Citations

SummaryBackgroundPatients with eosinophilic oesophagitis (EoE) commonly have asthma and atopy.AimsTo determine the predictive factors of EoE in patients with asthma.MethodsA retrospective analysis of a large database identified 156 asthma patients with EoE and 276 patients without EoE between 2000 and 2010. Clinical and laboratory characteristics were first analyzed in half of each group. Significant differences and modelling were then applied to the other half of each group in a split half analysis.ResultsOdds ratios and P‐values found to predict the presence of EoE in asthma patients were: allergic vs. non‐allergic asthma (4.07, <0.01), food allergies (45, <0.01), allergic rhinitis (2.13, =0.01) and peripheral eosinophilia (4.51, <0.01). The use of inhaled corticosteroids was negatively associated with EoE (0.41, <0.01) for asthma patients and (0.37, P < 0.01) for allergic type asthma patients. EoE patients were also younger (27.4 vs. 41.6 years old, P < 0.01). By logistic regression analysis, allergic asthma, presence of peripheral eosinophilia and use of inhaled steroids remained significant. From these parameters, a 3.5‐point scoring system model for EoE in asthma was formed with an ROC = 0.787 on split analysis.ConclusionsIn descending order, peripheral eosinophilia, allergic asthma and allergic rhinitis are associated with EoE in patients with asthma. Steroid inhalers appear to have a protective effect against EoE. An accurate and simple scoring system can be used as a screening tool to predict the presence of EoE in patients with asthma and dysphagia. EoE should be viewed as part of a generalised allergic phenotype rather than isolated oesophageal disease.

Abstract Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol. Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design. Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w × 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer. Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. ©2012 AACR.

Background Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia. Objective To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC. Methods A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥75% agreed or disagreed. Results There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz–Jeghers syndrome; and p16 , BRCA 2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended. Conclusions Screening is recommended for high-risk individuals, but more evidence is needed, particularly for how to manage patients with detected lesions. Screening and subsequent management should take place at high-volume centres with multidisciplinary teams, preferably within research protocols.

The di‐2‐pyridylketone thiosemicarbazone Dp44mT is a metal‐chelating compound that has been demonstrated to have potent activity as an anticancer agent. Here we report that it also has a dramatic inhibitory effect on T‐cell activation in vitro. We found that 10 nM Dp44mT (IC 50 3.2 nM) prevented the up‐regulation of surface CD25, and completely suppressed the activation and proliferation of splenic T cells isolated from Mus musculus that were stimulated with either T‐cell receptor (TCR) cross‐linking antibodies or phorbol ester plus ionomycin. In contrast, Dp44mT had no adverse effects on the survival of resting T cells. In addition, T cells stimulated in the presence of Dp44mT maintained the ability to upregulate CD69 surface expression and secrete interleu‐kin‐2. Consistent with these observations, Dp44mT did not inhibit multiple canonical signals downstream of the TCR, including the nuclear factor of activated T cells. The effects of Dp44mT were easily mitigated by addition of nontoxic copper chelators or N ‐acetylcysteine, indicating a role for copper and reactive oxygen species in its actions. Together, these findings suggest that Dp44mT may serve as a potent immunosuppressive agent that could complicate its use as a cancer therapeutic agent, but might have utility in the treatment of autoimmunity.—Gundelach, J. H., Madhavan, A. A., Wettstein, P. J., Bram, R. J. The anticancer drug Dp44mT inhibits T‐cell activation and CD25 through a copper‐dependent mechanism. FASEB J. 27, 782–792 (2013). www.fasebj.org

Common complex diseases are likely influenced by the interplay of hundreds, or even thousands, of genetic variants. Converging evidence shows that genetic variants with low marginal effects (LMEs) play an important role in disease development. Despite their potential significance, discovering LME genetic variants and assessing their joint association on high‐dimensional data (e.g., genome‐wide data) remain a great challenge. To facilitate joint association analysis among a large ensemble of LME genetic variants, we proposed a computationally efficient and powerful approach, which we call Trees Assembling Mann‐Whitney (TAMW). Through simulation studies and an empirical data application, we found that TAMW outperformed multifactor dimensionality reduction (MDR) and the likelihood ratio‐based Mann‐Whitney approach (LRMW) when the underlying complex disease involves multiple LME loci and their interactions. For instance, in a simulation with 20 interacting LME loci, TAMW attained a higher power (power = 0.931) than both MDR (power = 0.599) and LRMW (power = 0.704). In an empirical study of 29 known Crohn's disease (CD) loci, TAMW also identified a stronger joint association with CD than those detected by MDR and LRMW. Finally, we applied TAMW to Wellcome Trust CD GWAS to conduct a genome‐wide analysis. The analysis of 459K single nucleotide polymorphisms was completed in 40 hrs using parallel computing, and revealed a joint association predisposing to CD (P‐value = 2.763 × 10−19). Further analysis of the newly discovered association suggested that 13 genes, such as ATG16L1 and LACC1, may play an important role in CD pathophysiological and etiological processes.