Cardiovascular Morbidity in Monoclonal Gammopathy of Undetermined Significance: A Danish Nationwide Study.

Background: Monoclonal gammopathy of undetermined significance (MGUS) is associated with renal dysfunction, inflammation, and increased cardiovascular mortality, but the cardiovascular risks are not fully understood. Objectives: The authors explored the association of MGUS with a spectrum of cardiovascular diseases using the Danish nationwide databases. Methods: Between 1995 and 2018, patients 18 years and older with MGUS were age- and sex-matched (1:10) with control patients and followed prospectively until December 31, 2018, for the occurrence of cardiovascular diseases. Patients diagnosed with multiple myeloma, lymphoma, or amyloidosis were excluded. Multivariable adjusted hazard ratios (HRs) for cardiovascular outcomes were estimated using Cox proportional hazard regression. Results: Patients with MGUS (n = 8,189; mean age 69.8 ± 11.7 years; 51.2% male) had higher prevalence of cardiovascular risk factors at baseline, including hypertension (48.0% vs 38.5%) and type 2 diabetes (13.0% vs 9.3%), compared with control patients. Outcomes included an increased risk of heart failure (HR: 1.55; 95% CI: 1.41-1.69), acute myocardial infarction (HR: 1.22; 95% CI: 1.06-1.40), ischemic stroke (HR: 1.16; 95% CI: 1.03-1.30), atrial fibrillation (HR: 1.32; 95% CI: 1.23-1.42), aortic aneurysm (HR: 1.55; 95% CI: 1.28-1.89), aortic stenosis (HR: 1.60; 95% CI: 1.41-1.82), aortic regurgitation (HR: 1.67; 95% CI: 1.34-2.07), heart block (HR: 1.32; 95% CI: 1.08-1.61), peripheral artery disease (HR: 1.69; 95% CI: 1.47-1.95), cor pulmonale (HR: 2.06; 95% CI: 1.55-2.73), and venous thromboembolism (HR: 1.43; 95% CI: 1.24-1.65). A sensitivity analysis including only patients without certain comorbidities (type 2 diabetes, hypertension, acute myocardial infarction, and chronic kidney disease) yielded similar results. Conclusions: MGUS is associated with a broad spectrum of cardiovascular diseases, with greater relative risks observed for diseases previously associated with infiltrative and inflammatory disorders. Further studies are warranted to explore the underlying mechanisms.

Pulmonary Vascular Disease Due to Plasma Cell Dyscrasia.

Pulmonary hypertension (PH) has been described in myeloproliferative disorders; monoclonal plasma cell disorder such as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome; and plasma cell dyscrasias such as multiple myeloma and amyloidosis. We describe 4 cases of PH likely due to pulmonary vascular involvement and myocardial deposition from light chain deposition disease, amyloidosis, and multiple myeloma. On the basis of our clinical experience and literature review, we propose screening for plasma cell dyscrasia in patients with heart failure with preserved ejection fraction, unexplained PH, and hematological abnormalities. We also recommend inclusion of cardiopulmonary screening in patients with monoclonal gammopathy of undetermined significance.

Potential diagnostic value of circulating miRNA for multiple myeloma: A meta-analysis.

BACKGROUND: Multiple myeloma (MM) is the second incurable hematological malignancy. In recent years, due to the rise of microRNA (miRNA), many scholars have participated in the study of its value in the diagnosis of MM, and have obtained good but inconsistent results. Therefore, in order to determine the role of miRNA in the early diagnosis of MM, we performed this meta-analysis. METHODS: We searched for related studies including PubMed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Database as of July 20, 2020 to conduct this meta-analysis. To improve the accuracy, the quality assessment of Diagnostic Accuracy Study 2 (QUADAS-2) was used. We also applied random effects models to summarize sensitivity and specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and area under the curve (AUC) to measure diagnostic values, and subgroup analysis used to discover potential sources of heterogeneity. RESULTS: We finally collected 32 studies from 15 articles that included a total of 2053 MM patients and 1118 healthy controls in this meta-analysis. The overall sensitivity, specificity, PLR, NLR, DOR and AUC were 0.81, 0.85, 5.5, 0.22, 25 and 0.90, respectively. Subgroup analysis shows that the down-regulation of microRNA clusters with larger samples size of plasma type could carry out a better diagnostic accuracy of MM patients. In addition, publication bias was not found. CONCLUSIONS: Circulating miRNA could be a potential non-invasive biomarker for early diagnosis of MM. However, multi-center, more rigorous, and larger-scale studies are needed to verify our conclusions.

Temporal dispersion in demyelination of POEMS syndrome and Castleman disease.

OBJECTIVE: We detailed the electrophysiological patterns of peripheral nerve temporal dispersion across spectrum of POEMS syndrome and Castleman disease (CD). METHODS: Compound muscle action potentials (CMAP) duration of 3 patients with POEMS syndrome and 2 with hyaline vascular type CD without clonal plasma cell dyscrasia were retrospectively analysed. RESULTS: Median and ulnar nerves distal CMAP duration were prolonged in all patients irrespective of plasma cell dyscrasia or M protein. All lower limbs distal CMAP responses were absent. Greatest distal CMAP duration prolongation was observed in median nerves for POEMS syndrome (17.0 ms, 158% upper limit normal) and in ulnar nerves for CD (9.8 ms, 47% upper limit normal). Distal/proximal CMAP duration ratio of <0.7 were seen in 33% of median and ulnar nerves studied among POEMS syndrome. Among nerves with ratio >0.7, all had distal CMAP duration prolongation (Range 7%-158% of upper limit normal). CONCLUSIONS: Abnormal distal CMAP dispersion is not uncommon in POEMS syndrome and CD without clonal plasma cell dyscrasia or M protein. POEMS syndrome has greater distal CMAP duration in median and ulnar nerves, particularly in median nerve that can reach up to 150% of upper limit normal, compared to <50% in CD. SIGNIFICANCE: Detailed electrophysiological analysis of distal CMAP duration may help in distinguishing POEMS syndrome and CD.

Diagnosing cardiac amyloidosis in every-day practice: A practical guide for the cardiologist.

Cardiac amyloidosis (CA) has emerged as a previously underestimated cause of heart failure and mortality. Underdiagnosis resulted mainly from unawareness of the true disease prevalence and the non-specific symptoms of the disease. CA results from extracellular deposition of misfolded protein fibrils, commonly derived from transthyretin (ATTR) or immunoglobulin light chains (AL). A significant proportion of older patients with heart failure and other extracardiac manifestations suffer from ATTR-CA, whereas AL-CA is still considered a rare disease. This article provides an overview of CA with a special focus on current and emerging diagnostic modalities. Furthermore, we provide a diagnostic algorithm for the evaluation of patients with suspected CA in every-day practice.

Emerging Therapeutics for the Treatment of Light Chain and Transthyretin Amyloidosis.

Cardiac amyloidosis is a restrictive cardiomyopathy that results from the deposition of misfolded light chain or transthyretin proteins, most commonly, in cardiac tissue. Traditionally, treatment options for light chain (AL) and transthyretin (ATTR) amyloidosis have been limited. However, there are now multiple novel therapeutics in development and several therapeutics recently approved that promise to revolutionize clinical management of AL and ATTR. Most of these agents disrupt specific stages of amyloidogenesis such as light chain or transthyretin protein production, formation of amyloidogenic intermediates, or amyloid fibril aggregation. Others aim to remove existing amyloid tissue deposits using monoclonal antibody technology. Although these advances represent an important step forward in the care of cardiac amyloidosis patients, additional studies are needed to define the optimal treatment paradigms for AL and ATTR and to validate clinical, imaging, or serum biomarker strategies that may confirm a cardiac response to therapy.

AL Amyloidosis for the Cardiologist and Oncologist: Epidemiology, Diagnosis, and Management.

AL amyloidosis results from clonal production of immunoglobulin light chains, most commonly arising from a clonal plasma cell disorder. Once considered a nearly uniformly fatal disease, prognosis has improved markedly over the past 15 years, predominantly because of advances in light chain suppressive therapies. Cardiac deposition of amyloid fibrils is common, and the severity of cardiac involvement remains the primary driver of prognosis. Improvements in chemotherapy/immunotherapy have prompted a reassessment of the role of advanced cardiac therapies previously considered contraindicated in most patients, including the role of implantable cardioverter-defibrillators and cardiac transplantation. This state-of-the-art review highlights the current state of the field, including diagnosis, prognosis, and hematologic- and cardiac-specific therapies.

Successful Renal Outcome in Membranoproliferative Glomerulonephritis Following Treatment of the Underlying Subtle Clone: A Case Report.

Membranoproliferative glomerulonephritis (MPGN) secondary to a monoclonal gammopathy is a rare glomerular disease and is defined as a monoclonal gammopathy of renal significance. The disease is characterized by glomerular monotypic immunoglobulin deposits and specific changes on light microscopy and electron microscopy. Immunochemistry is required to establish monoclonality, and electron microscopy helps to characterize the deposits ultrastructurally. Investigation for the underlying monoclonal protein should be done. We report a case of MPGN secondary to monoclonal gammopathy of renal significance that responded to treatment of the underlying clone with chemotherapy, resulting in improvement in renal function. Patients with MPGN and immunoglobulin deposition should be evaluated for a monoclonal protein to guide the management strategy.

Monoclonal Gammopathy of Undetermined Significance: Follow-up Patterns in the United States and Concordance With Clinical Practice Guidelines.

OBJECTIVE: To determine follow-up practice patterns of US patients with monoclonal gammopathy of undetermined significance (MGUS) and their concordance with 4 clinical practice guidelines. PATIENTS AND METHODS: In a retrospective analysis of adult patients using the OptumLabs Data Warehouse database, we identified those who had an incident diagnosis of MGUS from January 1, 2006, through December 31, 2013, no history or subsequent diagnosis of lymphoplasmacytic malignancy, and at least 2 years of follow-up. RESULTS: A total of 11,676 patients with MGUS were included in the study. During the first 2 years after MGUS diagnosis, the distribution of patients by mean interval between visits was as follows: less than 6 months, 12.7%; every 6 to 12 months, 25.2%; every 13 to 24 months, 17.7%; and longer than 24 months, 44.4%. A higher proportion of patients were followed up at intervals of less than 13 months over time, from 32.7% to 41.1% (P<.001). Patients 60 years or older were more likely to be followed up at intervals of less than 13 months; those from the Northeast or younger than 50 years were more likely to be followed up at intervals longer than 24 months compared with their counterparts (P<.001). More than half of the patients 80 years or older were followed up at intervals of less than 6 months (12.3%), 6 to 12 months (27.8%), or 13 to 24 months (18.2%). Only approximately half of the patients (41.1%-58.8%) with MGUS diagnosed in 2013 were concordant with any of the 4 clinical guidelines. CONCLUSION: The MGUS follow-up practice patterns varied geographically and demographically and were frequently discordant with guideline recommendations. A large proportion of patients with limited life expectancy had frequent follow-up visits.

Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma.

While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8+ and CD4+ T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206+Tie2+ macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease.

Chondromyxoid fibroma involving the sphenoid sinus: Case report and literature review.

We present the case of a 62-year-old woman with chondromyxoid fibroma of the sphenoid sinus. Chondromyxoid fibroma is a rare bone tumor found most prevalently in long bones, so its presence at the cranial base is especially uncommon. The presence of a monoclonal gammopathy of undermined significance (MGUS) prompted consideration and investigation of a plasma cell disorder; however, CT and MRI findings followed by biopsy led to the correct diagnosis of chondromyxoid fibroma.