Martín M, Trigo Pérez JM, Rojo F, Jerez Y, Atienza M, Pernas S, Hernando A, Carrasco E, Benito S, Caballero R, Pandiella A. A phase I-II trial of dasatinib in combination with trastuzumab (T) and paclitaxel in the first line treatment of HER2 positive metastatic breast cancer (MBC) patients: GEICAM/2010-04. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-02.

Assessment of the Central Effects of Natural Uranium via Behavioural Performances and the Cerebrospinal Fluid Metabolome.

Natural uranium (NU), a component of the earth's crust, is not only a heavy metal but also an alpha particle emitter, with chemical and radiological toxicity. Populations may therefore be chronically exposed to NU through drinking water and food. Since the central nervous system is known to be sensitive to pollutants during its development, we assessed the effects on the behaviour and the cerebrospinal fluid (CSF) metabolome of rats exposed for 9 months from birth to NU via lactation and drinking water (1.5, 10, or 40 mg·L−1 for male rats and 40 mg·L−1 for female rats). Medium-term memory decreased in comparison to controls in male rats exposed to 1.5, 10, or 40 mg·L−1 NU. In male rats, spatial working memory and anxiety- and depressive-like behaviour were only altered by exposure to 40 mg·L−1 NU and any significant effect was observed on locomotor activity. In female rats exposed to NU, only locomotor activity was significantly increased in comparison with controls. LC-MS metabolomics of CSF discriminated the fingerprints of the male and/or female NU-exposed and control groups. This study suggests that exposure to environmental doses of NU from development to adulthood can have an impact on rat brain function.

Chelation therapy for treatment of systemic intoxication with uranium: A review

Elevated levels of naturally occurring uranium have been found in small geographic areas throughout the world. Exposure of the general public to uranium is most often by the ingestion of food and water containing natural uranium from the hydrogeological environment, but this likelihood is remote. However, the risk is increased in regions where uranium is mined, milled, processed and/or fabricated as well as in the vicinity of former battlefields where depleted uranium munitions were deployed. Exposure in such cases is by the inhalation route. Internalized uranium is a long-term hazard the toxicity of which depends upon the dose and the dose rate as well as other parameters such as the chemical form and site of deposition of the uranium and the physiology of the host. The radiological toxicity and the chemical toxicity of uranium and its compounds are responsible for kidney damage and lung cancer. The vulnerable groups are the very young and the very old, individuals predisposed to hypertension or osteoporosis and individuals with chronic kidney disease. Those subject to long-term exposure from internalized uranium are a greater risk for the long-term implications. The accumulation of uranium may be mitigated by decreasing its absorption, distribution and deposition and increasing its elimination with chelating agents. The formation of soluble chelates may enhance the mobilization of uranium deposited in tissue and expedite its transport to and elimination from the renal system. The focus of this review is on the use of chelating agents to enhance decorporation of uranium thereby reducing the risk of intoxication.

Pulmonary function and quality of life after VMAT-based stereotactic ablative radiotherapy for early stage inoperable NSCLC: a prospective study.

To analyze changes in pulmonary function and quality of life (QoL) at different time points after Stereotactic Ablative Radiotherapy (SABR) for early stage inoperable lung cancer, and potential correlations between radiation dose-volume parameters and pulmonary toxicity or changes in pulmonary function tests (PFT) and QoL. From July 2012 to October 2013, 30 patients were enrolled in this prospective observational study. Complete PFT were performed and Lung Cancer Symptoms Scale (LCSS) questionnaire administered prior to SABR; all patients then underwent Computed Tomography (CT) scan and PFT at 45, 135, 225 and 315 days after SABR, together with LCSS questionnaire. Clinical lung toxicity and radiological toxicity (acute and late) were prospectively recorded by using the Radiation Therapy Oncology Group (RTOG) scoring system. A decline in Slow Vital Capacity (SVC), Forced Expiratory Volume in 1s (FEV1), Single-breath lung diffusing capacity (DLCO) and blood partial pressure of oxygen (PaO2) was seen at 135 days post-SABR. PaO2 values rescued to normal levels at 315 days. None of the baseline PFT parameters resulted to be associated with the occurrence of pulmonary toxicity or with late radiological changes. Mean V5, V10, and V20 and MLD2Gy were higher in patients who developed radiation pneumonitis, even if not significantly associated at Cox regression analysis. LCSS QoL showed a significant worsening of the single item fatigue at 135 days after SABR. A small (mean 10%) but significant decline in lung volumes and DLCO was recorded after SABR, with clinical impact of such change difficult to estimate in individual patients. Global QoL was not significantly impaired. Dose-volume parameters did not emerge as significantly predictive of any clinical, radiological or functional toxicity.

Radiological and chemical toxicity due to ingestion of uranium through drinking water in the environment of Bangalore, India

Groundwater samples collected from 96 bore wells in the study area (city of Bangalore) were analysed for concentration of natural uranium using laser-induced fluorimetry. The risk to the population of the region associated with radiological and chemical toxicity of uranium due to its ingestion through drinking water over a lifetime was estimated. The concentration of uranium was found to be in the range 0.136 to 2027.5 μg L−1 with an average value of 92.42 μg L−1. In the present study, about 61% of the samples show concentrations of uranium within the safe limit of 30 μg L−1 as set by the world health organisation. The radiological risk estimated as lifetime cancer risk is in the range 4.3 × 10−7 to 6.4 × 10−3 with an average of 2.9 × 10−4. The chemical toxicity risk measured as lifetime average daily dose is found to range from 0.005 to 75.42 μg kg−1 d−1. The reference dose estimated as 1.12 μg kg−1 d−1 was used to assess the chemical toxicity. The results indicate that the chemical toxicity due to ingestion of uranium through drinking water is of more concern than the radiological toxicity. The present study, being the first of its kind in this region, will augment the database of uranium in groundwater.

Abstract OT1-1-06: A phase I study of LDE225 in combination with docetaxel in patients with triple negative (TN) advanced breast cancer (ABC): GEICAM/2012-12 (EDALINE study)

Abstract Background: LDE225 is a potent and selective oral inhibitor of Smo, a key component of the hedgehog (Hh) signaling pathway. Up-regulation of the Hh pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer. Here we report an ongoing phase I study exploring the combination of LDE225 with docetaxel in TN ABC patients to identify the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D) (ClinicalTrials.gov Identifier: NCT02027376). Trial Design: Eligibility criteria include patients with TN ABC candidates to receive treatment with docetaxel that have received a maximum of 3 prior chemotherapy regimens. Those patients with CNS involvement are also candidates if treated and clinically stable. Treatment consists of 21-day cycles with docetaxel 75mg/m2 on day 1, every 21 day and LDE225 once daily. We use a standard 3+3 design in sequential cohorts (3 dose levels (DL) of LDE225: 400mg once daily (DL1), 600mg once daily (DL2), 800mg once daily (DL3); and a DL-1: LDE225 400mg once daily and docetaxel 60mg/m2 every three weeks). The primary endpoint is the MTD and RP2D of the combination; secondary endpoints include evaluation of safety and tolerability, in addition to pharmacodynamic (PD) and pharmacokinetic (PK) studies. Patients are treated until radiologic or symptomatic progression or unacceptable toxicity occurs. PK will be performed to evaluate whether LDE225 influences the pharmacology of docetaxel. PD assessments include Hg gene expression signature associated to pathway activation in tumor samples and changes in Smo related biomarkers in skin and blood correlative samples. Efficacy will be measured in terms of time to progression and objective response rate. A minimum of 9 and a maximum of 18 patients will be included in this phase I. The study is approved by ERBs and Competent Authority and already recruiting patients (two patients included in DL1). Citation Format: Miguel Martin, Manuel Ruiz-Borrego, José M Trigo, Silvia Antolin, Jose A Garcia-Saenz, Andres Hernando, Alberto Ocaña, Federico Rojo, Sara Lopez-Tarruella, Jesus Corral, Nuria Ribelles, Lourdes Calvo, Fernando Moreno, Rosalia Caballero, Eva Carrasco. A phase I study of LDE225 in combination with docetaxel in patients with triple negative (TN) advanced breast cancer (ABC): GEICAM/2012-12 (EDALINE study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-06.

Su1959 Omega-3 Fatty Acid Infusion Reduces Gastrointestinal Toxicity and Prevents Thromboembolism in Patients With Advanced Esophagogastric Cancer Treated With Palliative Platinum Based Chemotherapy

Introduction The omega-3 fatty acids, EPA and DHA have proven anticancer activity in laboratory and clinical cancer studies. This clinical trial evaluated whether adding omega-3 fatty acids to palliative platinum based chemotherapy influenced the outcome of patients with oesophagogastric cancer compared to those given chemotherapy alone Method 21 participants in the 1st stage of a phase II single arm trial received palliative chemotherapy, intravenous (IV) epirubicin (50mg/m 2 ) and oxaliplatin (130mg/m 2 ) every 21 days, oral capecitabine (1250mg/m 2 ) daily for 21 days and IV omega-3 fatty acids (2ml/Kg/4 h) (Omegaven® Fresenius-Kabi). The Omegaven infusion was given immediately after the chemotherapy on days 1, 8 and 15 of each cycle (intervention). Clinical outcomes were compared to outcomes in 37 patients treated with chemotherapy alone (control). Toxicities were graded using the CTCAE v4.03. Clinical response rate was assessed by RECIST v1.1 criteria. Results Fifty-six patients eligible participants were screened for inclusion, 35 were excluded principally because of poor performance status. Twenty one patients were enrolled in the study, 20 received at least one treatment and they form the basis of this report. The radiological response and toxicity of the intervention and control groups are indicated (Table 1). The mean baseline and 7 day post treatment triglyceride levels were 1.7 mmol/l (95% CI 1.6- 1.79) and 1.66 mmol/l (95% CI 1.56–1.75) respectively. The highest recorded triglyceride level was 4.84 mmol/l. No patient experienced fat overload syndrome or grade 3/4 hypertriglyceridemia. Mean platelet counts were 217 X109/l in the intervention group (95% CI 207–226 X109/l) compared to 332 X109/l in the control group (95% CI 316–348 X109/l). Conclusion Compared to patients treated with chemotherapy alone, those treated with supplementary omega-3 fish oils had reduced chemotherapy related toxicity, notably fewer gastrointestinal and thromboembolic adverse effects. Omega-3 fatty acids have the potential to ameliorate the toxicity associated with chemotherapeutic agents. Disclosure of interest A. Eltweri Grant/ Research Support from: Fresenius-Kabi, A. Thomas Grant/ Research Support from: Fresenius-Kabi, A. Dennison Grant/ Research Support from: Fresenius-Kabi, M. Metcalfe Grant/ Research Support from: Fresenius-Kabi, D. Bowrey Grant/ Research Support from: Fresenius-Kabi, Nutricia

Germline Tyms Genotype is Highly Predictive in Patients with Advanced Colorectal and Gastroesophageal Cancer Independent of Fluoropyrimidine Pharmacology: Results from Two Prospective Translational Studies

ABSTRACT Aim: Germline gene polymorphisms may impact clinical outcome in patients with gastrointestinal malignancies, but there are no data on the interaction between chemotherapy pharmacokinetics (PK) and gene polymorphisms, to assess their independent predictive value. Methods: Two studies prospectively assessed 44 gene polymorphisms in 16 genes (TYMS, MTHFR, GSTP1, -M1, -T1, DPYD, XRCC1, XRCC3, XPD, ERCC1, RECQ1, RAD54L, ABCB1, ABCC2, ABCG2, UGT2B7) by Sanger sequencing in 64 patients with advanced colorectal cancer (CRC) receiving capecitabine/oxaliplatin chemotherapy, and 76 patients with advanced gastroesophageal (GE) cancer receiving epirubicin/cisplatin/capecitabine (ECC) chemotherapy, respectively. Plasma concentrations of all anticancer drugs were sampled for up to 24 hours, analyzed using validated LC-MS/MS (capecitabine), HPLC (epirubicin) and flameless atomic absorption spectrometry (platinum), and results submitted to population PK analysis using non-linear mixed effects modeling. We calculated the association between gene polymorphisms, anticancer drug exposure, radiological tumor response, progression-free survival (PFS), overall survival (OS) and chemotherapy-related toxicity using appropriate statistical tests. Results: Patients with a low clearance of the active metabolite 5FU had an increased risk of neutropenia in both groups (p A and A2846T were associated with diarrhea (p Conclusions: Carriers of the TYMS high-expression genotype have a markedly inferior outcome when receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. Therapeutic targeting of this molecularly-defined subgroup of patients should be explored to improve their prognosis. Disclosure: All authors have declared no conflicts of interest.

P13.03 * HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY (HSR) IN RECURRENT HIGH GRADE GLIOMA: A SAFE AND EFFECTIVE APPROACH

PURPOSE: Tumor control and survival in patients with high grade glioma (HGG) are limited. Local recurrence occurs usually in primary site within 1-3 years from initial treatment. Treatment at recurrence are not standardized and various therapeutic approach can be used. Hypofractionated Stereotactic Radiotherapy (HSR) has been shown as a feasible and effective treatment for recurrent high grade glioma previously treated with conventional radiotherapy. HSRS allows a precise delivery of radiation with optimal sparing of normal and functional brain in eloquent areas. In addition, hypofractionation of delivery dose could get a potential radiobiological advantage on tumor cells. The aim of this study is to evaluate safety and efficacy of salvage HSRS in recurrent high grade glioma patients. End points of the analyses are toxicity, rate of local control and patient's survival. MATERIALS AND METHODS: Adult patients with Karnosky Performance Status (KPS) ≥70 and a disease free interval higher than 1 year were included. Gadolinium- MRI and C11METPET were performed before and every 3 months thereafter. The Median dose delivered on the PTV was 25 Gy (range 25-50 Gy) in 5 fractions (range 5-10). Volumetric Modulated Arc therapy (VMAT) by Rapid Arc (RA) technique was used. Response and toxicity were evaluated using RANO criteria and CTCAE 3.0 respectively. RESULTS: Between January 2006 and December 2013, 25 patients (15 males and 10 females) were treated; the median age was 41 years (range 26-75 years). Sixteen of them had Glioblastoma, 5 Anaplastic Oligoastrocytoma and 4 Anaplastic Astrocytoma. At recurrence, before HSR 9 patients underwent partial surgical resection and 5 received a second line chemotherapy . Median time between the first RT treatment and HSRS re- irradiation was 18 months (range 12-77 months). The Median follow up was 11.1 months (1.3-19.2 months). No G3-G4 toxicity was observed. Response in according to RANO criteria was recorded in 14 patients (56%). Median survival was 11.5 months (range 1.3-19.2 months). PFS at 1 year was 30% and OS at 1 and 2 years were 40% and 20%. At the last follow up 12 patients were alive and 13 died. CONCLUSION: HSR re-irradiation is a feasible, safe and effective therapeutic option for patients with recurrent HGG. VMAT RA technique improves target coverage while minimizing higher dose to normal tissue with remarkable radiological and clinical response and negligible toxicity.