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Frontiers in Immunology 2024Infections are common in plasma cell cancer multiple myeloma (MM) due to disease-related immune deficiencies and cancer treatment. Myeloma cells express Toll-like...
Toll-like receptor signaling in multiple myeloma cells promotes the expression of pro-survival genes B-cell lymphoma 2 and MYC and modulates the expression of B-cell maturation antigen.
Infections are common in plasma cell cancer multiple myeloma (MM) due to disease-related immune deficiencies and cancer treatment. Myeloma cells express Toll-like receptors (TLRs), and TLR activation has been shown to induce proliferative and pro-survival signals in cancer cells. MM is a complex and heterogeneous disease, and expression levels of TLRs as well as downstream signaling components are likely to differ between patients. Here, we show that in a large cohort of patients, TLR1, TLR4, TLR6, TLR9, and TLR10 are the most highly expressed in primary CD138 cells. Using an MM cell line expressing TLR4 and TLR9 as a model, we demonstrate that TLR4 and TLR9 activation promoted the expression of well-established pro-survival and oncogenes in MM such as , , , and . TLR4 and TLR9 activation inhibited the efficacy of proteasome inhibitors bortezomib and carfilzomib, drugs used in the treatment of MM. Inhibiting the autophagosome-lysosome protein degradation pathway by hydroxychloroquine (HCQ) diminished the protective effect of TLR activation on proteasome inhibitor-induced cytotoxicity. We also found that TLR signaling downregulated the expression of , the gene encoding for B-cell maturation antigen (BCMA). , , and were upregulated in approximately 50% of primary cells, while the response to TLR signaling in terms of expression was dichotomous, as an equal fraction of patients showed upregulation and downregulation of the gene. While proteasome inhibitors are part of first-line MM treatment, several of the new anti-MM immune therapeutic drugs target BCMA. Thus, TLR activation may render MM cells less responsive to commonly used anti-myeloma drugs.
Topics: Humans; Multiple Myeloma; Signal Transduction; B-Cell Maturation Antigen; Cell Line, Tumor; Toll-Like Receptors; Proto-Oncogene Proteins c-myc; Gene Expression Regulation, Neoplastic; Proto-Oncogene Proteins c-bcl-2; Bortezomib; Male
PubMed: 38911853
DOI: 10.3389/fimmu.2024.1393906 -
Patient Preference and Adherence 2024Medication adherence is crucial for achieving clinical goals. Medication adherence drivers and behaviors were explored across multiple conditions, countries, and...
PURPOSE
Medication adherence is crucial for achieving clinical goals. Medication adherence drivers and behaviors were explored across multiple conditions, countries, and medication schedules/modalities to develop a conceptual model of medication adherence, which could later be used to support development of a patient-reported outcome (PRO) measure of adherence.
PATIENTS AND METHODS
Targeted review of qualitative literature identified important medication adherence concepts. Fifty-seven qualitative concept elicitation interviews were conducted (USA n=21, Spain n=18, Germany n=18). Participants were prescribed medication for: hypertension (n=9), asthma (n=8), multiple myeloma (n=8), psoriasis (n=8), diabetes (n=7), depression (n=7), multiple sclerosis (n=7), and/or schizophrenia (n=6). Thematic analysis of verbatim transcripts was performed. Expert clinicians (n=3) provided input throughout.
RESULTS
Nine qualitative articles were selected for review from 2168 screened abstracts. Forty-two medication adherence concepts were reported and grouped into 10 domains. Eight forms of medication adherence were reported during interviews, along with 27 drivers of non-adherence, all of which were incorporated into a conceptual model. Participants reported skipping medication doses (n=36/57; 63.2%) or taking medication later in the day than prescribed (n=29/57; 50.9%). Common drivers of non-adherence included forgetfulness (n=35/57; 61.4%), being out of the usual routine (n=31/57; 54.4%) and being busy (n=22/57; 38.6%). US participants were more likely to report non-adherence due to low perceived efficacy (n=6/21, 28.6%) and cost (n=5/21, 23.8%) than German (n=1/18, 5.6%; n=0/18, 0.0%) or Spanish (n=2/18, 11.1%; n=1/18, 5.6%) participants.
CONCLUSION
Findings highlight the diverse forms and drivers of medication non-adherence, informing the development of a comprehensive conceptual model of medication adherence. The conceptual model builds on and advances previous models of medication adherence and can be used by healthcare professionals to understand and interpret barriers to medication adherence and how best to support patients in taking their medication as intended.
PubMed: 38911591
DOI: 10.2147/PPA.S433662 -
Journal of Radiology Case Reports 2024Multiple myeloma is a plasma cell neoplasm, which may present as a solitary plasmacytoma and, uncommonly, as an extramedullary plasmacytoma. Intracranial plasmacytomas...
Multiple myeloma is a plasma cell neoplasm, which may present as a solitary plasmacytoma and, uncommonly, as an extramedullary plasmacytoma. Intracranial plasmacytomas may manifest in central nervous system involvement as cranial nerve palsies. Cranial nerve six palsy is the most common in cases of malignancy. However, isolated abducens palsy presenting as multiple myeloma recurrence is very uncommon. Here, we detail two cases in which intracranial plasmacytoma lesions were present within the region of the Dorello canal, resulting in acute isolated unilateral diplopia from disease recurrence in the absence of systemic marrow involvement.
Topics: Humans; Abducens Nerve Diseases; Multiple Myeloma; Neoplasm Recurrence, Local; Male; Magnetic Resonance Imaging; Middle Aged; Aged; Diagnosis, Differential; Plasmacytoma; Female; Diplopia; Brain Neoplasms
PubMed: 38910589
DOI: 10.3941/jrcr.v18i1.5240 -
Journal For Immunotherapy of Cancer Jun 2024Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor...
Circulating receptor activator of nuclear factor kappa-B ligand (RANKL) levels predict response to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC).
BACKGROUND
Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy.
METHODS
Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).
RESULTS
The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL's potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.
CONCLUSION
These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Male; Female; RANK Ligand; Lung Neoplasms; Immune Checkpoint Inhibitors; Aged; Middle Aged; Aged, 80 and over; Adult; B7-H1 Antigen; Biomarkers, Tumor; Prognosis
PubMed: 38908859
DOI: 10.1136/jitc-2024-009432 -
Scientific Reports Jun 2024Tumor-derived extracellular vesicles (EVs) show great potential as biomarkers for several diseases, including pancreatic cancer, due to their roles in cancer development...
Tumor-derived extracellular vesicles (EVs) show great potential as biomarkers for several diseases, including pancreatic cancer, due to their roles in cancer development and progression. However, the challenge of utilizing EVs as biomarkers lies in their inherent heterogeneity in terms of size and concentration, making accurate quantification difficult, which is highly dependent on the isolation and quantification methods used. In our study, we compared three EV isolation techniques and two EV quantification methods. We observed variations in EV concentration, with approximately 1.5-fold differences depending on the quantification method used. Interestingly, all EV isolation techniques consistently yielded similar EV quantities, overall size distribution, and modal sizes. In contrast, we found a notable increase in total EV amounts in samples from pancreatic cancer cell lines, mouse models, and patient plasma, compared to non-cancerous conditions. Moreover, individual tumor-derived EVs exhibited at least a 3-fold increase in several EV biomarkers. Our data, obtained from EVs isolated using various techniques and quantified through different methods, as well as originating from various pancreatic cancer models, suggests that EV profiling holds promise for the identification of unique and cancer-specific biomarkers in pancreatic cancer.
Topics: Pancreatic Neoplasms; Extracellular Vesicles; Humans; Biomarkers, Tumor; Animals; Mice; Cell Line, Tumor; Epithelial Cell Adhesion Molecule; Glypicans; Integrin alphaV
PubMed: 38902362
DOI: 10.1038/s41598-024-65209-8 -
PharmacoEconomics - Open Jun 2024This study aimed to assess the cost-effectiveness of two regimens regarded as the standard of care for the treatment of newly diagnosed, transplant-ineligible multiple...
BACKGROUND AND OBJECTIVE
This study aimed to assess the cost-effectiveness of two regimens regarded as the standard of care for the treatment of newly diagnosed, transplant-ineligible multiple myeloma in Singapore: (1) daratumumab, lenalidomide, and dexamethasone and (2) bortezomib, lenalidomide, and dexamethasone. Additionally, it aimed to explore potential strategies to manage decision uncertainty and mitigate financial risk.
METHODS
A cost-effectiveness analysis from the healthcare system perspective was conducted using a partitioned survival model to estimate lifetime costs and quality-adjusted life years (QALYs) associated with daratumumab-based treatment and the bortezomib-based regimen. The analysis used data from the MAIA and SWOG S0777 trials and incorporated local real-world data where available. Sensitivity analyses were performed to evaluate the robustness of the findings, and a risk analysis was conducted to analyze various payer strategies in terms of their payer strategy and uncertainty burden (P-SUB), which account for the decision uncertainty and the additional cost of choosing a suboptimal intervention.
RESULTS
The incremental cost-effectiveness ratio (ICER) for daratumumab, lenalidomide, and dexamethasone (DRd) compared with bortezomib, lenalidomide, and dexamethasone (VRd) was US $90,364 per QALY gained. The results were sensitive to variations in survival for DRd, postprogression treatment costs, cost of hospice care, and hazard ratio for progression-free survival. The scenarios explored indicated that structural assumptions, such as the time horizon of the analysis, significantly influenced the results due to uncertainties arising from immature trial data and treatment efficacy over time. Among the various payer strategies compared, an upfront price discount for daratumumab emerged as the best approach with the lowest P-SUB at US $14,708.
CONCLUSION
In conclusion, this study finds that daratumumab as a first-line treatment for myeloma exceeds the cost-effectiveness threshold considered in this evaluation. An upfront price reduction is the recommended strategy to manage uncertainties and mitigate financial risks. These findings highlight the importance of targeted payer strategies to address specific types and sources of uncertainty.
PubMed: 38900407
DOI: 10.1007/s41669-024-00503-9 -
Oncology (Williston Park, N.Y.) Jun 2024The June Hot Topics focuses on the challenges venetoclax regimens have faced in multiple myeloma trials.
The June Hot Topics focuses on the challenges venetoclax regimens have faced in multiple myeloma trials.
Topics: Multiple Myeloma; Humans; Bridged Bicyclo Compounds, Heterocyclic; Sulfonamides; Chromosomes, Human, Pair 14; Antineoplastic Agents; Translocation, Genetic; Chromosomes, Human, Pair 11; Clinical Trials as Topic; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38899981
DOI: 10.46883/2024.25921023 -
Haematologica Jun 2024Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the...
Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.
PubMed: 38899342
DOI: 10.3324/haematol.2022.282672 -
World Journal of Clinical Cases Jun 2024Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. Approximately half of patients with AITL may concurrently present with...
BACKGROUND
Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma. Approximately half of patients with AITL may concurrently present with hypergammaglobulinemia. Increased numbers of plasma cells in the bone marrow are commonly observed at diagnosis. These tumors mimic plasma cell myelomas, hindering a conundrum of clinical diagnoses and potentially delaying appropriate treatment.
CASE SUMMARY
A 78-year-old woman experienced poor appetite, weight loss of 5 kg, fatigue 2 months before presentation, and shortness of breath 2 d before presentation, but no fever or night sweats. Physical examination revealed splenomegaly and many palpable masses over the bilateral axillary regions, approximately > 2 cm in size, with rubbery consistency and no tenderness. Blood tests revealed anemia and thrombocytopenia, lactate dehydrogenase level of 153 U/L, total protein level of 10.9 g/dL, albumin to globulin ratio of 0.2, and immunoglobulin G level more than the upper limit of 3000 mg/dL. The free kappa and lambda light chain concentrations were 451 and 614 mg/L, respectively. A pathological examination confirmed the diagnosis of AITL. The initial treatment was the cyclophosphamide, epirubicin, vincristine, and prednisolone regimen. Following this treatment, pleural effusion was controlled, and the patient was discharged in a stable condition and followed up in our outpatient department.
CONCLUSION
This report highlights the importance of differentiating reactive plasmacytosis from plasma cell myeloma in patients with hypergammaglobulinemia. A precise diagnosis of AITL requires a comprehensive evaluation, involving clinical, immunophenotypic, and histological findings conducted by a multidisciplinary team to ensure appropriate treatment.
PubMed: 38898855
DOI: 10.12998/wjcc.v12.i17.3226 -
BMC Medical Genomics Jun 2024Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis...
BACKGROUND
Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis was used to construct the risk model and evaluate the prognostic value of ubiquitination-related genes in MM.
METHODS AND RESULTS
The data on ubiquitination-related genes and MM samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The consistent cluster analysis and ESTIMATE algorithm were used to create distinct clusters. The MM prognostic risk model was constructed through single-factor and multiple-factor analysis. The ROC curve was plotted to compare the survival difference between high- and low-risk groups. The nomogram was used to validate the predictive capability of the risk model. A total of 87 ubiquitination-related genes were obtained, with 47 genes showing high expression in the MM group. According to the consistent cluster analysis, 4 clusters were determined. The immune infiltration, survival, and prognosis differed significantly among the 4 clusters. The tumor purity was higher in clusters 1 and 3 than in clusters 2 and 4, while the immune score and stromal score were lower in clusters 1 and 3. The proportion of B cells memory, plasma cells, and T cells CD4 naïve was the lowest in cluster 4. The model genes KLHL24, HERC6, USP3, TNIP1, and CISH were highly expressed in the high-risk group. AICAr and BMS.754,807 exhibited higher drug sensitivity in the low-risk group, whereas Bleomycin showed higher drug sensitivity in the high-risk group. The nomogram of the risk model demonstrated good efficacy in predicting the survival of MM patients using TCGA and GEO datasets.
CONCLUSIONS
The risk model constructed by ubiquitination-related genes can be effectively used to predict the prognosis of MM patients. KLHL24, HERC6, USP3, TNIP1, and CISH genes in MM warrant further investigation as therapeutic targets and to combat drug resistance.
Topics: Humans; Multiple Myeloma; Computational Biology; Prognosis; Ubiquitination; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Nomograms; Cluster Analysis
PubMed: 38898455
DOI: 10.1186/s12920-024-01937-0