14 results on '"Davies, F E"'
Search Results
2. Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma.
- Author
-
Rasche L, Alapat D, Kumar M, Gershner G, McDonald J, Wardell CP, Samant R, Van Hemert R, Epstein J, Williams AF, Thanendrarajan S, Schinke C, Bauer M, Ashby C, Tytarenko RG, van Rhee F, Walker BA, Zangari M, Barlogie B, Davies FE, Morgan GJ, and Weinhold N
- Subjects
- Biomarkers, Tumor genetics, Follow-Up Studies, Humans, Multiple Myeloma pathology, Neoplasm, Residual diagnostic imaging, Neoplasm, Residual etiology, Prognosis, Remission Induction, Survival Rate, Transplantation, Autologous, Exome Sequencing, Diffusion Magnetic Resonance Imaging methods, Flow Cytometry methods, Hematopoietic Stem Cell Transplantation adverse effects, Multiple Myeloma therapy, Neoplasm, Residual diagnosis, Positron-Emission Tomography methods
- Abstract
The iliac crest is the sampling site for minimal residual disease (MRD) monitoring in multiple myeloma (MM). However, the disease distribution is often heterogeneous, and imaging can be used to complement MRD detection at a single site. We have investigated patients in complete remission (CR) during first-line or salvage therapy for whom MRD flow cytometry and the two imaging modalities positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DW-MRI) were performed at the onset of CR. Residual focal lesions (FLs), detectable in 24% of first-line patients, were associated with short progression-free survival (PFS), with DW-MRI detecting disease in more patients. In some patients, FLs were only PET positive, indicating that the two approaches are complementary. Combining MRD and imaging improved prediction of outcome, with double-negative and double-positive features defining groups with excellent and dismal PFS, respectively. FLs were a rare event (12%) in first-line MRD-negative CR patients. In contrast, patients achieving an MRD-negative CR during salvage therapy frequently had FLs (50%). Multi-region sequencing and imaging in an MRD-negative patient showed persistence of spatially separated clones. In conclusion, we show that DW-MRI is a promising tool for monitoring residual disease that complements PET and should be combined with MRD.
- Published
- 2019
- Full Text
- View/download PDF
3. Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients.
- Author
-
Shah V, Sherborne AL, Walker BA, Johnson DC, Boyle EM, Ellis S, Begum DB, Proszek PZ, Jones JR, Pawlyn C, Savola S, Jenner MW, Drayson MT, Owen RG, Houlston RS, Cairns DA, Gregory WM, Cook G, Davies FE, Jackson GH, Morgan GJ, and Kaiser MF
- Subjects
- Adult, Aged, Aged, 80 and over, Chromosome Aberrations, Chromosome Deletion, Clinical Trials, Phase III as Topic, Disease-Free Survival, Female, Humans, Male, Middle Aged, Multiple Myeloma genetics, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Prognosis, Proportional Hazards Models, Translocation, Genetic genetics, Transplantation, Autologous methods, Multiple Myeloma diagnosis, Multiple Myeloma pathology
- Abstract
Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 × 10
-7 ), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 × 10-14 ) and 1.68 (P=2.18 × 10-14 ), respectively. Patients with 'double-hit' defined by co-occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 × 10-27 ) for all patients and 3.19 (P=1.23 × 10-18 ) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 × 10-15 ), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment.- Published
- 2018
- Full Text
- View/download PDF
4. Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma.
- Author
-
Sawyer JR, Tian E, Shaughnessy JD Jr, Epstein J, Swanson CM, Stangeby C, Hale CL, Parr L, Lynn M, Sammartino G, Lukacs JL, Stein C, Bailey C, Zangari M, Davies FE, Van Rhee F, Barlogie B, and Morgan GJ
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Chromosome Banding, Cytogenetics, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Male, Multiple Myeloma mortality, Neoplasm Staging, Prognosis, Proportional Hazards Models, Chromosome Aberrations, Haploidy, Multiple Myeloma diagnosis, Multiple Myeloma genetics, Polyploidy
- Abstract
Hyperhaploid clones (24-34 chromosomes) were identified in 33 patients with multiple myeloma (MM), demonstrating a novel numerical cytogenetic subgroup. Strikingly, all hyperhaploid karyotypes were found to harbor monosomy 17p, the single most important risk stratification lesion in MM. A catastrophic loss of nearly a haploid set of chromosomes results in disomies of chromosomes 3, 5, 7, 9, 11, 15, 18, 19 and 21, the same basic set of odd-numbered chromosomes found in trisomy in hyperdiploid myeloma. All other autosomes are found in monosomy, resulting in additional clinically relevant monosomies of 1p, 6q, 13q and 16q. Hypotriploid subclones (58-68 chromosomes) were also identified in 11 of the 33 patients and represent a duplication of the hyperhaploid clone. Analysis of clones utilizing interphase fluorescence in situ hybridization (iFISH), metaphase FISH and spectral karyotyping identified either monosomy 17 or del17p in all patients. Amplification of 1q21 was identified in eight patients, demonstrating an additional high-risk marker. Importantly, our findings indicate that current iFISH strategies may be uninformative or ambiguous in the detection of these clones, suggesting this patient subgroup maybe underreported. Overall survival for patients with hyperhaploid clones was poor, with a 5-year survival rate of 23.1%. These findings identify a distinct numerical subgroup with cytogenetically defined high-risk disease.
- Published
- 2017
- Full Text
- View/download PDF
5. Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma?
- Author
-
Pawlyn C, Fowkes L, Otero S, Jones JR, Boyd KD, Davies FE, Morgan GJ, Collins DJ, Sharma B, Riddell A, Kaiser MF, and Messiou C
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Retrospective Studies, Diffusion Magnetic Resonance Imaging methods, Multiple Myeloma diagnostic imaging, Whole Body Imaging methods
- Published
- 2016
- Full Text
- View/download PDF
6. Clinical value of molecular subtyping multiple myeloma using gene expression profiling.
- Author
-
Weinhold N, Heuck CJ, Rosenthal A, Thanendrarajan S, Stein CK, Van Rhee F, Zangari M, Hoering A, Tian E, Davies FE, Barlogie B, and Morgan GJ
- Subjects
- Disease-Free Survival, Humans, Multiple Myeloma classification, Multiple Myeloma drug therapy, Multiple Myeloma mortality, Recurrence, Gene Expression Profiling, Multiple Myeloma genetics
- Abstract
Using a data set of 1217 patients with multiple myeloma enrolled in Total Therapies, we have examined the impact of novel therapies on molecular and risk subgroups and the clinical value of molecular classification. Bortezomib significantly improved the progression-free survival (PFS) and overall survival (OS) of the MMSET (MS) subgroup. Thalidomide and bortezomib positively impacted the PFS of low-risk (LoR) cases defined by the GEP70 signature, whereas high-risk (HiR) cases showed no significant changes in outcome. We show that molecular classification is important if response rates are to be used to predict outcomes. The t(11;14)-containing CD-1 and CD-2 subgroups showed clear differences in time to response and cumulative response rates but similar PFS and OS. Furthermore, complete remission was not significantly associated with the outcome of the MAF/MAFB (MF) subgroup or HiR cases. HiR cases were enriched in the MF, MS and proliferation subgroups, but the poor outcome of these groups was not linked to subgroup-specific characteristics such as MAF overexpression per se. It is especially important to define risk status if HiR cases are to be managed appropriately because of their aggressive clinical course, high rates of early relapse and the need to maintain therapeutic pressure on the clone.
- Published
- 2016
- Full Text
- View/download PDF
7. Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma.
- Author
-
Melchor L, Brioli A, Wardell CP, Murison A, Potter NE, Kaiser MF, Fryer RA, Johnson DC, Begum DB, Hulkki Wilson S, Vijayaraghavan G, Titley I, Cavo M, Davies FE, Walker BA, and Morgan GJ
- Subjects
- Aged, Animals, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Female, Genes, ras, Humans, Interferon Regulatory Factors genetics, Male, Mice, Mice, SCID, Middle Aged, Mutation, Selection, Genetic, Translocation, Genetic, Clonal Evolution, Multiple Myeloma genetics, Phylogeny, Single-Cell Analysis
- Abstract
Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rγ(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma.
- Published
- 2014
- Full Text
- View/download PDF
8. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma.
- Author
-
Dimopoulos MA, Leleu X, Palumbo A, Moreau P, Delforge M, Cavo M, Ludwig H, Morgan GJ, Davies FE, Sonneveld P, Schey SA, Zweegman S, Hansson M, Weisel K, Mateos MV, Facon T, and Miguel JF
- Subjects
- Age Factors, Clinical Trials as Topic, Dexamethasone administration & dosage, Drug Administration Schedule, Humans, Infections chemically induced, Multiple Myeloma genetics, Multiple Myeloma psychology, Neutropenia chemically induced, Peripheral Nervous System Diseases chemically induced, Quality of Life, Thalidomide administration & dosage, Thalidomide adverse effects, Thalidomide pharmacology, Thalidomide therapeutic use, Venous Thromboembolism chemically induced, Immunologic Factors therapeutic use, Multiple Myeloma drug therapy, Thalidomide analogs & derivatives
- Abstract
In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed.
- Published
- 2014
- Full Text
- View/download PDF
9. Understanding the interplay between the proteasome pathway and autophagy in response to dual PI3K/mTOR inhibition in myeloma cells is essential for their effective clinical application.
- Author
-
Aronson LI, Davenport EL, Mirabella F, Morgan GJ, and Davies FE
- Subjects
- Humans, Multiple Myeloma enzymology, Multiple Myeloma metabolism, Autophagy, Multiple Myeloma pathology, Phosphoinositide-3 Kinase Inhibitors, Proteasome Endopeptidase Complex metabolism, TOR Serine-Threonine Kinases antagonists & inhibitors
- Published
- 2013
- Full Text
- View/download PDF
10. A TC classification-based predictor for multiple myeloma using multiplexed real-time quantitative PCR.
- Author
-
Kaiser MF, Walker BA, Hockley SL, Begum DB, Wardell CP, Gonzalez D, Ross FM, Davies FE, and Morgan GJ
- Subjects
- Gene Expression Regulation, Neoplastic, Humans, Immunoglobulin Heavy Chains genetics, Multiple Myeloma mortality, Prognosis, Real-Time Polymerase Chain Reaction, Translocation, Genetic, Multiple Myeloma diagnosis, Multiple Myeloma genetics
- Published
- 2013
- Full Text
- View/download PDF
11. A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial.
- Author
-
Boyd KD, Ross FM, Chiecchio L, Dagrada GP, Konn ZJ, Tapper WJ, Walker BA, Wardell CP, Gregory WM, Szubert AJ, Bell SE, Child JA, Jackson GH, Davies FE, and Morgan GJ
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Multiple Myeloma genetics, Prognosis, Survival Analysis, Translocation, Genetic, Models, Theoretical, Multiple Myeloma pathology
- Abstract
The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.
- Published
- 2012
- Full Text
- View/download PDF
12. Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement.
- Author
-
Dimopoulos MA, Palumbo A, Attal M, Beksaç M, Davies FE, Delforge M, Einsele H, Hajek R, Harousseau JL, da Costa FL, Ludwig H, Mellqvist UH, Morgan GJ, San-Miguel JF, Zweegman S, and Sonneveld P
- Subjects
- Humans, Lenalidomide, Thalidomide therapeutic use, Antineoplastic Agents therapeutic use, Drug Resistance, Neoplasm drug effects, Multiple Myeloma drug therapy, Neoplasm Recurrence, Local drug therapy, Thalidomide analogs & derivatives
- Abstract
An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma.
- Published
- 2011
- Full Text
- View/download PDF
13. Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma.
- Author
-
Davenport EL, Zeisig A, Aronson LI, Moore HE, Hockley S, Gonzalez D, Smith EM, Powers MV, Sharp SY, Workman P, Morgan GJ, and Davies FE
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Benzhydryl Compounds pharmacology, Benzoquinones pharmacology, Blotting, Western, Cell Cycle, Cell Proliferation, Drug Synergism, HSP72 Heat-Shock Proteins genetics, HSP72 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins metabolism, Humans, Lactams, Macrocyclic pharmacology, Multiple Myeloma metabolism, Pyrrolidinones pharmacology, RNA, Messenger genetics, RNA, Small Interfering pharmacology, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factor CHOP genetics, Transcription Factor CHOP metabolism, Tumor Cells, Cultured, Apoptosis drug effects, HSP72 Heat-Shock Proteins antagonists & inhibitors, HSP90 Heat-Shock Proteins antagonists & inhibitors, Multiple Myeloma drug therapy, Multiple Myeloma pathology
- Published
- 2010
- Full Text
- View/download PDF
14. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications.
- Author
-
Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, Lin B, Lentzsch S, Davies FE, Chauhan D, Schlossman RL, Richardson P, Ralph P, Wu L, Payvandi F, Muller G, Stirling DI, and Anderson KC
- Subjects
- Angiogenesis Inhibitors pharmacology, Bone Marrow Cells cytology, Bone Marrow Cells physiology, Cell Adhesion, Cell Communication physiology, Coculture Techniques, Drug Interactions, Fibroblast Growth Factor 2 metabolism, Humans, Interleukin-6 metabolism, Multiple Myeloma metabolism, Multiple Myeloma physiopathology, Stromal Cells metabolism, Stromal Cells physiology, Thalidomide pharmacology, Tumor Cells, Cultured, Up-Regulation, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors, Endothelial Growth Factors metabolism, Lymphokines metabolism, Multiple Myeloma pathology, Stromal Cells cytology
- Abstract
Increased angiogenesis has recently been recognized in active multiple myeloma (MM). Since vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are two key mediators of angiogenesis, we characterized the production of VEGF, b-FGF and interleukin-6 (IL-6) (a MM growth and survival factor) in MM cell lines and Epstein-Barr virus (EBV) transformed B cell lines from MM patients, patient MM cells, as well as bone marrow stromal cells (BMSCs) from normal healthy donors and MM patients. We detected secretion of VEGF, but no bFGF and IL-6, in MM cell lines (MM.1S, RPMI 8226 and U266); EBV transformed B cell lines from MM patients (IM-9, HS-Sultan and ARH77); MM cell lines resistant to doxorubicin (RPMI-DOX40), mitoxantrone (RPMI-MR20), melphalan (RPMI-LR5) and dexamethasone (MM.1R); and patient MM cells (MM1 and MM2). BMSCs from MM patients and normal donors secreted VEGF, b-FGF and IL-6. Importantly, when MM cells were adhered to BMSCs, there was a significant increase in VEGF (1.5- to 3.1-fold) and IL-6 (1.9- to 56-fold) secretion. In contrast, the bFGF decreased in co-cultures of BMSCs and MM cells. Paraformaldehyde fixation of BMSCs or MM cells prior to adhesion revealed that VEGF was produced both from BMSCs and MM cells, though it may come primarily from BMSCs in some cultures. IL-6 was produced exclusively in BMSCs, rather than MM cells. Moreover, when MM cells were placed in Transwell insert chambers to allow their juxtaposition to BMSCs without cell to cell contact, induction of VEGF and IL-6 secretion persisted, suggesting the importance of humoral factors. Addition of exogenous IL-6 (10 ng/ml) increased VEGF secretion by BMSCs. Conversely, VEGF (100 ng/ml) significantly increased IL-6 secretion by BMSCs. Moreover, anti-human VEGF (1 microg/ml) and anti-human IL-6 (10 microg/ml) neutralizing antibodies reduced IL-6 and VEGF secretion, respectively, in cultures of BMSCs alone and co-cultures of BMSCs and MM cells. Finally, thalidomide (100 microM) and its immunomodulatory analog IMiD1-CC4047 (1 microM) decreased the upregulation of IL-6 and VEGF secretion in cultures of BMSCs, MM cells and co-cultures of BMSCs with MM cells. These data demonstrate the importance of stromal-MM cell interactions in regulating VEGF and IL-6 secretion, and suggest additional mechanisms whereby thalidomide and IMiD1-CC4047 act against MM cells in the BM millieu.
- Published
- 2001
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.