Diffuse large B-cell lymphoma (DLBCL) prognostication requires additional biologic markers. miRNAs may constitute markers for cancer diagnosis, outcome, or therapy response. In the present study, we analyzed the miRNA expression profile in a retrospective multicenter series of 258 DLBCL patients uniformly treated with chemoimmunotherapy. Findings were correlated with overall survival (OS) and progression-free survival (PFS). miRNA and gene-expression profiles were studied using microarrays in an initial set of 36 cases. A selection of miRNAs associated with either DLBCL molecular subtypes (GCB/ABC) or clinical outcome were studied by multiplex RT-PCR in a test group of 240 cases with available formalinfixed, paraffin-embedded (FFPE) diagnostic samples. The samples were divided into a training set (123 patients) and used to derive miRNA-based and combined (with IPI score) Cox regression models in an independent validation series (117 patients). Our model based on miRNA expression predicts OS and PFS and improves upon the predictions based on clinical variables. Combined models with IPI score identified a high-risk group of patients with a 2-year OS and a PFS probability of < 50%. In summary, a precise miRNA signature is associated with poor clinical outcome in chemoimmunotherapy-treated DLBCL patients. This information improves upon IPI-based predictions and identifies a subgroup of candidate patients for alternative therapeutic regimens. (Blood. 2011; 118(4):1034-1040) IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in adults, accounting for Ͼ 80% of aggressive lymphomas. 1 DLBCL is a heterogeneous group of tumors with different genetic abnormalities, clinical features, responses to treatment, and prognosis. 2 This heterogeneity hinders outcome prediction based on clinical and/or molecular parameters.Combination therapy that associates CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with rituximab (R-CHOP) has become a standard treatment for DLBCL, leading to complete remission rates of 75%-80% and a 3-to 5-year PFS of 50%-60%. [3][4][5][6][7][8] Nevertheless, patients who fail to respond to first-line therapy or relapse continue to pose a challenge, and identification at diagnosis of poor-outcome cases is crucial for deciding between alternative treatment schemes.The International Prognostic Index (IPI) has been the primary clinical tool for predicting the outcome of patients with aggressive non-Hodgkin lymphoma. 9 Original IPI factors were redistributed in patients treated with R-CHOP to give a revised score (R-IPI) that distinguishes 3 prognostic categories, with 4-year survival rates ranging from 94%-55% for poor-risk patients. 7 Nevertheless, the R-IPI does not discriminate patients with Ͻ 50% probability of survival, which restricts its clinical value. 7 The biologic heterogeneity of DLBCL has been shown substantially to reflect the cell origin of these tumors from germinal center or activated B cells. These differences are significant ind...
Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand–receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Significance: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception. This article is highlighted in the In This Issue feature, p. 2355
Telomere dysfunction is a crucial event in malignant transformation and tumorigenesis. Telomere length in peripheral blood leukocytes has been associated with lung cancer risk, but the relationship has remained controversial. In this study, we investigated whether the association might be confounded by study of different histological subtypes of lung cancer. We measured relative telomere lengths in patients in a large case-control study of lung cancer and performed stratified analyses according to the two major histological subtypes (adenocarcinoma [AC] and squamous cell carcinoma [SCC]). Notably, AC patients had longer telomeres than controls, whereas SCC patients had shorter telomeres compared to controls. Long telomeres were associated with increased risk of AC, with the highest risk associated with female sex, younger age (<60 years) and lighter smoking (<30 pack-years). In contrast, long telomeres were protective against SCC, particularly in male patients. Our results extend the concept that telomere length affects risk of lung cancer in a manner that differs with histological subtype.
Background Patients with colorectal adenoma polyps (PLP) are at higher risk of developing colorectal cancer (CRC). However, the development of improved and robust biomarkers to enable screening, surveillance and early detection of PLP and CRC continues to be a challenge. The aim of this study was to identify biomarkers of progression to CRC by metabolomic profiling of human serum samples using a multistage approach. Methods Metabolomic profiling was conducted using Metabolon platform for 30 PLP, 30 CRC and 30 control subjects followed by targeted validation of top metabolites in an additional set of 50 CRC, 50 PLP and 50 controls using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Unconditional multivariable logistic regression models adjusted for covariates were used to evaluate association with PLP and CRC risks. Results For the discovery phase, 404 serum metabolites were detected with 50 metabolites showing differential levels between PLP, CRC and controls (P for trend<0.05). Following validation, three top metabolites (xanthine, hypoxanthine and D-mannose) were validated showing lower levels of xanthine and hypoxanthine and higher level of D-mannose in PLP and CRC cases compared to controls. Further exploratory analysis of metabolic pathways revealed key roles for urea cycle and caffeine metabolism associated with PLP and CRC risks. Additionally, joint effect of top metabolites with smoking and significant interaction with BMI were also observed. Analysis of hypoxanthine to xanthine levels as ratio indicated association with CRC progression. Conclusions Our results suggest the potential utility of circulating metabolites as novel biomarkers for early detection of CRC.
A subset of patients with advanced classical Hodgkin's lymphoma is refractory to standard therapies. Therefore, it is relevant to identify new biologically-based prognostic markers. Recently, tumor associated macrophages have been proposed as a factor that predicts survival, although contradictory results have also been reported. Here we analyzed four macrophage markers (CD68, CD163, LYZ, and STAT1) using immunohistochemistry and automated quantification, in two independent series of advanced classical Hodgkin's lymphoma (n=266 and 103 patients, respectively). Our results did not confirm that specific macrophage immunohistochemical markers could be used as surrogates for gene expression profiling studies. Survival analyses did not show correlation between CD163, LYZ or STAT1 and either failure-free or disease-specific survival. There was an association between CD68 and disease-specific survival, but it was not consistent in both series. In conclusion, individual tumor associated macrophage markers cannot be used to predict outcome before technical standardization and prospective validation in independent series of patients with comparable stages and treatments.Key words: Hodgkin's lymphoma, outcome, tumor associated macrophages. Hodgkin's lymphoma. Haematologica 2012;97(7): 1080-1084. doi:10.3324/haematol.2011 This is an open-access paper. Citation: Sánchez-Espiridión B, Martin-Moreno AM, Montalbán C, Medeiros LJ, Vega F, Younes A, Piris MA, and Garcia JF. Immunohistochemical markers for tumor associated macrophages and survival in advanced classical ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nstage disease who had a survival rate of 100%. These results suggest that semi-quantitative assessment of CD68 + TAMs can be used to identify patients at high risk of disease relapse or progression, as well as patients with early-stage disease with low risk for relapse who are currently over-treated.11 However, this approach has a major drawback as the number of low-risk patients in the Steidl et al. study was low because very few cases of cHL had less than 5% of TAM. Therefore, about 72% of cases in the original report fall into the high-risk group 10 and might be selected for alternative treatments.Similar results about the predictive value of TAM in cHL have recently been reported by other groups. 12,13 However, the consistency of IHC markers in different series has not been clearly confirmed.14,15 Differences in the composition of the case series, technical variability, and different cut offs for expression of TAM associated markers could, in part, explain these diverse results. Also, roles for Epstein-Barr virus (EBV) and age as confounding factors have been claimed, since both variables influence the host immune response and TAM composition. 12,16We recently used GEP to identify specific genes associated with treatment failure in cHL patients 8,17 including gene signatures associated with reactive cells in the microenvironment. This gene signature was related to outcome in a selected series of advanced s...
Purpose: Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), f30% of patientsinadvancedstagesmayeventuallydie as resultof the disease,andcurrentmethods topredict prognosis are ratherunreliable.Thus, the applicationof robust techniques for theidentificationofbiomarkers associated with treatment response is essentialif new predictive tools are to be developed. Experimental Design: We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functionalpathways associated withunfavorable outcome that were significantly enrichedin either the Hodgkin's and Reed-Sternberg cells (regulation of the G 2 -M checkpoint, chaperones, histone modification, and signalingpathways) or the reactive cellmicroenvironment (mainly representedby specificT-cell populations and macrophage activation markers). Results:To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach. Conclusions:The results of this assay can be combined in a single risk score integrating these biologicalpathways associated with treatment response and eventually usedina larger series to develop a new molecular outcome predictor for advanced cHL.
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