Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study.

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial. ispartof: Eur J Cancer vol:127 pages:150-157 ispartof: location:England status: publishe

Biomarker analysis beyond angiogenesis : RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE-a global phase III study

Altres ajuts: This work was supported by Eli Lilly and Company. No grant number is applicable.: Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters. Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum. RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF -mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276). In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF -mutated tumours, although the P -values were not statistically significant. NCT01183780

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. NCT01183780

The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals

Flow shop rescheduling under different types of disruption

This is an Accepted Manuscript of an article published by Taylor & Francis in International Journal of Production Research on 2013, available online:http://www.tandfonline.com/10.1080/00207543.2012.666856Almost all manufacturing facilities need to use production planning and scheduling systems to increase productivity and to reduce production costs. Real-life production operations are subject to a large number of unexpected disruptions that may invalidate the original schedules. In these cases, rescheduling is essential to minimise the impact on the performance of the system. In this work we consider flow shop layouts that have seldom been studied in the rescheduling literature. We generate and employ three types of disruption that interrupt the original schedules simultaneously. We develop rescheduling algorithms to finally accomplish the twofold objective of establishing a standard framework on the one hand, and proposing rescheduling methods that seek a good trade-off between schedule quality and stability on the other.The authors would like to thank the anonymous referees for their careful and detailed comments that helped to improve the paper considerably. This work is partially financed by the Small and Medium Industry of the Generalitat Valenciana (IMPIVA) and by the European Union through the European Regional Development Fund (FEDER) inside the R + D program "Ayudas dirigidas a Institutos tecnologicos de la Red IMPIVA" during the year 2011, with project number IMDEEA/2011/142.Katragjini Prifti, K.; Vallada Regalado, E.; Ruiz García, R. (2013). Flow shop rescheduling under different types of disruption. International Journal of Production Research. 51(3):780-797. https://doi.org/10.1080/00207543.2012.666856S780797513Abumaizar, R. J., & Svestka, J. A. 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Functional KV10.1 Channels Localize to the Inner Nuclear Membrane

Ectopically expressed human KV10.1 channels are relevant players in tumor biology. However, their function as ion channels at the plasma membrane does not totally explain their crucial role in tumors. Both in native and heterologous systems, it has been observed that a majority of KV10.1 channels remain at intracellular locations. In this study we investigated the localization and possible roles of perinuclear KV10.1. We show that KV10.1 is expressed at the inner nuclear membrane in both human and rat models; it co-purifies with established inner nuclear membrane markers, shows resistance to detergent extraction and restricted mobility, all of them typical features of proteins at the inner nuclear membrane. KV10.1 channels at the inner nuclear membrane are not all transported directly from the ER but rather have been exposed to the extracellular milieu. Patch clamp experiments on nuclei devoid of external nuclear membrane reveal the existence of channel activity compatible with KV10.1. We hypothesize that KV10.1 channels at the nuclear envelope might participate in the homeostasis of nuclear K+, or indirectly interact with heterochromatin, both factors known to affect gene expression

Nucleolus: the fascinating nuclear body

Nucleoli are the prominent contrasted structures of the cell nucleus. In the nucleolus, ribosomal RNAs are synthesized, processed and assembled with ribosomal proteins. RNA polymerase I synthesizes the ribosomal RNAs and this activity is cell cycle regulated. The nucleolus reveals the functional organization of the nucleus in which the compartmentation of the different steps of ribosome biogenesis is observed whereas the nucleolar machineries are in permanent exchange with the nucleoplasm and other nuclear bodies. After mitosis, nucleolar assembly is a time and space regulated process controlled by the cell cycle. In addition, by generating a large volume in the nucleus with apparently no RNA polymerase II activity, the nucleolus creates a domain of retention/sequestration of molecules normally active outside the nucleolus. Viruses interact with the nucleolus and recruit nucleolar proteins to facilitate virus replication. The nucleolus is also a sensor of stress due to the redistribution of the ribosomal proteins in the nucleoplasm by nucleolus disruption. The nucleolus plays several crucial functions in the nucleus: in addition to its function as ribosome factory of the cells it is a multifunctional nuclear domain, and nucleolar activity is linked with several pathologies. Perspectives on the evolution of this research area are proposed