63 research outputs found
Tairona culture artefacts, Museo del Oro, Bogota, Colombia, 1977, [10] [picture] /
Condition: Good.; Title devised by cataloguer based on inscription on reverse.; Part of Wolfgang Sievers photographic archive.; Sievers number: EK-4560-add84 (devised number).; Inscriptions: "Tairona-24265-24665".; Also available in an electronic version via the Internet at: http://nla.gov.au/nla.pic-vn4195867
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Etiology of Waldenström macroglobulinemia: genetic factors and immune-related conditions
Epidemiologic studies provide an insight into the etiology of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, which indicates that repetitive immune stimulation and genetic factors play an important role. Here, the current understanding on the causes of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia are reviewed. Recent studies of the literature are discussed, and future population-based studies are proposed to further elucidate the molecular mechanisms that underlie these associations. Finally, the clinical implications of these data are outlined, and perspectives on clinical follow-up and counseling are provided
Gefitinib and Erlotinib in Metastatic Non‐Small Cell Lung Cancer: A Meta‐Analysis of Toxicity and Efficacy of Randomized Clinical Trials
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Severe peripheral neuropathy following carfilzomib, rituximab, and dexamethasone for initial treatment of Waldenström's macroglobulinemia
Smoldering multiple myeloma: special considerations surrounding treatment on versus off clinical trials
Serum free light chains as predictors of lymphomagenesis in patients with autosomal dominant hyper-immunoglobulin E syndrome (Job's syndrome)
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Pretreatment Plasma Cell Proteasome Levels Predict Responses To Treatment With Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Followed By Lenalidomide Extended Dosing (CRd-R) In Newly Diagnosed Multiple Myeloma Patients
Abstract
Background
Carfilzomib (Cz) is an irreversible proteasome inhibitor with potent anti-myeloma effects resulting in deep clinical responses and durable remissions in the majority of patients. In our two-stage phase II trial of 45 newly diagnosed multiple myeloma (MM) patients using carfilzomib (Cz), lenalidomide (Ln), and dexamethasone (Dx) combination therapy followed by 2 years of Ln maintenance, best responses after a median of 9 completed cycles (range 2-20), included 17-stringent-(s)-complete response-(CR)/1-CR/6-near-(n)-CR (63%), 10-very good partial response (VGPR) (26%), 3-partial response (PR) (8%), and 1-stable disease (SD) (3%) (reported in a separate abstract). In this pre-planned correlative sub-study based on our ongoing clinical CRd trial for newly diagnosed MM patients, we conducted a prospective flow cytometric study designed to characterize pretreatment levels of proteasomes and aggresomes in plasma cells in relation to response to therapy.
Methods
Bone marrow aspirates were collected at baseline and C1D2 (single agent Cz exposed). Permeabilized CD138 and CD38 positive plasma cells were tested using anti-19S proteasome subunit antibodies (Abcam, Cambridge, UK). In parallel, cells were labeled with ProteoStat Aggresome Detection Reagent (Enzo Life Sciences, Farmingdale, NY). Multicolor flow cytometric acquisition and analysis was performed using BD FACS CANTO and DIVA software. Data was expressed as mean fluorescence intensity (MFI) ratio using isotype-matched controls. Patients’ best responses to therapy after minimum of 4 cycles were correlated to the acquired proteasome and aggresome data. Statistical analysis was performed using DataPrism software. Statistical significance was considered as p-value <0.05.
Results
Total of 21 patients were assessed: 14 achieved CR (CR group), 4-VGPR, 2-PR and 1-SD (non-CR group). The median plasma cell 19S MFI ratio in the CR group was 20.21 (range 5.21-84.27), and in the non-CR group 6.19 (range 2.88-11.68), p<0.005. The percent of plasma cells in bone marrow aspirates was not statistically significantly different between two groups. 45% of non-CR patients had plasma cell 19S MFI ratio of less than 5, while 65% of CR patients had plasma cell 19S MFI ratio of over 12. After single agent Cz treatment (C1D2) plasma cell 19S proteasome MFI ratio in the CR group decreased in 90% of patients, while aggresome MFI ratio increased compared to baseline. Conversely, in the non-CR group, C1D2 plasma cell 19S MFI ratio increased in 80% of patients, while aggresome MFI ratio remained unchanged or decreased compared to baseline.
Conclusions
We found the pretreatment florescence intensity (MFI) ratio of 19S proteasome subunit in plasma cells to be significantly higher in MM patients who obtained CR (versus non-CR) when treated with CRd treatment. None of the patients with pretreatment 19S MFI ratio of less than 5 achieved CR; conversely, all patients with pretreatment 19S MFI ratio of over 12 achieved CR. After a single dose of carfilzomib, 90% of CR patients had decreased 19S MFI and increased aggresomes MFI ratio, while 80% of non-CR patients showed opposite changes: increased 19S MFI and unchanged/decreased aggresomes MFI ratio. We conclude that pretreatment plasma cell proteasome levels predict response to the CRd treatment in newly diagnosed MM patients.
Disclosures:
No relevant conflicts of interest to declare
Targeted single-cell proteomic analysis identifies new liquid biopsy biomarkers associated with multiple myeloma
Abstract Multiple myeloma (MM) is accompanied by alterations to the normal plasma cell (PC) proteome, leading to changes to the tumor microenvironment and disease progression. There is a great need for understanding the consequences that lead to MM progression and for the discovery of new biomarkers that can aid clinical diagnostics and serve as targets for therapeutics. This study demonstrates the applicability of utilizing the single-cell high-definition liquid biopsy assay (HDSCA) and imaging mass cytometry to characterize the proteomic profile of myeloma. In our study, we analyzed ~87,000 cells from seven patient samples (bone marrow and peripheral blood) across the myeloma disease spectrum and utilized our multiplexed panel to characterize the expression of clinical markers for PC classification, additional potential therapeutic targets, and the tumor microenvironment cells. Our analysis showed BCMA, ICAM3 (CD50), CD221, and CS1 (SLAMF7) as the most abundantly expressed markers on PCs across all myeloma stages, with BCMA, ICAM3, and CD221 having significantly higher expression levels on disease versus precursor PCs. Additionally, we identify significantly elevated levels of expression for CD74, MUM1, CD229, CD44, IGLL5, Cyclin D1, UBA52, and CD317 on PCs from overt disease conditions compared to those from precursor states
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