Purpose: This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. Experimental Design: In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005–10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. Conclusions: Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks. Clin Cancer Res; 21(19); 4286–93. ©2015 AACR. See related commentary by van Elsas et al., p. 4251
These results demonstrate that tissue-specific miRNAs may serve as diagnostically sensitive plasma biomarkers of tissue injury.
Background: Glomerular filtration rate (GFR) is routinely assessed by measuring the concentrations of endogenous serum markers such as blood urea nitrogen and serum creatinine (SCr). Although widely used, these endogenous markers are not ideal and do not perform optimally in certain clinical settings. The purpose of this review is to critically review the potential utility of cystatin C (CysC), especially in patient populations in which CysC may have an advantage over routinely used endogenous markers of GFR. Approach: In a narrative approach, we extensively review publications, primarily from the last 5 years, that address the development of methods to measure CysC, reference intervals, and the diagnostic accuracy of CysC to assess GFR. Between June 2000 and September 2001 Medline was searched using “cystatin c” as a textword, and articles that examined >75 individuals (except for renal transplant studies) and/or used accepted “gold standards” for assessing GFR were selected for inclusion. A total of 17 studies are reviewed that provide reference interval data for several populations. A total of 24 studies make conclusions about the utility of CysC vs SCr and/or creatinine clearance, with 20 providing data on the sensitivity and specificity of CysC for detecting impaired GFR. These publications are organized into subgroups that deal with specific patient populations or clinical situations. Content: This review focuses on two areas: (a) the evolution of immunoassays used to determine the concentration of CysC in serum, their analytic sensitivity, and reference intervals; and (b) the diagnostic performance of CysC against other renal markers in the general population and in specific subpopulations of patients. Summary: Studies of reference intervals for CysC overwhelmingly demonstrated that CysC values in blood are independent of age and sex. Of the 24 studies that examined clinical utility, 15 concluded that CysC is superior to SCr, whereas 9 concluded that CysC is equivalent but provides no advantage. Summary ROC plot analysis of 20 studies that provide sensitivity and specificity data strongly suggests that CysC will be superior to SCr for detecting impaired GFR. Taken together, it is clear that CysC performs at least as well as SCr in the population at large and that it is likely to be superior to SCr in specific patient populations.
background: Definitive diagnosis of Alzheimer disease (AD) can be made only by histopathological examination of brain tissue, prompting the search for premortem disease biomarkers. We sought to determine if the novel brain injury biomarker, visinin-like protein 1 (VLP-1), is altered in the CSF of AD patients compared with controls, and to compare its values to the other well-studied CSF biomarkers 42-amino acid amyloid-β peptide (Aβ1–42), total Tau (tTau), and hyperphosphorylated Tau (pTau). methods: Using ELISA, we measured concentrations of Aβ1–42, tTau, pTau, and VLP-1 in CSF samples from 33 AD patients and 24 controls. We compared the diagnostic performance of these biomarkers using ROC curves. results: CSF VLP-1 concentrations were significantly higher in AD patients [median (interquartile range) 365 (166) ng/L] compared with controls [244 (142.5) ng/L]. Although the diagnostic performance of VLP-1 alone was comparable to that of Aβ, tTau, or pTau alone, the combination of the 4 biomarkers demonstrated better performance than each individually. VLP-1 concentrations were higher in AD subjects with APOE ε4/ε4 genotype [599 (240) ng/L] compared with ε3/ε4 [376 (127) ng/L] and ε3/ε3 [280 (115.5) ng/L] genotypes. Furthermore, VLP-1 values demonstrated a high degree of correlation with pTau (r = 0.809) and tTau (r = 0.635) but not Aβ1–42 (r = −0.233). VLP-1 was the only biomarker that correlated with MMSE score (r = −0.384, P = 0.030). conclusions: These results suggest that neuronal injury markers such as VLP-1 may have utility as biomarkers for AD.
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