International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)

Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR: 2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities (t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1, intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years, respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical research and routine practice and will be widely applicable

Endothelial progenitor cells display clonal restriction in multiple myeloma

BACKGROUND: In multiple myeloma (MM), increased neoangiogenesis contributes to tumor growth and disease progression. Increased levels of endothelial progenitor cells (EPCs) contribute to neoangiogenesis in MM, and, importantly, covary with disease activity and response to treatment. In order to understand the mechanisms responsible for increased EPC levels and neoangiogenic function in MM, we investigated whether these cells were clonal by determining X-chromosome inactivation (XCI) patterns in female patients by a human androgen receptor assay (HUMARA). In addition, EPCs and bone marrow cells were studied for the presence of clonotypic immunoglobulin heavy-chain (IGH) gene rearrangement, which indicates clonality in B cells; thus, its presence in EPCs would indicate a close genetic link between tumor cells in MM and endothelial cells that provide tumor neovascularization. METHODS: A total of twenty-three consecutive patients who had not received chemotherapy were studied. Screening in 18 patients found that 11 displayed allelic AR in peripheral blood mononuclear cells, and these patients were further studied for XCI patterns in EPCs and hair root cells by HUMARA. In 2 patients whose EPCs were clonal by HUMARA, and in an additional 5 new patients, EPCs were studied for IGH gene rearrangement using PCR with family-specific primers for IGH variable genes (V(H)). RESULTS: In 11 patients, analysis of EPCs by HUMARA revealed significant skewing (≥ 77% expression of a single allele) in 64% (n = 7). In 4 of these patients, XCI skewing was extreme (≥ 90% expression of a single allele). In contrast, XCI in hair root cells was random. Furthermore, PCR amplification with V(H )primers resulted in amplification of the same product in EPCs and bone marrow cells in 71% (n = 5) of 7 patients, while no IGH rearrangement was found in EPCs from healthy controls. In addition, in patients with XCI skewing in EPCs, advanced age was associated with poorer clinical status, unlike patients whose EPCs had random XCI. CONCLUSION: Our results suggest that EPCs in at least a substantial subpopulation of MM patients are related to the neoplastic clone and that this is an important mechanism for upregulation of tumor neovascularization in MM

Calculating Stage Duration Statistics in Multistage Diseases

Many human diseases are characterized by multiple stages of progression. While the typical sequence of disease progression can be identified, there may be large individual variations among patients. Identifying mean stage durations and their variations is critical for statistical hypothesis testing needed to determine if treatment is having a significant effect on the progression, or if a new therapy is showing a delay of progression through a multistage disease. In this paper we focus on two methods for extracting stage duration statistics from longitudinal datasets: an extension of the linear regression technique, and a counting algorithm. Both are non-iterative, non-parametric and computationally cheap methods, which makes them invaluable tools for studying the epidemiology of diseases, with a goal of identifying different patterns of progression by using bioinformatics methodologies. Here we show that the regression method performs well for calculating the mean stage durations under a wide variety of assumptions, however, its generalization to variance calculations fails under realistic assumptions about the data collection procedure. On the other hand, the counting method yields reliable estimations for both means and variances of stage durations. Applications to Alzheimer disease progression are discussed

Prevalence of bisphosphonate associated osteonecrosis of the jaws in multiple myeloma patients

<p>Abstract</p> <p>Background</p> <p>Bisphosphonate-associated osteonecrosis of the jaws (BP-ONJ) is an adverse effect of bisphosphonate treatment with varying reported incidence rates.</p> <p>Methods</p> <p>In two neighboring German cities, prevalence and additional factors of the development of BP-ONJ in multiple myeloma patients with bisphosphonates therapy were recorded using a retrospective (RS) and cross-sectional study (CSS) design. For the RS, all patients treated from Jan. 2000 - Feb. 2006 were contacted by letter. In the CSS, all patients treated from Oct. 2006 - Mar. 2008 had a physical and dental examination. Additionally, a literature review was conducted to evaluate all articles reporting on BP-ONJ prevalence. PubMed search terms were: bisphosphonat, diphosphonate, osteonecrosis, prevalence and incidence.</p> <p>Results</p> <p>In the RS, data from 81 of 161 patients could be obtained; four patients (4.9%) developed BP-ONJ. In the CSS, 16 of 78 patients (20.5%) developed BP-ONJ. All patients with BP-ONJ had received zoledronate; 12 of these had had additional bisphosphonates. All except one had an additional trigger factor (tooth extraction [n = 14], dental surgical procedure [n = 2], sharp mylohyoid ridge [n = 3]).</p> <p>Conclusion</p> <p>The prevalence of BP-ONJ may have been underestimated to date. The oral examination of all patients in this CSS might explain the higher prevalence, since even early asymptomatic stages of BP-ONJ and previously unnoticed symptomatic BP-ONJ were recorded. Since nearly all patients with BP-ONJ had an additional trigger factor, oral hygiene and dental care might help to reduce BP-ONJ incidence.</p

What potential has tobacco control for reducing health inequalities? The New Zealand situation

In this Commentary, we aim to synthesize recent epidemiological data on tobacco and health inequalities for New Zealand and present it in new ways. We also aim to describe both existing and potential tobacco control responses for addressing these inequalities. In New Zealand smoking prevalence is higher amongst Māori and Pacific peoples (compared to those of "New Zealand European" ethnicity) and amongst those with low socioeconomic position (SEP). Consequently the smoking-related mortality burden is higher among these populations. Regarding the gap in mortality between low and high socioeconomic groups, 21% and 11% of this gap for men and women was estimated to be due to smoking in 1996–99. Regarding the gap in mortality between Māori and non-Māori/non-Pacific, 5% and 8% of this gap for men and women was estimated to be due to smoking. The estimates from both these studies are probably moderate underestimates due to misclassification bias of smoking status. Despite the modest relative contribution of smoking to these gaps, the absolute number of smoking-attributable deaths is sizable and amenable to policy and health sector responses. There is some evidence, from New Zealand and elsewhere, for interventions that reduce smoking by low-income populations and indigenous peoples. These include tobacco taxation, thematically appropriate mass media campaigns, and appropriate smoking cessation support services. But there are as yet untried interventions with major potential. A key one is for a tighter regulatory framework that could rapidly shift the nicotine market towards pharmaceutical-grade nicotine (or smokeless tobacco products) and away from smoked tobacco

CD40: Novel Association with Crohn's Disease and Replication in Multiple Sclerosis Susceptibility

Background: A functional polymorphism located at 21 from the start codon of the CD40 gene, rs1883832, was previously reported to disrupt a Kozak sequence essential for translation. It has been consistently associated with Graves’ disease risk in populations of different ethnicity and genetic proxies of this variant evaluated in genome-wide association studies have shown evidence of an effect in rheumatoid arthritis and multiple sclerosis (MS) susceptibility. However, the protective allele associated with Graves’ disease or rheumatoid arthritis has shown a risk role in MS, an effect that we aimed to replicate in the present work. We hypothesized that this functional polymorphism might also show an association with other complex autoimmune condition such as inflammatory bowel disease, given the CD40 overexpression previously observed in Crohn’s disease (CD) lesions. Methodology: Genotyping of rs1883832C.T was performed in 1564 MS, 1102 CD and 969 ulcerative colitis (UC) Spanish patients and in 2948 ethnically matched controls by TaqMan chemistry. Principal Findings: The observed effect of the minor allele rs1883832T was replicated in our independent Spanish MS cohort [p= 0.025; OR (95% CI)= 1.12 (1.01–1.23)]. The frequency of the minor allele was also significantly higher in CD patients than in controls [p= 0.002; OR (95% CI)= 1.19 (1.06–1.33)]. This increased predisposition was not detected in UC patients [p= 0.5; OR (95% CI)= 1.04 (0.93–1.17)]. Conclusion: The impact of CD40 rs1883832 on MS and CD risk points to a common signaling shared by these autoimmune conditions.Peer reviewe