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Genomic Alterations Observed in Colitis-associated Cancers are Distinct from Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease.

Patients with inflammatory bowel diseases such as Crohn’s disease (CD) or ulcerative colitis (UC) are at increased risk for small bowel or colorectal cancers (colitis-associated cancers, CACs). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC.
We studied tumor tissues from patients with CACs, treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture based next-generation sequencing analysis of over 300 cancer-related genes to comprehensively characterize genomic alterations.
We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n=2), right colon (n=18), left colon (n=6) and rectosigmoid or rectum (n=21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17/47 (36%) of CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC.
In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared to sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets.
Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Moment reconstruction and moment-adjusted imputation when exposure is generated by a complex, nonlinear random effects modeling process.

For the classical, homoscedastic measurement error model, moment reconstruction (Freedman et al., 2004, 2008) and moment-adjusted imputation (Thomas et al., 2011) are appealing, computationally simple imputation-like methods for general model fitting. Like classical regression calibration, the idea is to replace the unobserved variable subject to measurement error with a proxy that can be used in a variety of analyses. Moment reconstruction and moment-adjusted imputation differ from regression calibration in that they attempt to match multiple features of the latent variable, and also to match some of the latent variable’s relationships with the response and additional covariates. In this note, we consider a problem where true exposure is generated by a complex, nonlinear random effects modeling process, and develop analogues of moment reconstruction and moment-adjusted imputation for this case. This general model includes classical measurement errors, Berkson measurement errors, mixtures of Berkson and classical errors and problems that are not measurement error problems, but also cases where the data-generating process for true exposure is a complex, nonlinear random effects modeling process. The methods are illustrated using the National Institutes of Health-AARP Diet and Health Study where the latent variable is a dietary pattern score called the Healthy Eating Index-2005. We also show how our general model includes methods used in radiation epidemiology as a special case. Simulations are used to illustrate the methods.
© 2016, The International Biometric Society.

Discovery and characterization of a potent and selective EP4 receptor antagonist.

EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.
Copyright © 2015 Elsevier Ltd. All rights reserved.

A phase ib study of safety and pharmacokinetics of ramucirumab in combination with paclitaxel in patients with advanced gastric adenocarcinomas.

The pharmacokinetic results of this phase Ib study of ramucirumab combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastro-esophageal junction adenocarcinoma are in line with previous ramucirumab studies.This combination at the doses and schedule given did not result in any dose-limiting toxicities and appeared to be safe and well tolerated.
This phase Ib study evaluated the tolerability and pharmacokinetics of ramucirumab, an anti-VEGFR-2 antibody, combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma after first-line therapy with fluoropyrimidines and/or platinum.
Patients received ramucirumab 8 mg/kg on days 1 and 15 and paclitaxel 80 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Safety analyses included all patients (n = 6).
No dose-limiting toxicities occurred in the first cycle. All patients experienced ≥1 treatment-emergent adverse event (TEAE); 5 patients experienced grade ≥3 TEAEs. There were two deaths caused by disease progression. The best overall responses were stable disease (n = 5) and partial response (n = 1). Patients received ramucirumab and paclitaxel for a median of 12.5 weeks (range: 11.4-42.7 weeks) and 12.2 weeks (range: 11.0-41.0 weeks), respectively. Following a single dose of ramucirumab IV infusion 8 mg/kg, clearance was ∼0.017 L/hour, half-life (t1/2) was 138 to 225 hours, and steady-state volume of distribution (Vss) was ∼3 L.
The ramucirumab/paclitaxel combination appears to be well-tolerated in Japanese patients with advanced gastric adenocarcinomas. These results are in line with previous ramucirumab pharmacokinetic studies as anticipated.
©AlphaMed Press; the data published online to support this summary is the property of the authors.

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.

Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).