The triggering receptor expressed on myeloid cells (TREM)-1 is a recently discovered receptor expressed on the surface of neutrophils and a subset of monocytes. Engagement of TREM-1 has been reported ...to trigger the synthesis of proinflammatory cytokines in the presence of microbial products. Previously, we have identified a soluble form of TREM-1 (sTREM-1) and observed significant levels in serum samples from septic shock patients but not controls. Here, we investigated its putative role in the modulation of inflammation during sepsis. We observed that sTREM-1 was secreted by monocytes activated in vitro by LPS and in the serum of animals involved in an experimental model of septic shock. Both in vitro and in vivo, a synthetic peptide mimicking a short highly conserved domain of sTREM-1 appeared to attenuate cytokine production by human monocytes and protect septic animals from hyper-responsiveness and death. This peptide seemed to be efficient not only in preventing but also in down-modulating the deleterious effects of proinflammatory cytokines. These data suggest that in vivo modulation of TREM-1 by sTREM peptide might be a suitable therapeutic tool for the treatment of sepsis.
CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, ...thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only.
CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18–65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0–2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants.
Between May 30, 2016, and June 18, 2018, 886 patients (458 84% of 543 in the D-VTd group and 428 79% of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2–39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable NE–NE) with daratumumab versus 46·7 months (40·0–NE) with observation only (hazard ratio 0·53, 95% CI 0·42–0·68, p<0·0001). A prespecified analysis of progression-free survival results showed a significant interaction between maintenance and induction and consolidation therapy (p<0·0001). The most common grade 3 or 4 adverse events were lymphopenia (16 4% of 440 patients in the daratumumab group vs eight 2% of 444 patients in the observation-only group), hypertension (13 3% vs seven 2%), and neutropenia (nine 2% vs ten 2%). Serious adverse events occurred in 100 (23%) patients in the daratumumab group and 84 (19%) patients in the observation-only group. In the daratumumab group, two adverse events led to death (septic shock and natural killer-cell lymphoblastic lymphoma); both were related to treatment.
Daratumumab maintenance every 8 weeks for 2 years significantly reduced the risk of disease progression or death compared with observation only. Longer follow-up and other ongoing studies will shed further light on the optimal daratumumab-containing post-ASCT maintenance treatment strategy.
Janssen Research & Development, the Intergroupe Francophone du Myélome, and the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.
With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value ...of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome–negative ALL in first remission (265 B-cell precursor BCP and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10−4and unfavorable genetic characteristics (ie, MLLgene rearrangement or focal IKZF1gene deletion in BCP-ALL and no NOTCH1/FBXW7mutation and/or N/K-RASmutation and/or PTENgene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.govas #NCT00222027 and #NCT00327678, respectively.
•In adult ALL, oncogenetic markers and minimal residual disease levels are independent outcome predictors.•Both factors should be used for individual treatment stratification.
The diagnosis of lymphoma relies mainly on clinical examination and laboratory explorations. Among the latter, morphological and immunohistochemical analysis of a tissue biopsy are the cornerstones ...for proper identification and classification of the disease. In lymphoma with blood and/or bone marrow involvement, multiparameter flow cytometry is useful. This technique can also be applied to fresh cells released from a biopsy sample. For full comprehension of lymphomas, surgical biopsies are best and indeed recommended by the hematopathological community. Currently, however, there is a global trend towards less invasive procedures, resulting in smaller samples such as core needle biopsies or fine needle aspirations which can make the diagnosis quite challenging. In this review, the possibilities and limitations to make an accurate lymphoma diagnosis on such small volume material are presented. After recalling the major steps of lymphoma diagnosis, the respective value of histology, cytology, and flow cytometry is discussed, including handling of small specimens. The benefits of an integrated approach are then evoked, followed by discussion about which attitude to adopt in different contexts. Perhaps contrary to the prevailing view among many pathologists, a full diagnosis on small volume material, combined with relevant ancillary techniques, is often possible and indeed supported by recent literature. A glimpse at future evolutions, notably the merit of artificial intelligence tools, is finally provided. All in all, this document aims at providing pathologists with an overview of diagnostic possibilities in lymphoma patients when confronted with small volume material such as core needle biopsies or fine needle aspirations.
Although the outcome of sepsis benefits from the prompt administration of appropriate antibiotics on correct diagnosis, the assessment of infection in critically ill patients is often a challenge for ...clinicians. In this setting, simple biomarkers, especially when used in combination, could prove useful.
To determine the usefulness of combination biomarkers to diagnose sepsis.
Three hundred consecutive patients were enrolled to construct a biologic score that was next validated in an independent prospective cohort of 79 critically ill patients from another center.
Plasma concentrations of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) and procalcitonin (PCT) were assayed, and the expression of the high-affinity immunoglobulin-Fc fragment receptor I (FcγRI) CD64 on neutrophils (polymorphonuclear PMN CD64 index) in flow cytometry was measured. A "bioscore" combining these biomarkers was constructed. Serum concentrations of PCT and sTREM-1 and the PMN CD64 index were higher in patients with sepsis compared with all others (P < 0.001 for the three markers). These biomarkers were all independent predictors of infection, the best receiver-operating characteristic curve being obtained for the PMN CD64 index. The performance of the bioscore, better than that of each individual biomarker, was externally confirmed in the validation cohort.
This prospective study, including inceptive and validation cohorts of unselected intensive care unit patients, demonstrates the high performance of a bioscore combining the PMN CD64 index together with PCT and sTREM-1 serum levels in diagnosing sepsis in the critically ill patient.
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