Author
Douglas E. Joshua
Other affiliations: Bosch, University of Sydney, Centenary Institute of Cancer Medicine and Cell Biology ...read more
Bio: Douglas E. Joshua is an academic researcher from Royal Prince Alfred Hospital. The author has contributed to research in topics: Multiple myeloma & Cytotoxic T cell. The author has an hindex of 41, co-authored 150 publications receiving 12749 citations. Previous affiliations of Douglas E. Joshua include Bosch & University of Sydney.
Topics: Multiple myeloma, Cytotoxic T cell, T cell, Bortezomib, Population
Papers published on a yearly basis
Papers
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Cedars-Sinai Medical Center1, University of Salamanca2, University of Arkansas for Medical Sciences3, Mayo Clinic4, Alexandra Hospital5, Lund University6, Karolinska Institutet7, Ankara University8, Washington University in St. Louis9, Cross Cancer Institute10, University of Turin11, Royal Prince Alfred Hospital12, University of Texas MD Anderson Cancer Center13, University of Pavia14, Harvard University15, University of Bologna16, The Royal Marsden NHS Foundation Trust17
TL;DR: The European Group for Blood and Bone Marrow Transplant/International Bone Marrows Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system to adequately assess clinical outcomes in myeloma.
Abstract: New uniform response criteria are required to adequately assess clinical outcomes in myeloma. The European Group for Blood and Bone Marrow Transplant/International Bone Marrow Transplant Registry criteria have been expanded, clarified and updated to provide a new comprehensive evaluation system. Categories for stringent complete response and very good partial response are added. The serum free light-chain assay is included to allow evaluation of patients with oligo-secretory disease. Inconsistencies in prior criteria are clarified making confirmation of response and disease progression easier to perform. Emphasis is placed upon time to event and duration of response as critical end points. The requirements necessary to use overall survival duration as the ultimate end point are discussed. It is anticipated that the International Response Criteria for multiple myeloma will be widely used in future clinical trials of myeloma.
2,411 citations
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Mayo Clinic1, Leeds Teaching Hospitals NHS Trust2, University of Arkansas3, University of Nantes4, University of Turin5, University of South Florida6, National and Kapodistrian University of Athens7, University of Birmingham8, Lille University of Science and Technology9, Harvard University10, Cleveland Clinic11, University of Pittsburgh12, University of Salamanca13, Nagoya University14, McGill University15, Erasmus University Rotterdam16, Lund University17, University of Minnesota18, Medical College of Wisconsin19
TL;DR: The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations to facilitate comparison of therapeutic trial data.
Abstract: The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is greater than or equal to 30 g/l and/or bone marrow clonal cells greater than or equal to 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (+/- recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.
2,066 citations
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TL;DR: It is found that, on culture, centrocytes isolated from human tonsil kill themselves within a few hours by apoptosis, not a feature of other tonsillar B cells.
Abstract: The high affinity of antibodies produced during responses to T-cell-dependent antigens is associated with somatic mutation in the variable region of the immunoglobulin. Indirect evidence indicates that: (1) this arises by a process of hypermutation, acting selectively on rearranged immunoglobulin variable-region genes, which is activated in centroblasts within germinal centres; and (2) centrocytes, the progeny of centroblasts, undergo selection on the basis of their ability to receive a positive signal from antigen. We have now performed experiments analysing this selection process, and found that, on culture, centrocytes isolated from human tonsil kill themselves within a few hours by apoptosis. This is not a feature of other tonsillar B cells. Centrocytes can be prevented from entering apoptosis if they are activated both through their receptors for antigen and a surface glycoprotein recognized by CD40 antibodies.
1,091 citations
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University of Turin1, Mayo Clinic2, National and Kapodistrian University of Athens3, Harvard University4, University of Arkansas for Medical Sciences5, Wayne State University6, University of Bologna7, Cross Cancer Institute8, University of Tübingen9, Royal Prince Alfred Hospital10, Charité11, Catholic Medical Center12, University of Barcelona13, Lund University14, Cornell University15, Norwegian University of Science and Technology16, St James's University Hospital17, Emory University18, The Royal Marsden NHS Foundation Trust19, Cedars-Sinai Medical Center20, Erasmus University Rotterdam21, Cleveland Clinic22
TL;DR: This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model for venous thromboembolism (VTE), and recommends low-molecular-weight heparin (LMWH), warfarin or aspirin.
Abstract: The incidence of venous thromboembolism (VTE) is more than 1%omicron annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-Weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with <= 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.
763 citations
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Mayo Clinic1, Spanish National Research Council2, Masaryk University3, University of Turin4, Catholic Medical Center5, Emory University6, Alexandra Hospital7, Memorial Sloan Kettering Cancer Center8, University of Würzburg9, University of Arkansas for Medical Sciences10, University of Bologna11, Free University of Berlin12, Royal Prince Alfred Hospital13, Lund University14, Cedars-Sinai Medical Center15
TL;DR: Consensus guidelines for the use of the serum immunoglobulin-free light chain assay are provided, in the diagnosis and management of clonal PCD.
Abstract: The serum immunoglobulin-free light chain (FLC) assay measures levels of free κ and λ immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.
699 citations
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Mayo Clinic1, National and Kapodistrian University of Athens2, University of Turin3, Heidelberg University4, Harvard University5, Memorial Sloan Kettering Cancer Center6, University of Navarra7, University of Pennsylvania8, VU University Medical Center9, Emory University10, University of Bologna11, Mount Sinai Hospital12, Memorial Hospital of South Bend13, Karolinska University Hospital14, Carolinas Healthcare System15, Aalborg University16, Ankara University17, Cedars-Sinai Medical Center18
TL;DR: The disease definition of multiple myeloma is updated to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions), and specific metrics that new biomarkers should meet for inclusion in the disease definition are provided.
Abstract: This International Myeloma Working Group consensus updates the disease defi nition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identifi cation of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfi l the criteria for the presence of myeloma-defi ning CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specifi c metrics that new biomarkers should meet for inclusion in the disease defi nition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any diff erences in outcome that might occur as a result of the new disease defi nition.
3,049 citations
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University of Ulm1, University of Rome Tor Vergata2, Fred Hutchinson Cancer Research Center3, University of Münster4, University of Wales5, University of Chicago6, Nagoya University7, Leipzig University8, VU University Medical Center9, Northwestern University10, Erasmus University Medical Center11, Ohio State University12
TL;DR: An international expert panel is provided to provide updated evidence- and expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials.
3,000 citations
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TL;DR: The results indicate that the phase in apoptosis that is characterized by chromatin condensation coincides with phosphatidylserine exposure, which precedes membrane damage that might lead to release from the cells of enzymes that are harmful to the surrounding tissues.
2,465 citations
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TL;DR: This review discusses recent progress and areas of uncertainty or disagreement in the literature, and debates the developmental relationship between T(FH) cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg).
Abstract: T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (T(FH)) cells are the specialized providers of B cell help. T(FH) cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of T(FH) cells are the expression of CXCR5, PD-1, SAP (SH2D1A), IL-21, and ICOS, among other molecules, and the absence of Blimp-1 (prdm1). T(FH) cells are important for the formation of germinal centers. Once germinal centers are formed, T(FH) cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. This review covers T(FH) differentiation, T(FH) functions, and human T(FH) cells, discussing recent progress and areas of uncertainty or disagreement in the literature, and it debates the developmental relationship between T(FH) cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg).
2,442 citations
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2,428 citations