Search Results (5)

Monoclonal gammopathies of clinical significance (MGCSs) represent a group of diseases featuring the association of a nonmalignant B cells or plasma cells clone, the production of an M-protein, and singularly, the existence of organ damage. They present a current framework that is difficult to approach from a practical clinical perspective. Several points should be addressed in order to move further toward a better understanding. Overall, these entities are only partially included in the international classifications of diseases. Its definition and classification remain ambiguous. Remarkably, its real incidence is unknown, provided that a diagnostic biopsy is mandatory in most cases. In fact, amyloidosis AL is the final diagnosis in a large percentage of patients with renal significance. On the other hand, many of these young entities are syndromes that are based on a dynamic set of diagnostic criteria, challenging a timely diagnosis. Moreover, a specific risk score for progression is lacking. Despite the key role of the clinical laboratory in the diagnosis and prognosis of these patients, information about laboratory biomarkers is limited. Besides, the evidence accumulated for many of these entities is scarce. Hence, national and international registries are stimulated. In particular, IgM MGCS deserves special attention. Until now, therapy is far from being standardized, and it should be planned on a risk and patient-adapted basis. Finally, a comprehensive and coordinated multidisciplinary approach is needed, and specific clinical trials are encouraged. Full article

Monoclonal gammopathy and peripheral neuropathy are common diseases of elderly patients, and almost 10% of patients with neuropathy of unknown cause have paraprotein. However, growing evidence suggests that several hematological malignancies synthesize and release monoclonal proteins that damage the peripheral nervous system through different mechanisms. The spectrum of the disease varies from mild to rapidly progressive symptoms, sometimes affecting not only sensory nerve fibers, but also motor and autonomic fibers. Therefore, a multidisciplinary approach, mainly between hematologists and neurologists, is recommended in order to establish the correct diagnosis of monoclonal gammopathy of neurological significance and to tailor therapy based on specific genetic mutations. In this review, we summarize the spectrum of monoclonal gammopathies of neurological significance, their distinctive clinical and neurophysiological phenotypes, the most relevant pathophysiological events and new therapeutic approaches. Full article

Gaucher disease (GD) is a rare lysosomal autosomal-recessive disorder due to deficiency of glucocerebrosidase; polyclonal gammopathy (PG) and/or monoclonal gammopathy (MG) can occur in this disease. We aimed to describe these immunoglobulin abnormalities in a large cohort of GD patients and to study the risk factors, clinical significance, and evolution. Data for patients enrolled in the French GD Registry were studied retrospectively. The risk factors of PG and/or MG developing and their association with clinical bone events and severe thrombocytopenia, two markers of GD severity, were assessed with multivariable Cox models and the effect of GD treatment on gammaglobulin levels with linear/logarithmic mixed models. Regression of MG and the occurrence of hematological malignancies were described. The 278 patients included (132 males, 47.5%) were followed up during a mean (SD) of 19 (14) years after GD diagnosis. PG occurred in 112/235 (47.7%) patients at GD diagnosis or during follow-up and MG in 59/187 (31.6%). Multivariable analysis retained age at GD diagnosis as the only independent risk factor for MG (> 30 vs. ≤30 years, HR 4.71, 95%CI [2.40–9.27]; p < 0.001). Risk of bone events or severe thrombocytopenia was not significantly associated with PG or MG. During follow-up, non-Hodgkin lymphoma developed in five patients and multiple myeloma in one. MG was observed in almost one third of patients with GD. Immunoglobulin abnormalities were not associated with the disease severity. However, prolonged surveillance of patients with GD is needed because hematologic malignancies may occur. Full article

C-X3-C motif chemokine ligand 1 (CX3CL1)/fractalkine is a chemokine released after cleavage by two metalloproteases, ADAM metallopeptidase domain 10 (ADAM10) and ADAM metallopeptidase domain 17 (ADAM17), involved in inflammation and angiogenesis in the cancer microenvironment. The role of the CX3CL1/ C-X3-C motif chemokine receptor 1(CX3CR1) axis in the multiple myeloma (MM) microenvironment is still unknown. Firstly, we analyzed bone marrow (BM) plasma levels of CX3CL1 in 111 patients with plasma cell disorders including 70 with active MM, 25 with smoldering myeloma (SMM), and 16 with monoclonal gammopathy of undetermined significance (MGUS). We found that BM CX3CL1 levels were significantly increased in MM patients compared to SMM and MGUS and correlated with BM microvessel density. Secondly, we explored the source of CX3CL1 in MM and BM microenvironment cells. Primary CD138⁺ cells did not express CXC3L1 but up-regulated its production by endothelial cells (ECs) through the involvement of tumor necrosis factor alpha (TNFα). Lastly, we demonstrated the presence of CX3CR1 on BM CD14⁺CD16⁺ monocytes of MM patients and on ECs, but not on MM cells. The role of CX3CL1 in MM-induced angiogenesis was finally demonstrated in both in vivo chick embryo chorioallantoic membrane and in vitro angiogenesis assays. Our data indicate that CX3CL1, present at a high level in the BM of MM patients, is a new player of the MM microenvironment involved in MM-induced angiogenesis. Full article

Multiple myeloma (MM) is a genetically complex hematological cancer that is characterized by proliferation of malignant plasma cells in the bone marrow. MM evolves from the clonal premalignant disorder monoclonal gammopathy of unknown significance (MGUS) by sequential genetic changes involving many different genes, resulting in dysregulated growth of multiple clones of plasma cells. The migration, survival, and proliferation of these clones require the direct and indirect interactions with the non-hematopoietic cells of the bone marrow. We develop a hybrid discrete-continuous model of MM development from the MGUS stage. The discrete aspect of the modelisobservedatthecellularlevel: cellsarerepresentedasindividualobjectswhichmove,interact, divide, and die by apoptosis. Each of these actions is regulated by intracellular and extracellular processes as described by continuous models. The hybrid model consists of the following submodels that have been simplified from the much more complex state of evolving MM: cell motion due to chemotaxis, intracellular regulation of plasma cells, extracellular regulation in the bone marrow, and acquisition of mutations upon cell division. By extending a previous, simpler model in which the extracellular matrix was considered to be uniformly distributed, the new hybrid model provides a more accurate description in which cytokines are produced by the marrow microenvironment and consumed by the myeloma cells. The complex multiple genetic changes in MM cells and the numerous cell-cell and cytokine-mediated interactions between myeloma cells and their marrow microenviroment are simplified in the model such that four related but evolving MM clones can be studied as they compete for dominance in the setting of intraclonal heterogeneity. Full article