Oxidants, antioxidants, and respiratory tract lining fluids.

Respiratory tract lining fluids (RTLFs) are a heterogeneous group of substances covering the respiratory tract epithelial cells (RTECs) from nasal mucosa to alveoli. Antioxidant contained in the RTLFs can be expected to provide an initial defense against inhaled environmental toxins. The major antioxidants in RTLF include mucin, uric acid, protein (largely albumin), ascorbic acid, and reduced glutathione (GSH). RTLF antioxidants can be augmented by such processes as transudation/exudation of plasma constituents; RTEC secretory processes, including glandular mucus secretion; and cellular antioxidants derived from lysis of RTECs and of inflammatory cells. The antioxidant composition of RTLFs and their role in modulating normal and pathophysiologic RTEC functions under conditions of oxidative stress are yet to be fully characterized

A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma

PURPOSE: MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy. PATIENTS AND METHODS: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles. RESULTS: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% [7/42; 95% confidence interval (CI), 7.0-31.4] with combination treatment and 23.8% (5/21; 95% CI, 8.2-47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. CONCLUSIONS: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy

Validation of Serum Amyloid alpha as an Independent Biomarker for Progression-Free and Overall Survival in Metastatic Renal Cell Cancer Patients

Background: We recently identified apolipoprotein A2 (ApoA2) and serum amyloid a (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model. Objective: Validate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs). Design, setting, and participants: For training we used 114 interferon-treated mRCC patients (inclusion 2001-2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003-2009). Measurements: Using Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect. Results and limitations: Baseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA le Conclusions: SAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved

Minimally important differences for interpreting European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 scores in patients with head and neck cancer

Background: We aimed to estimate minimally important difference (MID) for interpreting group‐level change over time for European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQ‐C30) scores in head and neck cancer. Methods: Data were derived retrospectively from two published EORTC trials. Clinical anchors were selected using correlation strength and clinical plausibility of the given anchor/QLQ‐C30 scale pair. MIDs for within‐group and between‐group change were estimated via the mean change method and linear regression, respectively. Distribution‐based MIDs were also examined. MIDs for two of the scales, dyspnea and nausea/vomiting, are more uncertain considering their low correlations with the anchors. Results: Anchor‐based MIDs could be determined for deterioration in 7 of the 14 QLQ‐C30 scales assessed, and in 3 scales for improvement. MIDs varied by scale, direction of change, and anchor. Absolute MID values ranged from 5 to 15 points for within‐group change and 4 to 12 for between‐group change. Most MIDs were within 4 to 10 points. Conclusions: Our findings, if confirmed, will aid interpreting changes in selected QLQ‐C30 scale scores over time and inform sample size calculations in future clinical trials in head and neck cancer