Plasma microRNA profiling: Exploring better biomarkers for lymphoma surveillance

<div><p>Early detection of relapsed lymphoma improves response and survival. Current tools lack power for detection of early relapse, while being cumbersome and expensive. We searched for sensitive biomarkers that precede clinical relapse, and serve for further studies on therapy response and relapse. We recruited 20 healthy adults, 14 diffuse large B-cell lymphoma (DLBCL) patients and 11 Hodgkin lymphoma (HL) patients at diagnosis. Using small-RNA sequencing we identified in DLBCL patients increased plasma levels of miR-124 and miR-532-5p, and decreased levels of miR-425, miR-141, miR-145, miR-197, miR-345, miR-424, miR-128 and miR-122. In the HL group, we identified miR-25, miR-30a/d, miR-26b, miR-182, miR-186, miR-140* and miR-125a to be up-regulated, while miR-23a, miR-122, miR-93 and miR-144 were down-regulated. Pathway analysis of potential mRNAs targets of these miRNA revealed in the DLBCL group potential up-regulation of STAT3, IL8, p13k/AKT and TGF-B signaling, and potential down-regulation of the PTEN and p53 pathways; while in the HL group we have found the cAMP-mediated pathway and p53 pathway to be potentially down-regulated. Survival analyses revealed that plasma levels of miR-20a/b, miR-93 and miR-106a/b were associated with higher mortality. In conclusion, we identified sets of dysregulated circulating miRNA that might serve as reliable biomarkers for relapsed lymphoma.</p></div

Activity and Tolerability of Nilotinib A Retrospective Multicenter Analysis of Chronic Myeloid Leukemia Patients Who Are Imatinib Resistant or Intolerant

BACKGROUND: Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications. METHODS: Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT). RESULTS: Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P = .0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting. CONCLUSIONS: Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. Cancer 2010;116:4564-72. (C) 2010 American Cancer Society

Clinical characteristics of study participants.

<p>Clinical characteristics of study participants.</p

Top 10 influential miRNA for classification; inclusion rate in 200 iterations, each retaining 80 miRNAs.

<p>Top 10 influential miRNA for classification; inclusion rate in 200 iterations, each retaining 80 miRNAs.</p

Box plots showing levels of top 10 miRNA in healthy controls' plasma and corresponding levels in paired exosome preparations.

<p>Statistically differences between plasma and exosomes are not significant, as inferred from a DESeq2 analysis presented in Table A in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0187722#pone.0187722.s002" target="_blank">S2 File</a>.</p

miRNA profiles in patients vs. controls.

<p>(<b>A</b>) Principal component (PC) analysis plots based on miRNA profiles; left panel—PC2 vs. PC1, right panel—PC2 vs. PC4. (<b>B&C</b>) Differentially expressed miRNA in DLBCL patients (<b>B</b>) or HL patients (<b>C</b>) compared to healthy controls according to three independent statistical approaches. Red shades represent upregulated miRNA while green shades represent downregulated miRNA. Row annotations (left to right) represent the overall abundance of each miRNA and the statistical significance according to limma, edgeR and DESeq2 approaches.</p