Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial

BACKGROUND: Vascular-targeted photodynamic therapy, a novel tissue-preserving treatment for low-risk prostate cancer, has shown favourable safety and efficacy results in single-arm phase 1 and 2 studies. We compared this treatment with the standard of care, active surveillance, in men with low-risk prostate cancer in a phase 3 trial. METHODS: This randomised controlled trial was done in 47 European university centres and community hospitals. Men with low-risk, localised prostate cancer (Gleason pattern 3) who had received no previous treatment were randomly assigned (1:1) to vascular-targeted photodynamic therapy (4 mg/kg padeliporfin intravenously over 10 min and optical fibres inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light 753 nm with a fixed power of 150 mW/cm for 22 min 15 s) or active surveillance. Randomisation was done by a web-based allocation system stratified by centre with balanced blocks of two or four patients. Best practice for active surveillance at the time of study design was followed (ie, biopsy at 12-month intervals and prostate-specific antigen measurement and digital rectal examination at 3-month intervals). The co-primary endpoints were treatment failure (histological progression of cancer from low to moderate or high risk or death during 24 months' follow-up) and absence of definite cancer (absence of any histology result definitely positive for cancer at month 24). Analysis was by intention to treat. Treatment was open-label, but investigators assessing primary efficacy outcomes were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT01310894. FINDINGS: Between March 8, 2011, and April 30, 2013, we randomly assigned 206 patients to vascular-targeted photodynamic therapy and 207 patients to active surveillance. Median follow-up was 24 months (IQR 24-25). The proportion of participants who had disease progression at month 24 was 58 (28%) of 206 in the vascular-targeted photodynamic therapy group compared with 120 (58%) of 207 in the active surveillance group (adjusted hazard ratio 0·34, 95% CI 0·24-0·46; p<0·0001). 101 (49%) men in the vascular-targeted photodynamic therapy group had a negative prostate biopsy result at 24 months post treatment compared with 28 (14%) men in the active surveillance group (adjusted risk ratio 3·67, 95% CI 2·53-5·33; p<0·0001). Vascular-targeted photodynamic therapy was well tolerated. The most common grade 3-4 adverse events were prostatitis (three [2%] in the vascular-targeted photodynamic therapy group vs one [<1%] in the active surveillance group), acute urinary retention (three [2%] vs one [<1%]) and erectile dysfunction (two [1%] vs three [1%]). The most common serious adverse event in the vascular-targeted photodynamic therapy group was retention of urine (15 patients; severe in three); this event resolved within 2 months in all patients. The most common serious adverse event in the active surveillance group was myocardial infarction (three patients). INTERPRETATION: Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy. FUNDING: Steba Biotech

Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.: Apoptosis and regulatory T cells

International audienceApoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover

In Situ-Targeting of Dendritic Cells with Donor-Derived Apoptotic Cells Restrains Indirect Allorecognition and Ameliorates Allograft Vasculopathy

Chronic allograft vasculopathy (CAV) is an atheromatous-like lesion that affects vessels of transplanted organs. It is a component of chronic rejection that conventional immuno-suppression fails to prevent, and is a major cause of graft loss. Indirect allo-recognition through T cells and allo-Abs are critical during CAV pathogenesis. We tested whether the indirect allo-response and its impact on CAV is down-regulated by in situ-delivery of donor Ags to recipient's dendritic cells (DCs) in lymphoid organs in a pro-tolerogenic fashion, through administration of donor splenocytes undergoing early apoptosis. Following systemic injection, donor apoptotic cells were internalized by splenic CD11chi CD8α+ and CD8− DCs, but not by CD11cint plasmacytoid DCs. Those DCs that phagocytosed apoptotic cells in vivo remained quiescent, resisted ex vivo-maturation, and presented allo-Ag for up to 3 days. Administration of donor apoptotic splenocytes, unlike cells alive, (i) promoted deletion, FoxP3 expression and IL-10 secretion, and decreased IFN-γ-release in indirect pathway CD4 T cells; and (ii) reduced cross-priming of anti-donor CD8 T cells in vivo. Targeting recipient's DCs with donor apoptotic cells reduced significantly CAV in a fully-mismatched aortic allograft model. The effect was donor specific, dependent on the physical characteristics of the apoptotic cells, and was associated to down-regulation of the indirect type-1 T cell allo-response and secretion of allo-Abs, when compared to recipients treated with donor cells alive or necrotic. Down-regulation of indirect allo-recognition through in situ-delivery of donor-Ag to recipient's quiescent DCs constitutes a promising strategy to prevent/ameliorate indirect allorecognition and CAV

Apoptotic cell-based therapies against transplant rejection: role of recipient’s dendritic cells

One of the ultimate goals in transplantation is to develop novel therapeutic methods for induction of donor-specific tolerance to reduce the side effects caused by the generalized immunosuppression associated to the currently used pharmacologic regimens. Interaction or phagocytosis of cells in early apoptosis exerts potent anti-inflammatory and immunosuppressive effects on antigen (Ag)-presenting cells (APC) like dendritic cells (DC) and macrophages. This observation led to the idea that apoptotic cell-based therapies could be employed to deliver donor-Ag in combination with regulatory signals to recipient’s APC as therapeutic approach to restrain the anti-donor response. This review describes the multiple mechanisms by which apoptotic cells down-modulate the immuno-stimulatory and pro-inflammatory functions of DC and macrophages, and the role of the interaction between apoptotic cells and APC in self-tolerance and in apoptotic cell-based therapies to prevent/treat allograft rejection and graft-versus-host disease in murine experimental systems and in humans. It also explores the role that in vivo-generated apoptotic cells could have in the beneficial effects of extracorporeal photopheresis, donor-specific transfusion, and tolerogenic DC-based therapies in transplantation

Insuffisance rénale chronique et transplantation rénale

International audienceOBJECTIVES:To report epidemiology and characteristics of end-stage renal disease (ESRD) patients and renal transplant candidates, and to evaluate access to waiting list and results of renal transplantation.MATERIAL AND METHODS:An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords: "chronic kidney disease, epidemiology, kidney transplantation, cost, survival, graft, brain death, cardiac arrest, access, allocation". French legal documents have been reviewed using the government portal (http://www.legifrance.gouv.fr). Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and recommendations were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 3234 articles, 6 official reports and 3 newspaper articles were identified; after careful selection 99 publications were eligible for our review.RESULTS:The increasing prevalence of chronic kidney disease (CKD) leads to worsen organ shortage. Renal transplantation remains the best treatment option for ESRD, providing recipients with an increased survival and quality of life, at lower costs than other renal replacement therapies. The never-ending lengthening of the waiting list raises issues regarding treatment strategies and candidates' selection, and underlines the limits of organ sharing without additional source of kidneys available for transplantation.CONCLUSION:Allocation policies aim to reduce medical or geographical disparities regarding enrollment on a waiting list or access to an allotransplant

Troubles du bas appareil urinaire et de la statique pelvienne chez les candidats et receveurs d’une transplantation rénale

International audienceOBJECTIVES:To describe lower urinary tract symptoms (LUTS) and their management in renal transplant candidates and recipients.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) database using the following keywords, alone or in association: "transplantation", "prostate hyperplasia", "transurethral resection of prostate", "urinary incontinence", "LUTS", "pelvic floor dysfunction". Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and case reports were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 991 articles were analyzed and after careful selection, 47 publications were eligible for our review.RESULTS:Reduction of bladder capacity, due to dialysis and anuria, is correlated with dialysis duration. This reduction is reversible after renal transplantation and does not seem to put renal transplant recipients at risk for medical complications. Transplant procedure generally allows restoration of bladder maximal output, normal bladder capacity and compliance. Medical treatment of LUTS related to prostate hyperplasia (BPH) includes alpha-blockers and finasteride. Silodosin and dutasteride have not been evaluated in that setting. Antimuscarinics may be used with caution, and favor the use of solifenacin at 5mg per day. Surgical treatment of BPH requires a preserved urine output, otherwise must be delayed after transplantation; it may thus be performed safely in the early postoperative course. Botulinum toxin injections and surgical treatment of stress incontinence and prolapse are barely reported in this population.CONCLUSION:Precise assessment and optimal management of LUTS in renal transplant candidates and recipients are critical to improve quality of life and to preserve allotransplant function. Literature data lack evidence to propose robust recommendations. However, knowledge of reported specificities in this peculiar setting is mandatory for urologists to provide patients with finest options and optimal treatment timing

Le donneur décédé de rein

International audienceOBJECTIVES:To review epidemiologic data's and medical results of deceased donation in renal transplantation.MATERIAL AND METHODS:Relevant publications were identified through Medline (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) database using the following keywords, alone or in association, "brain death; cardiac arrest; deceased donation; organ procurement; transplantation". Articles were selected according to methods, language of publication and relevance. The reference lists were used to identify additional historical studies of interest. Both prospective and retrospective series, in French and English, as well as review articles and recommendations were selected. In addition, French national transplant and health agencies (http://www.agence-biomedecine.fr and http://www.has-sante.fr) databases were screened using identical keywords. A total of 2498 articles, 8 official reports and 17 newspaper articles were identified; after careful selection 157 publications were eligible for our review.RESULTS:Deceased donation may involve either brain death or non-heartbeating donors (NHBD). Organ shortage led to the procurement of organs from expanded-criteria donors, with an increased age at donation and extended vascular disease, leading to inferior results after transplantation and underlining the need for careful donor management during brain death or cardiac arrest. Evolution of French legislation covering bioethics allowed procurement from Maastricht categories II and recently III non-heartbeating donors.CONCLUSION:The increase of organ shortage emphasizes the need for a rigorous surgical technique during procurement to avoid loss of transplants. A history or current neoplasm in deceased-donors, requires attention to increase the pool of organs without putting the recipients at risk for cancer transmission. French NHBD program, especially from Maastricht category III, may stand for a potential source of valuable organs

Histoire chirurgicale de la transplantation rénale

International audienceOBJECTIVES:To perform a state of the art about the history of kidney transplantation.MATERIAL AND METHODS:An exhaustive systematic review of the scientific literature was performed in the Medline database (http://www.ncbi.nlm.nih.gov) and Embase (http://www.embase.com) using different associations of the following keywords (MESH): kidney transplantation, history, vascular anastomosis.RESULTS:From the first vascular ligations to the discovery of ciclosporin, the history of organ transplantation was made of surgical bets and medical discoveries, such as blood group, HLA-system, immunity, etc. The audacity of some surgeons led to the onset of renal transplantation as the treatment of choice for end stage renal disease.CONCLUSION:This article aims to describe the first surgical methods for vascular anastomosis and renal transplantation. Through a comprehensive search within the archives of the French National Library, the authors provide a precise description of the first renal transplantations performed, the technique that have been used and their authors