Search Results (103)

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a precursor to hematologic malignancies such as Multiple Myeloma (MM) and Waldenström Macroglobulinemia (WM). Accurate risk stratification of MGUS patients remains a clinical and computational challenge, with existing models often misclassifying both high-risk and low-risk individuals, leading to inefficient healthcare resource allocation. This study presents a machine learning (ML)-based approach for early prediction of MM/WM progression, using routinely collected hematological data, which are selected based on clinical relevance. A retrospective cohort of 292 MGUS patients, including 7 who progressed to malignancy, was analyzed. For each patient, a feature descriptor was constructed incorporating the latest biomarker values, their temporal trends over the previous year, age, and immunoglobulin subtype. To address the inherent class imbalance, data augmentation techniques were applied. Multiple ML classifiers were evaluated, with the Support Vector Machine (SVM) achieving the highest performance (94.3% accuracy and F1-score). The model demonstrates that a compact set of clinically relevant features can yield robust predictive performance. These findings highlight the potential of ML-driven decision-support systems in electronic health applications, offering a scalable solution for improving MGUS risk stratification, optimizing clinical workflows, and enabling earlier interventions. Full article

Rare plasma cell disorders—including IgD, IgE, and IgM multiple myeloma, non-secretory myeloma (NSMM), plasma cell leukemia (PCL), and heavy chain disease (HCD)—are biologically heterogeneous and often present with atypical features and aggressive behavior. This review synthesizes current evidence on their epidemiology, pathophysiology, diagnosis, and treatment. Advances in proteasome inhibitors, immunomodulatory agents, and autologous transplantation have improved outcomes in select subtypes. However, challenges persist in distinguishing IgM myeloma from Waldenström macroglobulinemia, monitoring non-secretory disease, and treating highly aggressive forms such as IgE myeloma and PCL. Standardized diagnostic criteria and prospective trials are essential to guide future management. Full article

Waldenström Macroglobulinemia (WM) is a rare, indolent B-cell lymphoproliferative disorder characterized by the production of monoclonal IgM paraprotein and infiltration of the bone marrow by lymphoplasmacytic cells. While WM generally exhibits a slow clinical course, it has the potential to progress into more aggressive hematologic malignancies, such as diffuse large B-cell lymphoma. The TP53 gene, often referred to as the “guardian of the genome”, plays a pivotal role in maintaining genomic stability, regulating the cell cycle, and orchestrating apoptosis. Mutations in TP53 undermine these essential processes, resulting in dysregulated cellular proliferation, defective apoptotic mechanisms, and genomic instability—hallmarks of cancer development. Although TP53 mutations have been extensively investigated in several hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndromes, and chronic lymphocytic leukemia, their role in WM remains underexplored. Emerging evidence suggests that TP53 mutations may have a significant impact on the disease progression and therapeutic response in WM. This review examines the current knowledge of TP53 mutations in WM, highlighting their implications for prognosis and therapeutic strategies. A deeper understanding of the role of TP53 in WM could provide critical insights for improving disease management and advancing the development of targeted therapies. Full article

CD19 and CXCR4 are pivotal regulators of B-cell activation and migration, respectively. Specifically, CXCR4 signaling critically influences the dissemination of various malignant B cells through constitutive activation and aberrant expression. This study explores the interaction between CD19 and CXCR4 signaling in the context of B-cell lymphomas, particularly focusing on diffuse large B-cell lymphoma (DLBCL) and Waldenström Macroglobulinemia (WM). We assessed the roles of CD19 in survival and CXCL12-induced migration by using knockout (KO) cells of DLBCL and WM origin alongside evaluating the impact of CD19 monoclonal antibodies (mAbs) on antibody-dependent cell-mediated cytotoxicity (ADCC). Our results highlight that CD19 is important for survival and CXCL12-induced migration, and mAbs variably increase CXCL12-induced migration and enhance ADCC. Additionally, we demonstrate that the endogenous peptide inhibitor of the CXCR4 (EPI-X4) derivative JM#21 effectively inhibits CD19-mediated migration enhancement and promotes ADCC, thereby augmenting the therapeutic efficacy of CD19 mAb-based immunotherapy in lymphoma models. Our study underscores the potential of targeting both CD19 and CXCR4 to refine therapeutic strategies for treating B-cell malignancies, suggesting a synergistic approach could improve clinical outcomes in WM treatment. Full article

Background/Objectives: Bence Jones proteins (BJPs) are monoclonal immunoglobulin free light chains (FLCs) that appear in the urine of patients with plasma cell disorders, including multiple myeloma (MM), Waldenström’s macroglobulinemia (WM), or light chain amyloidosis (AL). Their presence can provide valuable information about disease progression and treatment efficacy. These proteins are typically detected through a 24-h urine collection, as recommended by clinical guidelines. However, this method can be inconvenient for both patients and laboratory personnel due to its time-consuming nature and the potential for collection errors. We propose an algorithm based on serum FLC (sFLC) to rule out the presence of BJPs and diminish the need for urine testing. Methods: A retrospective data analysis of 268 serum and urine samples from 44 patients with MM was performed, and cutoffs were established to predict BJP absence: total urine protein (0.115 g/L), sFLC κ/λ ratio (>0.82 λ monoclonality and <1.99 κ monoclonality), and difference of involved–uninvolved FLC (dFLC; <11.93 mg/L). A subsequent algorithm validation was performed in 716 samples from patients who underwent the same testing in routine 2023 other laboratory activity. Results: The validation of these cutoffs to rule out the presence of BJP showed that, if the protocol based on the sFLC κ/λ ratio and dFLC had been applied, 42% of the urine studies would have been avoided, achieving a sensitivity of 93.9% and a false negative rate of 6.11%. Conclusions: We propose a laboratory work protocol that would allow for the avoidance of almost half of the 24-h urine studies based on sFLC measurement, a faster and more objective alternative to urine analysis for screening out the presence of BJP, with a good sensitivity and a low false negative rate. Full article

Waldenstrom’s Macroglobulinemia (WM) is a heterogeneous disease, and the majority of patients tend to have a long course. Nevertheless, it is imperative to detect patients who have a high risk of progression and who benefit from closer follow-up. Many recent studies have displayed the CD163-positive tumor-associated macrophages (TAMs) contribution in the pathogenesis of various hematological neoplasms and solid tumors. Soluble CD163 (sCD163) can be measured in serum, along with other TAM-chemoattractant cytokines, such as CCL2 and CCL4, and their levels are used to determine macrophage activation. In the current study, we investigated the correlation between sCD163, CCL2, and CCL4, with parameters of WM progression and survival. Out of a total of 204 WM patients, serum sCD163, CCL2, and CCL4 were measured in 75, 64, and 65 patients’ frozen sera at diagnosis, along with 30 healthy individuals (HIs) using an enzyme-linked immunosorbent assay (ELISA). We achieved to demonstrate that shorter Time to Treatment (TTT) was observed in 2 years and 7 years intervals in all patients with a ratio of CD163/CCL4 above median (p = 0.003 and p = 0.024, respectively) and decreased TTT was observed in all asymptomatic WM (AWM) patients with values of CCL4 above the median (p = 0.018). Moreover, significantly decreased overall survival (OS) (p = 0.033) was observed in all WM patients with CCL2 values above the median. Our results indicate that sCD163, CCL2, and CCL4 could be utilized as prognostic markers in WM. Full article

Background/Objectives: Anti-MAG polyneuropathy is a demyelinating peripheral neuropathy associated with IgM monoclonal gammopathies, particularly MGUS (monoclonal gammopathy of undetermined significance) and Waldenström macroglobulinemia. It is characterized by a subacute onset of distal sensory symptoms, with distal motor dysfunction typically appearing only in the later stages of the disease. The condition is caused by the presence of autoantibodies directed against myelin-associated glycoprotein, a structural protein of myelin. This leads to abnormalities in electrophysiological studies, such as markedly delayed distal latencies without conduction blocks or temporal dispersion of potentials. While rituximab (RTX) is the primary treatment, its efficacy is limited, with improvement seen in only 30–50% of patients. Recently, acute worsening of symptoms after RTX treatment has been increasingly reported. Methods: This systematic review compiles case reports and series from inception to June 2024 published on Scopus, PubMed or Cochrane, documenting acute exacerbations after RTX treatment in patients with anti-MAG polyneuropathy. Additionally, we present a case report from our institution that highlights this phenomenon. Results: We identified 13 clinical cases of acute deterioration in patients with anti-MAG polyneuropathy. Among these, eight patients (62%) achieved full recovery following additional treatment, while five patients (38%) did not return to their previous level of function. Plasmapheresis led to complete recovery in all four patients who received this intervention. Interestingly, many patients also experienced recovery after discontinuation of rituximab (RTX) treatment without the need for further therapeutic intervention. Conclusions: Acute clinical deterioration following RTX treatment in anti-MAG polyneuropathy is a possible occurrence. However, to date, no studies have assessed the true prevalence of this phenomenon. Further research is warranted to identify potential predictors of worsening following RTX treatment in this patient population. Full article

Waldenstrom macroglobulinemia (WM) is a non-Hodgkin B-cell lymphoma, characterized by bone marrow infiltration with plasma cells and lymphocytes. The tumor microenvironment (TME) plays an important role in mediating WM cell biology, but the effects of macrophages on WM biology remains unclear. Here, we investigated the effects of macrophages on WM growth and survival and identified a novel role for transcription factor GLI3 in macrophage polarization. We found that co-culture of M0 and M2 macrophages promoted WM cell growth and survival, and co-culture WM cells with M0 macrophages induced M2-like phenotypes. Interestingly, GLI3 expression was induced in M2 macrophages (not M1), leading us to perform analysis of macrophages from mice lacking Gli3 in myeloid cells (M-Gli3^−/− mice). A subset of differentially expressed genes implicated a role for GLI3 in macrophage polarization. Macrophages from M-Gli3^−/− mice did not induce WM cell proliferation and reduced survival compared to M2 macrophages from WT mice. In addition, in vitro polarization of M0 macrophages from M-Gli3^−/− was not able to induce M2 markers such as CD163, despite inducing iNos expression (M1 marker). Taken together, these results suggest a role for M2 macrophages in promoting WM cell growth and identify GLI3 as a modulator of macrophage polarization. Full article

(1) Background: In general, it is known that continuity of care can contribute to an increase in patient satisfaction, reduce health care costs, and improve patient outcomes. A guarantee of continuity in pharmacotherapy is a big challenge facing Japanese health care as a system that encourages cooperation/collaboration for pharmacists with other health care professions is currently lacking. (2) Method: This is a narrative review. (3) Results: The Lund Integrated Medicine Management (LIMM) model describes a systematic approach to individuals and was developed in Sweden to optimize pharmacotherapy among elderly inpatients. The aim of the LIMM model is to provide patients with continuous pharmacotherapy at different levels of care. The LIMM model, in which a clinical pharmacist is the catalyst and leads other health care professions in completing the process, has the potential to reduce potentially inappropriate prescriptions, reduce rehospitalization risk, unscheduled hospital revisits due to problems related to medications, reduce total medical expenditure, and provide a comprehensive understanding of patients’ conditions of taking medicine. (4) Conclusions: Introducing a framework such as Sweden’s LIMM model, anchored by clinical pharmacists, could provide a good opportunity to promote collaborations among different health care professionals and improve continuity in pharmacotherapy. Full article

Background: Monoclonal protein (MP) presents in various monoclonal gammopathies, ranging from benign conditions such as monoclonal gammopathy of undetermined significance (MGUS) to life-threatening conditions such as lymphoplasmacytic malignancies (LPMs), which include multiple myeloma (MM) and Waldenström macroglobulinemia (WM). Few studies have comprehensively assessed the clinical spectrum of MP and its factors associated with LPMs. This study aimed to determine the clinical spectrum of MP and identify factors associated with LPMs. Methods: This retrospective study included patients who were first tested for capillary electrophoresis (CEP) and identified as having MP between 2014 and 2023 at two university hospitals. Univariate (crude) and multivariate (adjusted) logistic regression analyses were performed to identify factors associated with LPMs. Results: Among the 1135 included patients with MP, 744 (65.6%) were diagnosed with LPMs and 391 (34.4%) with MGUS. Among the 391 patients with MGUS, 310 (79.3%) had at least 1 clinical association, including 204 with renal diseases, 35 with autoimmune diseases, 33 with chronic liver diseases, 22 with hematologic diseases, and 96 with other conditions. Multivariate analyses indicated that LPMs were associated with female sex (OR = 2.08), lower age (OR = 0.95), higher MP level (OR = 3.53), an abnormal FLC ratio (OR = 6.15), lower hemoglobin level (OR = 0.82), and higher total calcium level (OR = 1.81) (all p < 0.05). Conclusions: This study provides insight into the distribution of MPs and their clinical association with MGUS and identifies factors related to LPM. These can help clinicians manage patients more effectively in the early stages of these conditions. Full article

The term monoclonal gammopathy of clinical significance (MGCS) refers to a group of symptomatic monoclonal gammopathies that do not meet the diagnostic criteria for malignant plasma cell disorders, such as multiple myeloma or Waldenström macroglobulinemia. These symptoms are attributable to the paraneoplastic effects of monoclonal immunoglobulins that occur through diverse mechanisms. The presence of symptoms distinguishes MGCS from monoclonal gammopathy of undetermined significance, which lacks significant symptomatic presentation. The presentations of MGCS are manifold, adding to the diagnostic challenge. Clinical suspicion is key for accurate and timely diagnosis. Radiologic imaging can provide pivotal information to guide the diagnosis. In this review, we discuss MGCS from a radiology perspective and highlight pertinent imaging features associated with the disorders. Full article

Bruton’s tyrosine kinase (BTK), a non-receptor tyrosine kinase crucial for B cell development and function, acts downstream of the B cell receptor (BCR) in the BCR pathway. Other kinases involved downstream of the BCR besides BTK such as Syk, Lyn, PI3K, and Mitogen-activated protein (MAP) kinases also play roles in relaying signals from the BCR to provide pro-survival, activation, and proliferation cues. BTK signaling is implicated in various B-cell lymphomas such as mantle cell lymphoma, Waldenström Macroglobulinemia, follicular lymphoma, and diffuse large B cell lymphoma, leading to the development of transformative treatments like ibrutinib, the first-in-class covalent BTK inhibitor, and pirtobrutinib, the first-in-class noncovalent BTK inhibitor. However, kinase-deficient mutations C481F, C481Y, C481R, and L528W in the BTK gene confer resistance to both covalent and non-covalent BTK inhibitors, facilitating B cell survival and lymphomagenesis despite kinase inactivation. Further studies have revealed BTK’s non-catalytic scaffolding function, mediating the assembly and activation of proteins including Toll-like receptor 9 (TLR9), vascular cell adhesion protein 1 (VCAM-1), hematopoietic cell kinase (HCK), and integrin-linked kinase (ILK). This non-enzymatic role promotes cell survival and proliferation independently of kinase activity. Understanding BTK’s dual roles unveils opportunities for therapeutics targeting its scaffolding function, promising advancements in disrupting lymphomagenesis and refining B cell lymphoma treatments. Full article

Bing–Neel syndrome (BNS) is a rare condition that may occur in patients with Waldenstrom macroglobulinemia (WM) and is caused by lymphoplasmacytic infiltration into the central nervous system. BNS is an extramedullary manifestation of WM which may present with various neurological signs and symptoms that make the diagnosis difficult to achieve. We present a case of BNS in a 60-year-old patient diagnosed 6 years after recovering from Waldenstrom’s macroglobulinemia. We observed the patient for a secondary generalized focal motor seizure. Unenhanced brain CT revealed slight hyperdensity of left parietal subarachnoid spaces. The MRI of the brain and spinal cord showed leptomeningeal enhancement in both parietal lobes. The presence of monoclonal bands (light chain k and IgM) was found in cerebrospinal fluid, leading to the diagnosis of BNS. The patient started treatment with ibrutinib and remains clinically stable during a 1-year follow-up. However, the MRI showed the appearance of a new subcortical left parietal lesion. BNS is an extremely rare presentation of WM that should be recognized and considered early in the presence of unexplained neurological symptoms in patients with a history of WM, even if the patient appears to have recovered. Full article

Background/Objectives: Recent decades have witnessed a sharp increase in research investigating the association between hearing loss and cognitive impairment. Few previous studies have stratified for sex when investigating this issue, where results were inconsistent and require further clarification. Thus, the objective was to investigate the association between self-reported hearing loss and levels of cognitive impairment, stratified for sex. Methods: In this cross-sectional study, data were collected from 2001 to 2016. The study sample consisted of 5075 individuals, 2325 (45.8%) men, mean age 68.3 years, and 2750 (54.2%) women, mean age 70.0 years. Multiple variate ordinal regression models were constructed and adjusted for age, marital status, education, physical activity, depressive mood, hypertension, stroke, diabetes, and use of sedatives to investigate associations between groups of self-reported untreated and treated hearing loss and those reporting no hearing loss in relation to levels of cognitive impairment assessed by the Mini-Mental State Examination scale. Results: In men, treated hearing loss was associated with levels of cognitive impairment, odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.14–2.36. In women, both untreated hearing loss, (OR = 1.45, CI 1.07–1.98) and treated hearing loss (OR= 1.46, CI 1.06–2.04) were associated with levels of cognitive impairment. Conclusions: Hearing loss was found to be associated with cognitive impairment despite hearing aid use as well as awareness amongst physicians. The introduction of screening programs for hearing loss in older adults could be a crucial step for earlier identification of individuals at higher risk of developing cognitive impairment and dementia. Full article

Cryoglobulins are immunoglobulins that precipitate at temperatures below 37 °C and dissolve upon reheating. They can induce small-vessel vasculitis with renal involvement. Cryoglobulinemic glomerulonephritis is a rare manifestation that occurs in patients with monoclonal gammopathy, specifically Waldenström’s macroglobulinemia. We present the case of a 52-year-old patient with a history of cutaneous vasculitis and hypothyroidism, who presented with generalized edema, moderate anemia, hypercholesterolemia, nephrotic range proteinuria of 12.69 g/day, microhematuria, arterial hypertension, and hypocomplementemia via the classical pathway, without acute kidney injury and with negative serological studies and positive cryoglobulins in the second determination. Serum and urine protein electrophoresis and immunofixation studies showed a monoclonal band of IgM and kappa light chain. Renal biopsy was consistent with cryoglobulinemic glomerulonephritis. In the context of dysproteinemia and cryoglobulinemic glomerulonephritis, bone-marrow aspiration and biopsy were performed, leading to the diagnosis of Waldenström’s macroglobulinemia. Monoclonal gammopathies have been described in association with type I cryoglobulinemias. This described association is uncommon, which is why we present this case, along with a review of the literature. Full article