ABSTRACT
Background-smoldering multiple myeloma (SMM) risk of progression to multiple myeloma (MM) is highly heterogeneous and several models have been suggested to predict this risk. Lakshman et al. recently proposed a model based on three biomarkers: bone marrow plasma cell (BMPC) percentage > 20%, free light chain ratio (FLCr) > 20 and serum M protein > 20 g/L. The goal of our study was to test this "20/20/20" model in our population and to determine if similar results could be obtained in another cohort of SMM patients. Method-we conducted a retrospective, single center study with 89 patients diagnosed with SMM between January 2008 and December 2019. Results-all three tested biomarkers were associated with an increased risk of progression: BMPC percentage ≥ 20% (hazard ratio [HR]: 4.28 [95%C.I., 1.90-9.61]; p < 0.001), serum M protein ≥ 20 g/L (HR: 4.20 [95%C.I., 1.90-15.53]; p = 0.032) and FLCr ≥ 20 (HR: 3.25 [95%C.I., 1.09-9.71]; p = 0.035). The estimated median time to progression (TTP) was not reached for the low and intermediate risk groups and was 29.1 months (95%C.I., 3.9-54.4) in the high-risk group (p = 0.006). Conclusions-the 20/20/20 risk stratification model adequately predicted progression in our population and is easy to use in various clinical settings.
Subject(s)
Multiple Myeloma , Smoldering Multiple Myeloma , Disease Progression , Humans , Multiple Myeloma/diagnosis , Multiple Myeloma/epidemiology , Retrospective Studies , Risk Factors , Smoldering Multiple Myeloma/diagnosis , Smoldering Multiple Myeloma/etiologyABSTRACT
INTRODUCTION: Fluorescence in situ hybridization (FISH) is currently the standard for diagnosing anaplastic lymphoma kinase (ALK)-rearranged (ALK+) lung cancers for ALK inhibitor therapies. ALK immunohistochemistry (IHC) may serve as a screening and alternative diagnostic method. The Canadian ALK (CALK) study was initiated to implement a multicenter optimization and standardization of laboratory developed ALK IHC and FISH tests across 14 hospitals. METHODS: Twenty-eight lung adenocarcinomas with known ALK status were used as blinded study samples. Thirteen laboratories performed IHC using locally developed staining protocols for 5A4, ALK1, or D5F3 antibodies; results were assessed by H-score. Twelve centers conducted FISH using protocols based on Vysis' ALK break-apart FISH kit. Initial IHC results were used to optimize local IHC protocols, followed by a repeat IHC study to assess the results of standardization. Three laboratories conducted a prospective parallel IHC and FISH analysis on 411 consecutive clinical samples using post-validation optimized assays. RESULTS: Among study samples, FISH demonstrated 22 consensus ALK+ and six ALK wild type tumors. Preoptimization IHC scores from 12 centers with 5A4 and the percent abnormal cells by FISH from 12 centers showed intraclass correlation coefficients of 0.83 and 0.68, respectively. IHC optimization improved the intraclass correlation coefficients to 0.94. Factors affecting FISH scoring and outliers were identified. Post-optimization concurrent IHC/FISH testing in 373 informative cases revealed 100% sensitivity and specificity for IHC versus FISH. CONCLUSIONS: Multicenter standardization study may accelerate the implementation of ALK testing protocols across a country/region. Our data support the use of an appropriately validated IHC assay to screen for ALK+ lung cancers.
Subject(s)
Adenocarcinoma/enzymology , Lung Neoplasms/enzymology , Receptor Protein-Tyrosine Kinases/metabolism , Adenocarcinoma/diagnosis , Adenocarcinoma/genetics , Adenocarcinoma of Lung , Anaplastic Lymphoma Kinase , Canada , DNA, Neoplasm/genetics , Female , Follow-Up Studies , Humans , Immunohistochemistry , In Situ Hybridization, Fluorescence/methods , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Male , Middle Aged , Prospective Studies , Receptor Protein-Tyrosine Kinases/genetics , Reproducibility of Results , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Evaluation of genotoxic effects of potassium chromate (K2CrO4) and cadmium chloride (CdCl2) was carried out in human blood lymphocytes in vitro as measured by the electron microscopy in situ end-labeling (EM-ISEL). EM-ISEL was used to assess DNA single-strand breaks (SSBs) expressed as number of immunogold particles per microm2 of chromatin at both chromosomal and nuclear DNA levels. Human lymphocytes were cultured in supplemented RPMI medium for 72 h including treatment for 2 h with K2CrO4 (0-150 microM), CdCl2 (0-150 microM) or methyl methanesulfonate (500 microM) as a positive control. Quantification of SSBs by EM-ISEL showed that both compounds are genotoxic agents at non-cytotoxic concentrations. This study brings new information on the utility of EM-ISEL for the evaluation of genotoxicity and confirms the genotoxic effects induced by chromium and cadmium.
