Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.clinicaltrials.gov as NCT03676504

''Sex changes'? Paradigm shifts in 'sex' and 'gender' following the gender recognition act?'

Gender transformations are normatively understood as somatic, based on surgical reassignment, where the sexed body is aligned with the gender identity of the individual through genital surgery - hence the common lexicon 'sex change surgery'. We suggest that the UK Gender Recognition Act 2004 challenges what constitutes a 'sex change' through the Act's definitions and also the conditions within which legal 'recognition' is permitted. The sex/gender distinction, (where sex normatively refers to the sexed body, and gender, to social identity) is demobilised both literally and legally. This paper discusses the history of medico-socio-legal definitions of sex have been developed through decision making processes when courts have been faced with people with gender variance and , in particular, the implications of the Gender Recognition Act for our contemporary legal understanding of sex. We ask, and attempt to answer, has 'sex' changed

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

‘You’re basically calling doctors torturers’:stakeholder framing issues around naming intersex rights claims as human rights abuses

In this article we address activist, patient advocate and medic perspectives on framing intersex, variations of sex characteristics and disorders/differences in sex development medical treatment as human rights abuses. Problematic aspects of intersex medical treatment have increasingly been highlighted in national debates and international human rights bodies. Some intersex activists have framed aspects of intersex medical treatment as human rights abuses since the 1990s. Other stakeholders in shaping medical treatment, such as patient advocates and medical professionals, are not always content with human rights framing, or even the term intersex. In order to address the different perspectives in this arena we provide background on the primary rights claims that have arisen followed by key human rights framing of these claims. We provide a short discussion of activism styles, looking at pan-intersex social movements and variation-specific patient associations as different styles of health social movements. The analysis of stakeholder perspectives on the use of human rights strategy in health areas provides a useful case study for medical sociology and policy in general