Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development

Vinflunine, the most recent Vinca alkaloid in clinical development, demonstrated superior antitumour activity to other Vincas in preclinical tumour models. This study aimed to define its molecular mechanisms of cell killing in both parental sensitive and vinflunine-resistant P388 leukaemia cells. Vinflunine treatment of these cells resulted in apoptosis characterized by DNA fragmentation and proteolytic cleavage of poly-(ADP-ribose) polymerase. Apoptosis-inducing concentrations of vinflunine caused c-Jun N-terminal kinase 1 stimulation, as well as caspases-3/7 activation. This activation of caspases and the induction of apoptosis could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. Interestingly, the apoptosis signal triggered by vinflunine in these P388 cells was not mediated through Bcl-2 phosphorylation. In addition, when vinflunine resistance was developed in P388 cells, it was associated with resistance to vinflunine-induced apoptosis, as reflected by a loss of capacity to induce DNA fragmentation and PARP degradation, and characterized by increased levels of Bcl-2 and Bfl-1/A1. Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms

Standards for the care of people with cystic fibrosis; establishing and maintaining health

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy

A conceptual framework to develop a patient-reported experience questionnaire on the cystic fibrosis journey in France: the ExPaParM collaborative study

International audienceAbstract Background The objective of the study was to elaborate a conceptual framework related to the domains of patient experience along the cystic fibrosis (CF) journey from the patients and parents of children with CF to inform the design of a patient-reported experience questionnaire. Method A collaborative research group including patients and parents with clinicians and academic researchers was set up. They identified the situations along the CF care pathway from diagnosis to paediatric care, transition to adult care and adult follow-up, transfer to transplant centres and follow-up after transplantation. Participants were recruited by CF centres in metropolitan France and overseas departments. Semi-structured interviews were conducted, transcribed verbatim and subjected to an inductive analysis conducted in duos of researchers/co-researchers using NVivo®. The conceptual framework was discussed with the research group and presented to the CF centres during two video conferences. The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888-no. 20-700). Results The analysis led to a conceptual framework composed of domains of the CF journey, each divided into several items. 1. CF care: Management of care by the CF centre team; in-hospital care; quality of care in the community; therapeutic education and self-management support; at-home care; new therapies and research; procreation; 2. Transplant care: management of transplant and CF care; coordination with other specialties; education and self-management support; at-home care; procreation; new therapies and research; 3. Turning points along the journey: diagnosis of CF, transition to adult care, transfer to transplantation; 4. Social life with CF: housing, employment and education, social relations, social welfare and family finances. The number of patients included and the diversity of situations made it possible to achieve a sufficient richness and saturation of codes by domain to develop patient experience questionnaires. Conclusion This conceptual framework, resulting from the participants’ experience, will inform the design of a patient-reported experience tool, whose construct will be tested during the next phase of the ExPaParM project to assess its fidelity, intelligibility, and ability to report patient experience of the CF journey

Collaborative research protocol to define patient-reported experience measures of the cystic fibrosis care pathway in France: the ExPaParM study

International audienceAbstract Introduction In France, the cystic fibrosis (CF) care pathway is coordinated by multidisciplinary teams from specialised CF centres or transplant centres. It includes the care provided at home or out of hospital, risk prevention in daily life and adjustments to social life, which together contribute to the person’s quality of life. Patient experience is used to describe and evaluate the care and life of patients living with the disease. Objectives Our collaborative research aims to identify the most significant areas and criteria that characterise the CF pathway. It will lead to the development of a questionnaire to collect patients' experience, which can be administered to all patients or parents of children registered and followed in the centres. The article describes the protocol developed in partnership with patients and parents of children living with the disease. Method A multidisciplinary research group brings together researchers, patients, parents of children with CF and health care professionals. The patient partnership is involved in the 4 phases of the protocol: (1) setting up the study, recruiting patient and parent co-researchers, training them in qualitative research methods, defining the situations and profiles of patients in the study population, elaborating the protocol; (2) selecting the study sites, recruiting participants, carrying out semi-structured interviews, analysing verbatims using the grounded theory approach; (3) co-elaborating Patient-Reported Experience Measures (PREM) questionnaires adapted to the 4 types of participants: parents, adolescents, non-transplanted adults and transplanted adults; (4) validating the construct with participants and professionals from the study centres. Results The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888—no. 20-700). Training was provided to the 5 patients and 2 parent co-researchers to enable them to participate effectively in the research. Eleven centres participated in the recruitment of participants in mainland France and Reunion Island. Eighty hours of interviews were conducted. Discussion The PREM questionnaires to be elaborated will have to undergo psychometric validation before being used by the actors of the CF network to assess the impact on the care pathways of quality approaches or new therapies available in cystic fibrosis. Trial Registration Registry : IRB00003888 – no. 20-700. Issue date: 06/09/2020