Early CAR- CD4+ T-lymphocytes recovery following CAR-T cell infusion: A worse outcome in diffuse large B cell lymphoma.

CAR- CD4+ T cell lymphopenia is an emerging issue following CAR-T cell therapy. We analyzed the determinants of CD4+ T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR-T for diffuse large B-cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric-flow cytometry. Six-month cumulative incidence of CAR- CD4+ T cell recovery (≥200 cells/µL) was 0.43 (95% confidence interval [CI]: 0.28-0.65). Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16-24.12] p = 0.016). Higher CD4+ T cell counts resulted with TSA at month-1, -2 and -3. Moderate-to-severe infections were registered with prolonged CD4+ T cell lymphopenia. Early, month-1 CD4+ T cell recovery was associated with a worse outcome in the DLBCL cohort, upheld in a multivariate regression model for overall survival (HR: 4.46 [95% CI: 1.12-17.71], p = 0.03). We conclude that a faster CAR- CD4+ T cell recovery is associated with TSA as compared to AXI/BRX. Month-1 CAR- CD4+ T cell subset recovery could represent a "red flag" for CAR-T cell therapy failure in DLBCL patients.

Slow-release oral morphine as maintenance therapy for opioid dependence.

BACKGROUND: Opioid substitution treatments are effective in retaining people in treatment and suppressing heroin use. An open question remains whether slow-release oral morphine (SROM) could represent a possible alternative for opioid-dependent people who respond poorly to other available maintenance treatments. OBJECTIVES: To evaluate the efficacy of SROM as an alternative maintenance pharmacotherapy for the treatment of opioid dependence. SEARCH METHODS: We searched Cochrane Drugs and Alcohol Group's Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library Issue 3, 2013), MEDLINE (January 1966 to April 2013), EMBASE (January 1980 to April 2013) and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised trials assessing efficacy of SROM compared with other maintenance treatment or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently selected articles for inclusion, extracted data and assessed risk of bias of included studies. MAIN RESULTS: Three studies with 195 participants were included in the review. Two were cross-over trials and one was a parallel group RCT. The retention in treatment appeared superior to 80% in all the three studies (without significant difference with controls). Nevertheless, it has to be underlined that the studies had different durations. One lasted six months, and the other two lasted six and seven weeks. The use of opioids during SROM provision varied from lower to non-statistically or clinically different from comparison interventions, whereas there were no differences as far as the use of other substances was concerned.SROM seemed to be equal to comparison interventions for severity of dependence, or mental health/social functioning, but there was a trend for less severe opiate withdrawal symptoms in comparison with methadone (withdrawal score 2.2 vs. 4.8, P value = 0.06). Morphine was generally well tolerated and was preferred by a proportion of participants (seven of nine people in one study). Morphine appeared to reduce cravings, depressive symptoms (measured using the Beck Depression Inventory; P value < 0.001), physical complaints (measured using the Beschwerde-Liste (BL); P value < 0.001) and anxiety symptoms (P value = 0.008). Quality of life in people treated with SROM resulted in no significant difference or a worst outcome than in those taking methadone and buprenorphine. Other social functioning measures, such as finances, family and overall satisfaction, scored better in people maintained with the comparison substances than in those maintained with SROM. In particular, people taking methadone showed more favourable values for leisure time (5.4 vs. 3.7, P value < 0.001), housing (6.1 vs. 4.7, P value < 0.023), partnerships (5.7 vs. 4.2, P value = 0.034), friend and acquaintances (5.6 vs. 4.4, P value = 0.003), mental health (5.0 vs. 3.4, P value = 0.002) and self esteem (8.2 vs. 5.7, P value = 0.002) compared to people taking SROM; while people taking buprenorphine obtained better scores for physical health.Medical adverse events were consistently higher in people in SROM than in the comparison groups. None of the studies included people with a documented poor response to other maintenance treatment. AUTHORS' CONCLUSIONS: The present review did not identify sufficient evidence to assess the effectiveness of SROM for opioid maintenance because only three studies meeting our inclusion criteria have been identified. Two studies suggested a possible reduction of opioid use in people taking SROM. In another study, the use of SROM was associated with fewer depressive symptoms. Retention in treatment was not significantly different among compared interventions while the adverse effects were more frequent with the people given SROM.

Media campaigns for the prevention of illicit drug use in young people.

BACKGROUND: Substance-specific mass media campaigns which address young people are widely used to prevent illicit drug use. They aim to reduce use and raise awareness of the problem. OBJECTIVES: To assess the effectiveness of mass media campaigns in preventing or reducing the use of or intention to use illicit drugs amongst young people. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2013, Issue 1), including the Cochrane Drugs and Alcohol Group's Specialised Register; MEDLINE through PubMed (from 1966 to 29 January 2013); EMBASE (from 1974 to 30 January 2013) and ProQuest Dissertations & Theses A&I (from 1861 to 3 February 2013). SELECTION CRITERIA: Cluster-randomised controlled trials, prospective and retrospective cohort studies, interrupted time series and controlled before and after studies evaluating the effectiveness of mass media campaigns in influencing drug use, intention to use or the attitude of young people under the age of 26 towards illicit drugs. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures of The Cochrane Collaboration. MAIN RESULTS: We included 23 studies involving 188,934 young people, conducted in the USA, Canada and Australia between 1991 and 2012. Twelve studies were randomised controlled trials (RCT), two were prospective cohort studies (PCS), one study was both a RCT and a PCS, six were interrupted time series and two were controlled before and after (CBA) studies. The RCTs had an overall low risk of bias, along with the ITS (apart from the dimension 'formal test of trend'), and the PCS had overall good quality, apart from the description of loss to follow-up by exposure.Self reported or biomarker-assessed illicit drug use was measured with an array of published and unpublished scales making comparisons difficult. Pooled results of five RCTs (N = 5470) show no effect of media campaign intervention (standardised mean difference (SMD) -0.02; 95% confidence interval (CI) -0.15 to 0.12).We also pooled five ITS studies (N = 26,405) focusing specifically on methamphetamine use. Out of four pooled estimates (two endpoints measured in two age groups), there was evidence of a reduction only in past-year prevalence of methamphetamine use among 12 to 17 years old.A further five studies (designs = one RCT with PCS, two PCS, two ITS, one CBA, N = 151,508), which could not be included in meta-analyses, reported a drug use outcome with varied results including a clear iatrogenic effect in one case and reduction of use in another. AUTHORS' CONCLUSIONS: Overall the available evidence does not allow conclusions about the effect of media campaigns on illicit drug use among young people. We conclude that further studies are needed.

EMCDDA Best Practice Promotion in Europe: an internet based dissemination tool.

Best practice is the best application of available evidence to current activities in the drugs field. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) created a web-based tool aimed at bridging together scientific evidence and current practices in the drug addiction field. Beyond dissemination of evidence, the scope is to share best practice among the European countries. The synthesis of the evidence is based on the methods of the Cochrane collaboration (the Drugs and Alcohol Group) and the Grade working group. As of February 2013 the portal encompasses four modules on the effectiveness of demand reduction interventions, a collection of European projects on prevention, treatment, harm reduction and social reintegration and an inventory of European Guidelines and Standards including a bank of instruments to evaluate interventions (http://www.emcdda.europa.eu/bestpractice). The summaries of evidence are presented in a plain language format and include brief explanation of the measures of effect supporting the evidence, but do not provide specific recommendations. The main future challenge of EMCDDA's best practice promotion is to become a service for those willing to implement best practice. The Best Practice Portal should become a platform where to find all is needed for successful implementation (handbooks, training materials, guidelines for evaluation and contacts for mentoring).

Donor selection for adoptive immunotherapy with NK cells in AML patients: Comparison between analysis of lytic NK cell clones and phenotypical identification of alloreactive NK cell repertoire.

Natural killer (NK) cell-based adoptive immunotherapy in leukemia patients is an emerging field of interest based on clinical evidence of efficacy and safety. Elderly acute myeloid leukemia (AML) patients have been successfully treated with NK cells from HLA-haploidentical donors, especially when high amounts of alloreactive NK cells were infused. The aim of this study was comparing two approaches to define the size of alloreactive NK cells in haploidentical donors for AML patients recruited in two clinical trials with the acronym "NK-AML" (NCT03955848), and "MRD-NK". The standard methodology was based on the frequency of NK cell clones capable of lysing the related patient-derived cells. The alternative approach consisted of the phenotypic identification of freshly derived NK cells expressing, as inhibitory receptors, only the inhibitory KIR(s) specific for the mismatched KIR-Ligand(s) (HLA-C1, HLA-C2, HLA-Bw4). However, in KIR2DS2+ donors and HLA-C1+ patients, the unavailability of reagents staining only the inhibitory counterpart (KIR2DL2/L3) may lead to an underestimated identification of the alloreactive NK cell subset. Conversely, in the case of HLA-C1 mismatch, the alloreactive NK cell subset could be overestimated due to the ability of KIR2DL2/L3 to recognize with low-affinity also HLA-C2. Especially in this context, the additional exclusion of LIR1-expressing cells might be relevant to refine the size of the alloreactive NK cell subset. We could also associate degranulation assays, using as effector cells IL-2 activated donor peripheral blood mononuclear cells (PBMC) or NK cells upon co-culture with the related patient target cells. The donor alloreactive NK cell subset always displayed the highest functional activity, confirming its identification accuracy by flow cytometry. Despite the phenotypic limitations and considering the proposed corrective actions, a good correlation was shown by the comparison of the two investigated approaches. In addition, the characterization of receptor expression on a fraction of NK cell clones revealed expected but also few unexpected patterns. Thus, in most instances, the quantification of phenotypically defined alloreactive NK cells from PBMC can provide data similar to the analysis of lytic clones, with several advantages, such as a shorter time to achieve the results and, perhaps, higher reproducibility/feasibility in many laboratories.

Identification of a novel cord blood NK cell subpopulation expressing functional programmed death receptor-1.

Background: Natural Killer cells (NKs) represent the innate counterpart of TCRαß lymphocytes and are characterized by a high anti-tumor and an anti-viral cytotoxic activity. Recently, it has been demonstrated that NKs can express PD-1 as an additional inhibitory receptor. Specifically, PD-1 was identified on a subpopulation of terminally differentiated NKs from healthy adults with previous HCMV infection. So far it is unknown whether PD-1 appears during NK-cell development and whether this process is directly or indirectly related to HCMV infection. Methods: In this study, we analyzed the expression and function of PD-1 on Cord Blood derived NKs (CB-NKs) on a large cohort of newborns through multiparametric cytofluorimetric analysis. Results: We identified PD-1 on CB-NKs in more than of half the newborns analyzed. PD-1 was present on CD56dim NKs, and particularly abundant on CD56neg NKs, but only rarely present on CD56bright NKs. Importantly, unlike in adult healthy donors, in CB-NKs PD-1 is co-expressed not only with KIR, but also with NKG2A. PD-1 expression was independent of HCMV mother seropositivity and occurs in the absence of HCMV infection/reactivation during pregnancy. Notably, PD-1 expressed on CB-NKs was functional and mediated negative signals when triggered. Conclusion: To our understanding, this study is the first to report PD-1 expression on CB derived NKs and its features in perinatal conditions. These data may prove important in selecting the most suitable CB derived NK cell population for the development of different immunotherapeutic treatments.

CD19-Targeted Immunotherapies for Diffuse Large B-Cell Lymphoma.

Surgical resection, chemotherapy and radiotherapy were, for many years, the only available cancer treatments. Recently, the use of immune checkpoint inhibitors and adoptive cell therapies has emerged as promising alternative. These cancer immunotherapies are aimed to support or harness the patient's immune system to recognize and destroy cancer cells. Preclinical and clinical studies, based on the use of T cells and more recently NK cells genetically modified with chimeric antigen receptors retargeting the adoptive cell therapy towards tumor cells, have already shown remarkable results. In this review, we outline the latest highlights and progress in immunotherapies for the treatment of Diffuse Large B-cell Lymphoma (DLBCL) patients, focusing on CD19-targeted immunotherapies. We also discuss current clinical trials and opportunities of using immunotherapies to treat DLBCL patients.

Post-Transplant Nivolumab Plus Unselected Autologous Lymphocytes in Refractory Hodgkin Lymphoma: A Feasible and Promising Salvage Therapy Associated With Expansion and Maturation of NK Cells.

Immune checkpoint inhibitors (CI) have demonstrated clinical activity in Hodgkin Lymphoma (HL) patients relapsing after autologous stem cell transplantation (ASCT), although only 20% complete response (CR) rate was observed. The efficacy of CI is strictly related to the host immune competence, which is impaired in heavily pre-treated HL patients. Here, we aimed to enhance the activity of early post-ASCT CI (nivolumab) administration with the infusion of autologous lymphocytes (ALI). Twelve patients with relapse/refractory (R/R) HL (median age 28.5 years; range 18-65), underwent lymphocyte apheresis after first line chemotherapy and then proceeded to salvage therapy. Subsequently, 9 patients with progressive disease at ASCT received early post-transplant CI supported with four ALI, whereas 3 responding patients received ALI alone, as a control cohort. No severe adverse events were recorded. HL-treated patients achieved negative PET scan CR and 8 are alive and disease-free after a median follow-up of 28 months. Four patients underwent subsequent allogeneic SCT. Phenotypic analysis of circulating cells showed a faster expansion of highly differentiated NK cells in ALI plus nivolumab-treated patients as compared to control patients. Our data show anti-tumor activity with good tolerability of ALI + CI for R/R HL and suggest that this setting may accelerate NK cell development/maturation and favor the expansion of the "adaptive" NK cell compartment in patients with HCMV seropositivity, in the absence of HCMV reactivation.

Nine reasons why ecstasy is not quite what it used to be.

This paper explores the recent resurgence in use of ecstasy/MDMA in Europe and highlights keys areas of continuity and divergence between the ecstasy market of the 1990s and the current MDMA market. Based on a scoping study involving a targeted multi-source data collection exercise on MDMA, it highlights nine areas that have undergone some level of change, linked with both supply and demand for the drug. Factors discussed include: innovation in production techniques; changes in precursor chemical availability; the role of online markets; competition with other stimulants and new psychoactive substances; the increased availability of high-strength MDMA; and the shift from subcultural towards more mainstream use of the drug. The paper proposes that the MDMA on Europe's contemporary market is in some respects a third generation product with a different consumer profile, with implications that responses developed at the time of the drug's earlier iteration, may be in need of a review and revamp.

New psychoactive substances: Current health-related practices and challenges in responding to use and harms in Europe.

BACKGROUND: The availability of new psychoactive substances (NPS) in Europe has rapidly increased over the last decade. Although prevalence levels of NPS use remain low in the general European population, there are serious concerns associated with more problematic forms of use and harms in particular populations and settings. It has thus become a priority to formulate and implement effective public health responses. However, considerable knowledge gaps remain on current practices as well as on the challenges and needs of European health professionals who are responding to use and harms caused by these substances. The aim of this study was to explore current health responses to NPS, and highlight key issues in order to inform planning and implementation of adequate responses. METHODS: This scoping study was based on a targeted multi-source data collection exercise focusing on the provision of health and drug interventions associated with NPS use and harms, in selected intervention settings across Europe. RESULTS: Findings revealed that in the absence of specific evidence, health professionals across most intervention settings rely primarily on acquired expertise with traditional drugs when addressing NPS-related harms. This study also identified a gap in the availability and access to timely and reliable information on NPS to users and health professionals. Health professionals in sexual health settings and custodial settings in contact with certain risk groups reported particular challenges in responding to NPS-related harms. CONCLUSION: Immediate investments are required in expanding substance identification capabilities, competence building among professionals and dissemination of risk information among relevant stakeholders. The risks of neglecting under-served risk populations and failure to address the information needs of health professionals and users on NPS harms in a context of rapid changing drug markets in Europe may have unforeseeable consequences at societal level.

Are mass-media campaigns effective in preventing drug use? A Cochrane systematic review and meta-analysis.

OBJECTIVE: To determine whether there is evidence that mass-media campaigns can be effective in reducing illicit drug consumption and the intent to consume. DESIGN: Systematic review of randomised and non-randomised studies. METHODS: We searched four electronic databases (MEDLINE, EMBASE, ProQuest Dissertations & Theses A&I and CENTRAL) and further explored seven additional resources to obtain both published and unpublished materials. We appraised the quality of included studies using standardised tools. We carried out meta-analyses of randomised controlled trials and a pooled analysis of interrupted time-series and controlled before-and-after studies. RESULTS: We identified 19 studies comprising 184,811 participants. Pooled analyses and narrative synthesis provided mixed evidence of effectiveness. Eight interventions evaluated with randomised controlled trials leaned towards no evidence of an effect, both on drug use (standardised mean difference (SMD) -0.02; 95% CI -0.15 to 0.12) and the intention to use drugs (SMD -0.07; 95% CI -0.19 to 0.04). Four campaigns provided some evidence of beneficial effects in preventing drug use and two interventions provided evidence of iatrogenic effects. CONCLUSIONS: Studies were considerably heterogeneous in type of mass-media intervention, outcome measures, underlying theory, comparison groups and design. Such factors can contribute to explaining the observed variability in results. Owing to the risk of adverse effects, caution is needed in disseminating mass-media campaigns tackling drug use. Large studies conducted with appropriate methodology are warranted to consolidate the evidence base.