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Concept: Monoclonal gammopathy of undetermined significance

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The purpose of this study was to determine if there is an increased risk of acute leukemia and myelodysplastic syndromes (MDS) in persons with monoclonal gammopathy of undetermined significance (MGUS). We utilized a large population-based cohort of individuals systematically screened for the presence or absence of MGUS. MGUS status was then linked to the diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and MDS. 17 315 patients age 50 and older (605 MGUS and 16 710 controls) with a cumulative 435 021 person-years of follow-up were studied. MGUS patients had a significantly higher risk of developing MDS compared with controls, hazard ratio 2.4 (95%CI 1.08,5.32), P=0.031. There was no statistically significant increase in the risk of AML (RR 1.36 P=0.675), and no increased risk of developing ALL.Leukemia accepted article preview online, 5 February 2013; doi:10.1038/leu.2013.34.

Concepts: Hematology, Leukemia, Acute myeloid leukemia, Blood disorders, Acute lymphoblastic leukemia, Monoclonal gammopathy of undetermined significance, Myelodysplastic syndrome, French-American-British classification

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High resolution digital imaging systems were recently introduced to capture and visualize serum protein electrophoresis results. In this study, we compared the performance of five, experienced interpreters using digital images and physical gels to identify and characterize monoclonal gammopathies by immunofixation.

Concepts: Gel electrophoresis, Computer graphics, Electrophoresis, Digital photography, Monoclonal gammopathy of undetermined significance, Protein electrophoresis, Digital image, Serum protein electrophoresis

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A 12-year-old, spayed female, mixed-breed dog was presented for acute hematuria, stranguria, polyuria, and polydipsia, as well as lameness for 8 days. Previous medical history included treatment for infection with Ehrlichia canis, Anaplasma phagocytophilum, Leishmania infantum, and Dirofilaria immitis 6.5 years prior to presentation. Besides persistently increased antibody titers to E canis and A phagocytophilum, polyclonal gammopathy with a monoclonal spike and moderate hypercalcemia were observed. There was marked hematuria, and Staphylococcus aureus was cultured from urine. Two weeks after successful treatment of the urinary tract infection, radiographs showed an extensive destructive monostotic lesion of the right humerus. Cytologic examination of fine-needle aspirates of this lesion revealed a neoplastic round cell population suggestive of multiple myeloma. The dog was treated with melphalan and prednisolone for suspected multiple myeloma and doxycycline for suspected ehrlichiosis and anaplasmosis. Treatments lead to resolution of the clinical signs, hypercalcemia, and monoclonal gammopathy, and there was radiographic improvement of bone lesions; polyclonal gammopathy persisted. About one year after presentation the dog was still in clinical remission. This is a rare report of a dog with suspected multiple myeloma and a history of multiple chronic infectious diseases, suggesting that chronic infection and uncontrolled long-term stimulation of the immune system could contribute to the pathogenesis of multiple myeloma.

Concepts: Immune system, Medicine, Infectious disease, Staphylococcus aureus, Urine, Infection, Monoclonal gammopathy of undetermined significance, Dog

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The exact function of MAGE-C1/CT7 and MAGE-C2/CT10 is not yet understood in multiple myeloma (MM). However, the homologs MAGE-C1/CT7 and MAGE-C2/CT10 genes encode highly immunogeneic cancer/testis antigens (CTAs) and can be potential targets for T cell-based immunotherapy. MAGE-C1/CT7 and MAGE-C2/CT10 mRNA expression were investigated in MM patients, solitary plasmacytomas, monoclonal gammopathies of undetermined significance (MGUS) and bone marrow (BM) aspirates from healthy donors by RT-PCR. MAGE-C1/CT7 and MAGE-C1/CT10 were expressed in 67 and 59 % of the 46 MM analyzed patients. At least one of the genes was expressed in 76 % of MM cases. Solitary plasmacytoma also showed MAGE-C1/CT7 and MAGE-C2/CT10 expression. MAGE-C1/CT7 and MAGE-C2/CT10 were not expressed in normal BM samples, showing restricted expression of these CTA genes in MM, solitary plasmacytoma and MGUS. In the present study, we found high expression of the homologs MAGE-C1/CT7 and MAGE-C2/CT10 in monoclonal gammopathies and speculate whether these genes might represent a valuable therapeutic option for myeloma, in particular for combined immunotherapy.

Concepts: Multiple myeloma, Genetics, Gene expression, Bone marrow, Monoclonal gammopathy of undetermined significance, Protein electrophoresis, Plasmacytoma, Paraprotein

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The prevalence of monoclonal gammopathy of undetermined significance (MGUS) is generally estimated at 3.4% in the general population over 50 years, and its incidence increases with age. MGUS represents a preneoplastic entity that can transform into multiple myeloma or other lymphoproliferative disorders. The risk of malignant transformation is estimated at 1% per year and persists over time. Predictors of malignant transformation have been identified such as the heavy chain isotype, The level of monoclonal proteins, increasing levels of the monoclonal component during the first years off follow-up, the percentage of bone marrow plasmocytosis, the dosage of serum free light chains, the presence of immunophenotypically abnormal plasma cells, aneuploidy, and the presence of circulating plasma cells. Prognostic scores that combine certain of these factors have been proposed and allow the identification of high-risk patients. Their use could assist in tailoring the care for each patient, based on his/her risk profile.

Concepts: Multiple myeloma, Cancer, Bone marrow, Hematology, Monoclonal gammopathy of undetermined significance, Protein electrophoresis, Plasmacytoma, Paraprotein

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Serum immunoglobulin free light chain assay has proved to be an invaluable biological tool for diagnosis and monitoring of monoclonal gammopathies including multiple myeloma, primary amyloidosis, solitary plasmocytoma or monoclonal gammopathy of undetermined significance. Free light chain quantification, although essential, cannot be achieved by serum protein electrophoresis either because there is no monoclonal peak or because the peak is hidden in beta or alpha-globulin fraction. As for serum protein immunofixation, this major test allows the typing of the paraprotein but does not provide any quantitative evaluation. Hence, the development of free light chain assays constitutes a significant improvement in the management of these patients. In this context, we compared the results of serum free light chains quantification and of calculation of the ratio kappa/lambda, indicator of monoclonality, in forty samples performed on BN ProSpec(®) analyzer, with the two methods available on the European market. This comparative analysis provided evidence of a good correlation of results between the two methods. However, we noticed clinically significant differences in four samples. In addition, this evaluation highlighted the fact that all free light chain results must be biologically validated on the light of different criteria such as serum protein electrophoresis, serum protein immunofixation, presence of proteinuria, presence of renal failure, and additional clinical data, in order to ascertain the best interpretation for clinical use.

Concepts: Multiple myeloma, Gel electrophoresis, Electrophoresis, Monoclonal gammopathy of undetermined significance, Protein electrophoresis, Immunoglobulin light chain, Paraprotein, Serum protein electrophoresis

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The daily productivity of a clinical laboratory depends on the large number of interferences that affect analytical accuracy. Obviously, they have always been considered as a very important aspect to keep accuracy under control. Nevertheless, we wondered if this aspect would be beneficial. In this article, we propose a method for finding monoclonal gammopathies that are based on the fact that the presence of paraprotein in the sample may interfere with routine laboratory assays, specifically, with the quantification of uric acid and conjugated bilirubin.

Concepts: Scientific method, Ammonia, Diagnosis, Greek loanwords, Uric acid, Monoclonal gammopathy of undetermined significance, Medical laboratory, Interference

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The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.

Concepts: DNA, Protein, Multiple myeloma, Gene, Genetics, Histone, Chromosome, Monoclonal gammopathy of undetermined significance

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Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.

Concepts: Multiple myeloma, Clinical trial, Bone marrow, Nocebo, Chemotherapy regimens, Prognosis, Monoclonal gammopathy of undetermined significance, Virtual Karyotype

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Background Monoclonal gammopathy of undetermined significance (MGUS) occurs in approximately 3% of persons 50 years of age or older. Methods We studied 1384 patients who were residing in southeastern Minnesota and in whom MGUS was diagnosed at the Mayo Clinic in the period from 1960 through 1994; the median follow-up was 34.1 years (range, 0.0 to 43.6). The primary end point was progression to multiple myeloma or another plasma-cell or lymphoid disorder. Results During 14,130 person-years of follow-up, MGUS progressed in 147 patients (11%), a rate that was 6.5 times (95% confidence interval [CI], 5.5 to 7.7) as high as the rate in the control population. The risk of progression without accounting for death due to competing causes was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. Among patients with IgM MGUS, the presence of two adverse risk factors - namely, an abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter) - was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. Patients with MGUS had shorter survival than was expected in the control population of Minnesota residents of matched age and sex (median, 8.1 vs. 12.4 years; P<0.001). Conclusions Significant differences were noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS. Overall survival was shorter among patients with MGUS than was expected in a matched control population. (Funded by the National Cancer Institute.).

Concepts: Multiple myeloma, Statistics, Medical statistics, Risk, National Cancer Institute, Normal distribution, Monoclonal gammopathy of undetermined significance, Paraprotein