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SummaryBackgroundThe goal of hepatorenal syndrome type 1 (HRS‐1) treatment is to improve renal function. Terlipressin, a synthetic vasopressin analogue, is a systemic vasoconstrictor used for the treatment of HRS‐1, where it is available.AimTo compare the efficacy of terlipressin plus albumin vs. placebo plus albumin in patients with HRS‐1.MethodsPooled patient‐level data from two large phase 3, randomised, placebo‐controlled studies were analysed for HRS reversal [serum creatinine (SCr) value ≤133 μmol/L], 90‐day survival, need for renal replacement therapy and predictors of HRS reversal. Patients received intravenous terlipressin 1–2 mg every 6 hours plus albumin or placebo plus albumin up to 14 days.ResultsThe pooled analysis comprised 308 patients (terlipressin: n = 153; placebo: n = 155). HRS reversal was significantly more frequent with terlipressin vs. placebo (27% vs. 14%; P = 0.004). Terlipressin was associated with a more significant improvement in renal function from baseline until end of treatment, with a mean between‐group difference in SCr concentration of −53.0 μmol/L (P < 0.0001). Lower SCr, lower mean arterial pressure and lower total bilirubin and absence of known precipitating factors for HRS were independent predictors of HRS reversal and longer survival in terlipressin‐treated patients.ConclusionsTerlipressin plus albumin resulted in a significantly higher rate of HRS reversal vs. albumin alone in patients with HRS‐1. Terlipressin treatment is associated with improved renal function. (ClinicalTrials.gov identifier: OT‐0401, NCT00089570; REVERSE, NCT01143246).

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72 -associated amyotrophic lateral sclerosis.

The purpose of this study was to develop a simplified methodology that will produce Monte Carlo (MC) dose distribution for proton therapy which can be used as a clinical aid in determining the adequacy of proton plans produced from the treatment planning system (TPS). The Geant4 Monte Carlo toolkit was used for all simulations. The geometry of the double scatter nozzle in the simulation was a simplification of the treatment nozzle. The proton source was modeled as discrete energy layers, each with a unique energy distribution and weighting factor. The simplified MC system was designed to give the same dose distribution as the measured data used to commission the TPS. After the simplified MC system was finalized, a series of verification comparisons were made between it, measurements, and the clinically used TPS. Comparisons included the lateral profile of a stair‐shaped compensator that simulated a sharp lateral heterogeneity and depth‐dose measurements through heterogeneous materials. The simplified MC system matched measurements to within 2% or 2 mm for all commissioning data under investigation; moreover, the distal edge and lateral penumbra was within 1 mm of the measurements. The simplified MC system was able to better reproduce the measured profiles for a stair‐shaped compensator than the TPS. Both MC and TPS matched the measured depth dose through heterogeneous materials to within 2% or 2 mm. The simplified MC system was straightforward to implement, and produced accurate results when compared to measurements. Therefore, it holds promise as a clinically useful methodology to validate the relative dose distribution of patient treatment plans produced by the treatment planning systems.PACS number: 87.55.K‐, 87.55.ne

259 Background: Belinostat is a novel histone deactylase inhibitor which demonstrates preclinical activity in HCC. We report the results of a phase I/II study on belinostat in patients (pts) with unresectable HCC. Methods: Major eligibility criteria included histologically confirmed HCC not amenable to curative treatment; PS ≤ 2; adequate organ function; prior systemic therapy was allowed. In the phase I portion, belinostat was given i.v. on D1-5 every 3 weeks with dose levels of 600, 900, 1200 and 1400 mg/m2/day. In the phase II portion, belinostat was tested at the MTD. Primary endpoint was PFS and secondary endpoints were RR according to RECIST and OS. CT assessment was done every 8 weeks. Results: Phase I portion: a total of 18 pts were accrued; no DLTs were observed at 1400mg/m2/day for 5 days, and this dose was selected for phase II development. Phase II portion: 42 pts were accrued; Median age = 57.5 years; 41 had Child’s A function, and 24 pt had ECOG 0. Sixteen (38%) had previous systemic therapy, and 21 (50%) had previous transarterial therapy. Median follow-up was 20.0 months. The PR and SD rate was 2.4% (1/42) and 45.2% (19/42). Median PFS was 2.64 months (95%C.I. 1.55-3.17) and OS was 6.60 months (95%C.I. 4.53-11.60). Grade 3 or higher toxicities (>5% rate) were abdominal pain (9.5%), (9.5%) hyperbilirubinemia (9.5%), raised ALT (9.5%); anemia (7.1%) and vomiting (7.1%). Conclusions: Belinostat demonstrates disease stabilization in a predominantly pretreated population of pts with unresectable HCC with an acceptable safety profile. Further randomized studies are warranted.Supported in part by N01-CM-62205.

LBA7005 Background: In meta-analyses, platinum-based adjuvant (adj) chemotherapy (CT) in completely resected NSCLC increased cure rate by ∼5%. At BR.19 initiation, adj study results with third-generation agents were unavailable. Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, showed activity in monotherapy trials. We report a trial of adj gefitinib versus placebo after complete resection of NSCLC. Methods: Patients (pts) with stage IB-IIIA NSCLC were stratified by sex, stage, histology, post-op radiation, and after Jan 2003, adj CT. Pts were randomized to gefitinib 250 mg or placebo daily x 2 years. Study endpoints included overall survival (OS), disease free survival (DFS), toxicity, preplanned correlative studies. Study closed prematurely in Apr. 2005. Trial committee and NCIC CTG staff remained blinded to study drug. Results: 503 pts randomized (Sep 2002-Apr 2005); median age 67, males 54%, PS 0 54%; stage IB 49%, II 38%, III 13%; adenocarcinoma 59%, squamous 28%; ever smokers 89%; adj CT 17%; lobectomy 82%. Commonest grade 3/4 toxicities = fatigue 5%, rash 4% and diarrhea 5%. grade 3+ pneumonitis in 7 (1.4%) pts and led to death in 1. Median follow-up is 4.7 yrs; median treatment time is 4.8 mos. For gefitinib versus placebo, median DFS is 4.2 yrs versus not yet reached (NYR) HR1.22 (95% C.I. 0.93-1.61), p=0.15 and median OS 5.1 yrs versus NYR HR 1.24 (95% C.I. 0.94-1.64), p=0.14. In multivariate analysis, tumor size >4cm was predictive of poor DFS (p<0.0001) and never smoking for better OS with gefitinib (p=0.02). Results for KRAS and EGFR copy are available on 350 and 348 pts respectively. KRAS mutations were neither prognostic HR 1.12 (95% C.I. 0.67-1.86), p=0.66 nor predictive of gefitinib benefit (p = 0.16) on OS. EGFRcopy whether low/high polysomy or amplification was neither prognostic (p=0.77) nor predictive of OS benefit from gefitinib. Conclusions: Adjuvant gefitinib after complete resection of early stage NSCLC did not confer DFS or OS advantage in overall population. KRAS and EGFR copy were neither prognostic nor predictive of benefit from gefitinib. EGFR mutational analysis will be presented. [Table: see text]

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.