Search

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Summary Systemic light chain (AL) amyloidosis is a rare clonal plasma cell disorder characterized by the production of amyloidogenic immunoglobulin light chains, which causes the formation and deposition of amyloid fibrils, leading to multi‐organ dysfunction. Current treatment is directed at the underlying plasma cell clone to achieve a profound reduction in the monoclonal free light chain production. The standard‐of‐care first‐line therapy is a combination of daratumumab, cyclophosphamide, bortezomib and dexamethasone (D‐VCd regimen), resulting in high rates of haematological and organ responses. However, AL amyloidosis remains incurable, and all patients inevitably relapse. Hence, novel treatment options are needed for patients with an inadequate response or relapsed/refractory disease. B‐cell maturation antigen (BCMA) is a tumour necrosis factor (TNF receptor superfamily receptor overexpressed on plasma cells in multiple myeloma (MM) and AL amyloidosis. Recently, several novel anti‐BCMA immunotherapies have been approved for the treatment of relapsed/refractory MM, including antibody–drug conjugate belantamab mafodotin, bispecific antibodies teclistamab and elranatamab and chimeric antigen receptor T‐cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel. Despite lower expression than in MM, BCMA is also a promising target in AL amyloidosis. This review aims to provide up‐to‐date information on the efficacy and toxicity of anti‐BCMA therapy in AL amyloidosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This multicenter study assessed the incidence of pneumonia and its impact on survival in 322 patients with chronic lymphocytic leukemia (CLL) who were treated with venetoclax-based regimens. In real-world settings, patients with CLL who are treated with venetoclax-based regimens are at a higher risk of pneumonia, especially patients with R/R CLL who are treated with venetoclax in combination with rituximab compared to registration trials. Pneumonia has a negative impact on overall survival (OS) in patients with CLL who are receiving venetoclax-based therapy. However, in patients treated with first-line venetoclax and obinutuzumab, despite the high burden of comorbidities, the occurrence of pneumonia does not affect OS. Key risk factors for shorter event-free survival (EFS) in patients with CLL who were treated with venetoclax-based regimens included chronic obstructive pulmonary disease/asthma, spleen enlargement, elevated creatinine levels, and severe anemia; we identified a subgroup of patients at a high risk of pneumonia who particularly required anti-infective prophylaxis, appropriate treatment of underlying diseases, and close monitoring. Neutropenia, although common (59%), was not linked to an increased risk of pneumonia. These findings highlight the important issue of pneumonia and its impact on OS in the CLL patient population treated with venetoclax-based regimens, especially in patients following earlier lines of treatment, with R/R disease. Background/Objectives: Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections that can affect their clinical outcomes. Aims: The aims of this study were to assess the following: (1) the incidence of pneumonia in CLL patients treated with venetoclax-based regimens in a real-world setting, (2) the risk factors for event-free survival (EFS), and (3) overall survival (OS). Methods: This multicenter study included 322 patients from eight centers. Univariable and multivariable analyses (MVA) were performed, with the development of pneumonia during venetoclax-based treatment and OS as outcomes. Results: The most common complication was neutropenia (59%). During treatment with venetoclax-based regimens, 66 (20%) patients developed pneumonia—50 (23%) patients in the rituximab-plus-venetoclax (R-VEN) group and 13 (16%) patients in the obinutuzumab-plus-venetoclax (O-VEN) group (p = 0.15). Chronic obstructive pulmonary disease (COPD)/asthma, splenomegaly, elevated creatinine, and anemia < 8 g/dL were the risk factors for EFS in MVA (HR = 2.08, 95%CI 1.16–3.74, p = 0.014; HR 1.73, 95%CI 1.08–2.78, p = 0.02; HR 2.13, 95%CI 1.10–4.11, p = 0.03, HR 3.58, 95%CI 2.18–5.89, p < 0.001, respectively). Relapsed/refractory (R/R) CLL patients treated with R-VEN with pneumonia had worse OS than those without (p < 0.001). In patients treated with O-VEN, median OS did not differ between patients with and without pneumonia (p = 0.45). Conclusions: Our real-world study showed that pneumonia during venetoclax treatment occurs more frequently than reported in registration trials and has a negative impact on OS, especially in patients with R/R CLL who are treated with R-VEN. Neutropenia is not a risk factor for pneumonia. [ABSTRACT FROM AUTHOR]

Venetoclax, a BH3 mimetic, is a novel targeted anti-cancer drug with a unique mechanism of action leading to the execution of apoptosis through inhibition of the Bcl-2 protein. The development of venetoclax has revolutionized the treatment paradigm of several hematologic malignancies, including treatment-naïve and relapsed or refractory chronic lymphocytic leukemia (CLL) as well as acute myeloid leukemia (AML) in unfit patients. However, despite the high effectiveness of venetoclax in these diseases, some patients, as in the case with other targeted therapies, develop primary or secondary resistance to the drug. Various mechanisms contributing to the resistance to venetoclax have been elucidated, including selection of mutations in the BCL-2 binding groove which decrease affinity to venetoclax, or compensatory overexpression of anti-apoptotic proteins such as MCL-1. Moreover, alterations in cell metabolism and signaling pathways like MAPK or ERK activation have also been reported, suggesting the resistance to venetoclax is highly complex and involves multiple pathways. This review aimed to describe the mechanisms of resistance to venetoclax in AML, CLL, multiple myeloma, and other hematologic malignancies, as well as to propose a perspective to circumvent it. [ABSTRACT FROM AUTHOR]

Among the materials used for components subjected to abrasive wear, chromium cast iron, hardfaced layers, martensitic steels and Hadfield steel should be singled out. Each of these types of materials exhibits a different morphology of structure and strength properties. Hadfield steel, characterized by an austenitic microstructure, shows the ability to strengthen the subsurface layers by cold work, while maintaining a ductile core. Hardox steels belong to the group of low-alloy martensitic boron steels. However, it should be noted that increasing hardness does not always translate into low wear values due to a change in the nature of wear. In view of the above, the authors decided to subject selected Hardox steels and Hadfield cast steels in the post-operational condition to abrasive wear tests in the presence of loose abrasive. The study showed that Hardox Extreme steel exhibits the highest resistance to abrasive wear (value of the coefficient kb is equal to 1.39). In the case of Hadfield steel, the recorded values are slightly lower (kb = 1.32 and 1.33), while the above ratios remain higher compared to Hardox 600 and Hardox 500 steels. The main wear mechanism of high-manganese steels is microploughing, plastic deformation and breakouts of larger fragments of material. In the case of Hardox 450 and Hardox 500 steels, the predominant wear mechanisms are microploughing and breaking out of material fragments. As the hardness of the steel increases, the proportion of wear by microcutting and scratching predominates. [ABSTRACT FROM AUTHOR]

Horses have been companions of people for thousands of years. Areas in which humans use these animals include, for example, transport, participation in sports competitions, or during rehabilitation (hippotherapy). Unfortunately, injuries such as lower limb fracture very often require euthanasia due to the significant difficulties in conducting fracture therapy/repair. Therefore, there are still many possibilities for the improvement of existing treatments. The aim of the study was to conduct a numerical analysis enabling the prediction of bone union of the third metacarpal bone of a horse. The loading conditions and type of fracture were based on a pony weighing 120 kg; however, research on a live animal was not the purpose of this study. Numerical studies were carried out for three different methods of stabilization using bone plates in the Ansys program (lateral, anterior, and lateral–anterior stabilization). An algorithm based on the Carter model was used to predict bone union, while linear-coupled models were used to describe the behaviour of materials. The authors also performed dynamic analyses in the Abaqus/Explicit program to determine the maximum speed at which the horse could move so that the fracture would not deepen. For dynamic analyses, the authors used nonlinear models—Johnson–Cook in the case of the 316L surgical steel material and cortical bone. Material failure was described using the Johnson–Cook failure model for steel and the limit strain model for cortical bone. A series of numerical simulations allowed to determine the direction of bone union building, and the most favourable case of stabilization was determined. [ABSTRACT FROM AUTHOR]

Here we perform the first genome-wide association study (GWAS) of multiple myeloma (MM) survival. In a meta-analysis of 306 MM patients treated at UCSF and 239 patients treated at the Mayo clinic, we find a significant association between SNPs near the gene FOPNL on chromosome 16p13 and survival (rs72773978; P=6 × 10(-10)). Patients with the minor allele are at increased risk for mortality (HR: 2.65; 95% CI: 1.94-3.58) relative to patients homozygous for the major allele. We replicate the association in the IMMEnSE cohort including 772 patients, and a University of Utah cohort including 318 patients (rs72773978 P=0.044). Using publicly available data, we find that the minor allele was associated with increased expression of FOPNL and increased expression of FOPNL was associated with higher expression of centrosomal genes and with shorter survival. Polymorphisms at the FOPNL locus are associated with survival among MM patients.

Bruton's tyrosine kinase inhibitors (BTKis) have become one of the most vital drugs in the treatment of patients with chronic lymphocytic leukemia (CLL). BTKis are currently a well-established therapy for treatment-naïve, as well as relapsed or refractory, cases. BTKis have been shown to be crucial in the treatment of high-risk CLL patients bearing TP53 aberrations or characterized by the unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib was the first-in-class BTK inhibitor; however, despite its therapeutic potential, it is also characterized by specific adverse events, including hypertension, increased bleeding risk, cardiac toxicity, and skin changes. Although the next generation of BTKis was shown to be more specific, this adverse event profile is regarded currently as class--specific. In this review, we discuss the current status of acalabrutinib, a second-generation BTKi. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 20-year-old female patient diagnosed with chronic myeloid leukemia (CML) who developed sudden central vision loss in her right eye during treatment for hyperleukocytosis. It highlights the importance of early ophthalmologic evaluation in CML patients with high white blood cell counts, as the patient's vision loss was linked to leukostasis, with findings such as retinal hemorrhages, optic disc swelling, and tortuous retinal vessels.