ABSTRACT
Prospective identification of patients with chronic lymphocytic leukemia (CLL) destined to progress would greatly facilitate their clinical management. Recently, whole-genome DNA methylation analyses identified three clinicobiologic CLL subgroups with an epigenetic signature related to different normal B-cell counterparts. Here, we developed a clinically applicable method to identify these subgroups and to study their clinical relevance. Using a support vector machine approach, we built a prediction model using five epigenetic biomarkers that was able to classify CLL patients accurately into the three subgroups, namely naive B-cell-like, intermediate and memory B-cell-like CLL. DNA methylation was quantified by highly reproducible bisulfite pyrosequencing assays in two independent CLL series. In the initial series (n=211), the three subgroups showed differential levels of IGHV (immunoglobulin heavy-chain locus) mutation (P<0.001) and VH usage (P<0.03), as well as different clinical features and outcome in terms of time to first treatment (TTT) and overall survival (P<0.001). A multivariate Cox model showed that epigenetic classification was the strongest predictor of TTT (P<0.001) along with Binet stage (P<0.001). These findings were corroborated in a validation series (n=97). In this study, we developed a simple and robust method using epigenetic biomarkers to categorize CLLs into three subgroups with different clinicobiologic features and outcome.
Subject(s)
B-Lymphocytes/metabolism , Biomarkers, Tumor/genetics , Epigenesis, Genetic , Immunoglobulin Heavy Chains/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Transcriptome , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , B-Lymphocytes/classification , B-Lymphocytes/pathology , DNA Methylation , Disease Progression , Female , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/classification , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Proportional Hazards Models , Support Vector Machine , Survival Analysis , Time-to-Treatment , Treatment OutcomeABSTRACT
PURPOSE: The present study examines the differences of radiological diagnosis of lumbar prolaps with quantitative and morphological criteria. Advantages and disadvantages of both methods were analysed. METHOD: Concerning the "Deutsche Wirbelsäulenstudie" (DWS) 286 male and 278 female patients between 25 and 70 years of age undergoing clinical or ambulant therapy for radicular symptoms and the diagnosis of a lumbar prolaps in CT and/or MRT were integrated into our study. Actual MRT and CT pictures of the patients' lumbar spine were analysed by an independent radiologist (primary radiologist). Radiological diagnosis was concerned with quantitative and morphological criteria. Radiological images of 100 selected patients were reexamined by another radiologist (secondary radiologist). On the basis of these results, the interobserver reliability (kappa) was calculated. RESULTS: In 95.2% of all segments a prolaps was seen with quantitative and morphological criteria, in 4.5% a prolaps was analysed with quantitative and in 0.3% a prolaps was seen with morphological criteria. The radiological diagnosis of prolaps by quantitative criteria was confirmed by the operative findings. Many prolapses with lateral localisation were seen in these cases. Therefore radiological diagnosis on the basis of morphological criteria could be difficult. For both radiological methods similar interobserver reliabilities were calculated. To sum up both radiological methods are even equivalent. It is also possible to graduate the diagnosis with quantitative criteria. Detrimental effects of quantitative criteria could be difficulties in measurement with non-digital images. CONCLUSION: Besides several recommendations in the international literature on the radiological analysis of prolaps with morphological criteria, diagnosis with quantitative criteria is also an effective method.
