Clinical drug resistance linked to interconvertible phenotypic and functional states of tumor-propagating cells in multiple myeloma.

The phenotype and function of cells enriched in tumor-propagating activity and their relationship to the phenotypic architecture in multiple myeloma (MM) are controversial. Here, in a cohort of 30 patients, we show that MM composes 4 hierarchically organized, clonally related subpopulations, which, although phenotypically distinct, share the same oncogenic chromosomal abnormalities as well as immunoglobulin heavy chain complementarity region 3 area sequence. Assessed in xenograft assays, myeloma-propagating activity is the exclusive property of a population characterized by its ability for bidirectional transition between the dominant CD19(-)CD138(+) plasma cell (PC) and a low frequency CD19(-)CD138(-) subpopulation (termed Pre-PC); in addition, Pre-PCs are more quiescent and unlike PCs, are primarily localized at extramedullary sites. As shown by gene expression profiling, compared with PCs, Pre-PCs are enriched in epigenetic regulators, suggesting that epigenetic plasticity underpins the phenotypic diversification of myeloma-propagating cells. Prospective assessment in paired, pretreatment, and posttreatment bone marrow samples shows that Pre-PCs are up to 300-fold more drug-resistant than PCs. Thus, clinical drug resistance in MM is linked to reversible, bidirectional phenotypic transition of myeloma-propagating cells. These novel biologic insights have important clinical implications in relation to assessment of minimal residual disease and development of alternative therapeutic strategies in MM.

Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features.

Thrombotic thrombocytopenic purpura (TTP) is an acute, rare, life-threatening disorder. This report presents the South East (SE) England registry for TTP, from April 2002 to December 2006, which included 176 patients and 236 acute episodes; 75% of patients were female and 25% were male, overall median age at presentation was 42 years. Mortality was 8.5%, most cases died before treatment was instigated. The main ethnic groups were Caucasian (64%) and Afro Caribbean (27%). Seventy-seven percent of cases were idiopathic, 5% were congenital and the remaining cases had a defined precipitant. Neurological features were the most prevalent, but cardiac involvement accounted for 42% of presenting features. The overall median number of plasma exchanges (PEXs) to remission was 15; between April 2002 and December 2003, the median number of PEXs was 19 and it was 12 between January 2004 and December 2006 (P < 0.0001). In the latter period, adjuvant therapies were reduced, but Rituximab was increased. ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity was <10% in 74% and 95% of these cases had positive IgG antibodies to ADAMTS 13. Renal impairment and delayed normalisation of platelet count were the main differences between idiopathic and secondary TTP.

Serum-free light chains in HIV-associated lymphoma: no correlation with histology or prognosis.

OBJECTIVES: Serum-free light chains (sFLCs) are a biomarker of B-cell proliferation. Two case-control studies found elevated levels of polyclonal sFLCs predict the development of HIV-associated lymphomas (HALs) in people living with HIV. This effect appears greater for non-Hodgkin's lymphomas than Hodgkin's lymphoma. In this study, we measured sFLCs at diagnosis of HALs, and correlated levels with histology and survival. METHODS: The clinic database of the National Centre for HIV Malignancy was used to identify HAL patients, in the antiretroviral treatment era. Levels of sFLCs were measured using stored sera (cases from 1996 to 2008) and prospectively from 2008 to 2014. Serum immunoglobulins were available for 201 patients. We assessed correlations between sFLCs, serum immunoglobulins, and histological subtypes and overall survival. RESULTS: Two hundred and sixty-four patients were identified and 70% had polyclonal sFLC, 8% monoclonal sFLC (90% kappa sFLC), and 22% normal sFLC levels. No significant difference in sFLCs was observed between the three major histological subtypes of HAL (Hodgkin's lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma). Elevated sFLCs did not influence overall survival in HAL or for the three subtypes individually. DISCUSSION: Whilst these data confirm the finding of elevated sFLC in HAL, there was no significant difference in sFLC measurements between histological subtypes despite differences in pathogenesis. sFLC did not predict survival in HAL overall or by histological subtype. Elevated sFLCs may predict HAL, but measurement of sFLCs has limited utility in the classification and prognostication of these cases.

Initial treatment of pulmonary embolism.

Acute pulmonary embolism (PE) is a common presentation on the acute medical take. In our previous article in Vol 6 issue 1 we discussed the diagnostic approach to this condition. This article concentrates on the treatment of PE, including guidance for treatment of PE in pregnancy and cancer. This article also discusses the role of alternative anticoagulants, thrombolysis, surgery and inferior vena caval filters.

Coagulation factor levels in cryosupernatant prepared from plasma treated with amotosalen hydrochloride (S-59) and ultraviolet A light.

BACKGROUND: The standard treatment for thrombotic thrombocytopenic purpura (TTP) is plasma exchange with fresh-frozen plasma (FFP). Exposure to large volumes of FFP increases the risk of transfusion-transmitted infections. Cryosupernatant (CSP) offers a theoretical advantage over FFP, because it lacks the large von Willebrand factor (VWF) forms implicated in the pathogenesis of TTP. This study compared the hemostatic variables of CSP prepared from FFP treated with a photochemical pathogen inactivation process to CSP prepared from conventional FFP. STUDY DESIGN AND METHODS: Forty CSP units were prepared from North American blood group A donor FFP. Twenty-one of the FFP units were individually treated with amotosalen hydrochloride (S-59) and ultraviolet A light (test, photochemically treated FFP), and 19 units were not treated (control, FFP). RESULTS: Hemostatic variables of test and control CSP were similar and within reported ranges for conventional FFP with the exception of those properties depleted in CSP. VWF-cleaving protease activity (VWF:CP) and protein S (PS) levels (total and free antigen and activity) were within the conventional FFP reference range for test and control CSP. There were statistical differences between test and control CSP for alpha(2)-antiplasmin, antithrombin, protein C, and VWF:CP on a per-volume basis, but all levels were within the reference range for FFP, and the differences were not significant when expressed per gram of CSP protein. CONCLUSION: S-59-treated CSP retained adequate levels of critical plasma proteins for plasma exchange therapy in acute TTP. The data indicate good preservation of hemostasis control proteins such as PS, alpha(2)-antiplasmin, and VWF:CP activity (ADAMTS13).

An update on the pathogenesis and management of acquired thrombotic thrombocytopenic purpura.

PURPOSE OF REVIEW: Thrombotic thrombocytopenic purpura, a clinical syndrome characterized by thrombocytopenia and microangiopathic haemolytic anaemia, was almost universally fatal until the introduction of plasma exchange therapy in the 1970s. Current outcomes have improved dramatically with the initiation of prompt plasma exchange, a treatment routinely used without any real understanding of why it is effective. RECENT FINDINGS: Recent advances suggest that a deficiency of a specific plasma metalloprotease, responsible for the physiological processing of von Willebrand factor multimers, plays a substantial role in the pathogenesis of congenital and acquired idiopathic thrombotic thrombocytopenic purpura. The von Willebrand factor-cleaving protease has now been identified as a new member of the ADAMTS family of metalloproteases, designated ADAMTS13. The acquired form of thrombotic thrombocytopenic purpura is associated with inhibitory autoantibodies against ADAMTS13, and the congenital chronic relapsing form is caused by mutations in the ADAMTS13 gene, resulting in a constitutional deficiency. Plasma exchange has been proved to be the most important therapy in thrombotic thrombocytopenic purpura, but clinical data for adjunctive therapies, such as corticosteroids, antiplatelet drugs and other immunosuppressive agents often used in combination with plasma exchange, are less well defined. SUMMARY: Recent advances in our understanding of the pathological mechanisms of thrombotic thrombocytopenic purpura not only provide a rationale for the previously empirical plasma exchange therapy (removal of the inhibitory antibodies and replacement of the deficient protease from the plasma infused), but may also help in developing more rational and targeted treatment strategies. This review discusses the clinical presentation, pathophysiology and current management of thrombotic thrombocytopenic purpura.

Venous thromboembolism associated with the management of acute thrombotic thrombocytopenic purpura.

Venous thromboembolism (VTE) is not a feature of thrombotic thrombocytopenic purpura (TTP), but there has been a recent report of VTE in association with plasma exchange (PEX) treatment for TTP using the solvent detergent (SD) plasma, PLAS+SD. We reviewed the occurrence of VTE in 68 consecutive patients with TTP (25 men, 43 women). Eight documented VTE events [six deep venous thromboses (DVTs), three pulmonary emboli] were identified in seven patients (all female) during PEX therapy. All six DVTs were associated with central lines at the site of thrombosis. Other known precipitating factors included pregnancy, immobility, obesity and factor V Leiden heterozygosity. VTE occurred at a mean of 53 d following the first PEX. The European SD plasma, Octaplas was the last plasma to be used in PEX prior to the VTE in 7/8 events. This is the first report of VTE following Octaplas infusion. VTE is a multifactorial disease and, although several known precipitating factors were present in all patients in this study, the use of large volumes of SD plasma in PEX may be an additional risk factor. We recommend prevention of VTE with graduated elastic compression stockings (class I) at diagnosis and prophylactic low-molecular-weight heparin once the platelet count rises above 50 x 10(9)/l.