Molecular Tumor Boards: Ethical Issues in the New Era of Data Medicine.

The practice and development of modern medicine requires large amounts of data, particularly in the domain of cancer. The future of personalized medicine lies neither with "genomic medicine" nor with "precision medicine", but with "data medicine" (DM) (big data, data mining). The establishment of this DM has required far-reaching changes, to establish four essential elements connecting patients and doctors: biobanks, databases, bioinformatic platforms and genomic platforms. The "transformation" of scientific research areas, such as genetics, bioinformatics and biostatistics, into clinical specialties has generated a new vision of care. Molecular tumor boards (MTB) are one response to these changes and are now providing better access to next-generation sequencing (NGS) and new cancer treatments to patients with inoperable or metastatic cancers, and those for whom the usual treatment has failed. However, MTB face a crucial ethical challenge: maintaining and improving the trust of patients, clinicians, researchers and industry in academic medical centers supported by private or public funding rather than providing genetic data directly to private companies. We believe that, in this era of DM, appropriate modern digital communication networks will be required to maintain this trust and to improve the organization and effectiveness of the system. There is, therefore, a need to reconsider the form and content of informed consent (IC) documents at all academic medical centers and to introduce dynamic and electronic informed consent (e-IC).

23andMe: a new two-sided data-banking market model.

BACKGROUND: Since 2006, the genetic testing company 23andMe has collected biological samples, self-reported information, and consent documents for biobanking and research from more than 1,000,000 individuals (90% participating in research), through a direct-to-consumer (DTC) online genetic-testing service providing a genetic ancestry report and a genetic health report. However, on November 22, 2013, the Food and Drug Administration (FDA) halted the sale of genetic health testing, on the grounds that 23andMe was not acting in accordance with federal law, by selling tests of undemonstrated reliability as predictive tests for medical risk factors. Consumers could still obtain the genetic ancestry report, but they no longer had access to the genetic health report in the United States (US). However, this did not prevent the company from continuing its health research, with previously obtained and future samples, provided that consent had been obtained from the consumers concerned, or with health reports for individuals from other countries. Furthermore, 23andMe was granted FDA authorization on February 19, 2015, first to provide reports about Bloom syndrome carrier status, and, more recently, to provide consumers with "carrier status" information for 35 genes known (with high levels of confidence) to cause disease. DISCUSSION: In this Debate, we highlight the likelihood that the primary objective of the company was probably two-fold: promoting itself within the market for predictive testing for human genetic diseases and ancestry at a low cost to consumers, and establishing a high-value database/biobank for research (one of the largest biobanks of human deoxyribonucleic acid (DNA) and personal information). By dint of this marketing approach, a two-sided market has been established between the consumer and the research laboratories, involving the establishment of a database/DNA biobank for scientific and financial gain. We describe here the profound ethical issues raised by this setup.

[Ethics and kidney transplants with living donors]. / Éthique et transplantation rénale avec donneurs vivants.

The ethical debate surrounding transplant practices questions our societies. International recommendations set out numerous precautions which must be taken to ensure that donors act with their free will. While in most countries, including France, organ donation is a voluntary and non-commercial act, a black market exists in the world resulting in the trafficking of organs and tragic transplant tourism.

Improving the Quality of Host Country Ethical Oversight of International Research: The Use of a Collaborative 'Pre-Review' Mechanism for a Study of Fexinidazole for Human African Trypanosomiasis.

Developing countries face numerous barriers to conducting effective and efficient ethics reviews of international collaborative research. In addition to potentially overlooking important scientific and ethical considerations, inadequate or insufficiently trained ethics committees may insist on unwarranted changes to protocols that can impair a study's scientific or ethical validity. Moreover, poorly functioning review systems can impose substantial delays on the commencement of research, which needlessly undermine the development of new interventions for urgent medical needs. In response to these concerns, the Drugs for Neglected Diseases Initiative (DNDi), an independent nonprofit organization founded by a coalition of public sector and international organizations, developed a mechanism to facilitate more effective and efficient host country ethics review for a study of the use of fexinidazole for the treatment of late stage African Trypanosomiasis (HAT). The project involved the implementation of a novel 'pre-review' process of ethical oversight, conducted by an ad hoc committee of ethics committee representatives from African and European countries, in collaboration with internationally recognized scientific experts. This article examines the process and outcomes of this collaborative process.

Maintaining calcineurin inhibition after the diagnosis of post-transplant lymphoproliferative disorder improves renal graft survival.

Post-transplant lymphoproliferative disorder (PTLD) is an uncontrolled proliferation of transformed lymphocytes fostered by immunosuppression. In addition to chemotherapy, treatment of PTLD includes a reduction of maintenance immunosuppression. Patients with PTLD have an increased risk of graft loss, suggesting that reduced immunosuppression strategy needs to be optimized with regard to graft outcome. Here we retrospectively reviewed 101 cases involving PTLD to identify the risks associated with graft loss. During a median follow-up of 70 months, 39 patients died and 21 lost their graft. Multivariate analysis found that an eGFR under 30 ml/min per 1.73 m(2) at PTLD diagnosis, a biopsy-proven acute rejection episode following reduction of immunosuppression, and the absence of calcineurin inhibition in maintenance immunosuppression are independent risk factors for allograft loss. Neither the type of PTLD nor the chemotherapy regimen was predictive of allograft failure. Histological analysis of graft biopsies showed that maintaining calcineurin inhibition after the diagnosis of PTLD reduced the risk of developing de novo anti-HLA antibodies and humoral rejection. Remarkably, calcineurin inhibitor maintenance was neither associated with higher mortality nor with worse progression-free survival. Thus, maintaining calcineurin inhibition at a reduced dose after the diagnosis of PTLD seems safe and may improve renal graft outcome, possibly through better control of the recipient's humoral immune response.

A multistep voriconazole-related phototoxic pathway may lead to skin carcinoma: results from a French nationwide study.

BACKGROUND: Voriconazole long-term therapy is suspected to induce cutaneous squamous cell carcinoma (SCC), as suggested by 18 case reports worldwide and 3 retrospective studies. METHODS: To better characterize the natural history of these potentially voriconazole-associated tumors, a nationwide call for notification of skin cancers and other skin lesions observed between 2002 and 2012 in patients treated by voriconazole was launched in France. A multidisciplinary committee evaluated voriconazole involvement in each case. RESULTS: Nineteen SCCs were reported. The committee determined the likelihood of voriconazole involvement to be high in 15 cases, intermediate in 2, and low in 2. In the 17 patients with high/intermediate likelihood of voriconazole involvement, the mean time between voriconazole initiation and SCC diagnosis was 39 ± 18 months (range, 28-84 months), and was shorter in transplant recipients (35 vs 45 months, P < .05). Cumulative mean duration of voriconazole therapy at SCC diagnosis was 35 months (range, 7-63 months). A multistep process was noted in 14 of 17 patients: acute phototoxicity during the first year of voriconazole therapy (mean time, 6 months [range, 0-18 months]), actinic keratosis (AK) of the same sun-exposed skin area in the second/third year (mean, 30 months [range, 11-57 months]), followed by SCC during the third year or later. Five cases of AK without SCC and 37 cases of other skin lesions were also reported. CONCLUSIONS: Our results suggest that long-term voriconazole prescription may be associated with a multistep phototoxic process involving acute skin lesions followed by AK then by SCC. Discontinuation of voriconazole should be strongly considered in patients experiencing chronic phototoxicity.

Late-onset post-transplantation lymphoproliferative disorders after kidney transplantation: a monocentric study over three decades.

BACKGROUND: Late-onset post-transplantation lymphoproliferative disorders (PTLDs) occur 1 year after transplantation and are associated with poor prognosis. Initial treatment usually involves a reduction in immunosuppressive treatment. While early-onset PTLDs have a good prognosis following RI, this approach is generally inadequate for late-onset PTLDs. We assessed the specific outcome of late-onset PTLDs after kidney transplantation during the past three decades. METHODS: We reviewed the clinical and biological data of 52 kidney transplant recipients who developed late-onset PTLDs at our centre between 1980 and 2010. We compared clinical features, long-term outcome and renal prognosis of late-onset PTLDs both before and after the era of rituximab. RESULTS: Before 2000, 38% of the patients underwent surgery and 76% received chemotherapy either immediately or after surgery. After 2000, rituximab was administrated to 70% of the patients either alone (23%) or in combination with chemotherapy (77%). Chemotherapy alone was administrated in 26% of the cases. Before and after 2000, complete remission was achieved in 38 and 87% of the cases, respectively (P = 0.0005). The 5-year overall survival (OS) was 33.3 and 69% (P = 0.003), and 5-year disease-free survival was 37.5 and 80%, respectively (P = 0.19). Renal function was preserved in 70% of the cases at the end of the follow-up. CONCLUSIONS: This study shows an increase in OS and low graft loss for patients with late-onset PTLDs during the last decade, which may be attributed to multiple changes in clinical practice, including a more standardized treatment and the use of rituximab in combination with chemotherapy.

Outcomes of renal transplantation in patients with autosomal dominant polycystic kidney disease: a nationwide longitudinal study.

Renal transplantation in patients with autosomal dominant polycystic kidney disease (ADPKD) is a medical and surgical challenge. Detailed longitudinal epidemiological studies on large populations are lacking and it is mandatory to care better for these patients. The success of such a project requires the development of a validated epidemiological database. Herein, we present the results of the largest longitudinal study to date on renal transplant in patients with ADPKD. The 15-year outcomes following renal transplantation of 534 ADPKD patients were compared with 4779 non-ADPKD patients. This comprehensive, longitudinal, multicenter French study was performed using the validated database, DIVAT (Données Informatisées et VAlidées en Transplantaion). We demonstrate that renal transplantation in ADPKD is associated with better graft survival, more thromboembolic complications, more metabolic complications, and increased incidence of hypertension, whereas the prevalence of infections is not increased. This study provides important new insights that could lead to a better care for renal transplant patients with ADPKD.

Human listeriosis caused by Listeria ivanovii.

Two species of Listeria are pathogenic; L. monocytogenes infects humans and animals, and L. ivanovii has been considered to infect ruminants only. We report L. ivanovii-associated gastroenteritis and bacteremia in a man. This isolate was indistinguishable from prototypic ruminant strains. L. ivanovii is thus an enteric opportunistic human pathogen.

Proteinuria >0.5 g/d, a prevalent prognostic factor for patient and graft survival in kidney transplantation.

UNLABELLED: Proteinuria >0.5 g/d (HP) and serum creatinine (Scr) >120 micromol/L (HSC) at three months, two and five yr were compared as prognostic factors in kidney transplantation. We retrospectively analyzed 454 first transplants (follow-up: 100 +/- 3.2 months). Donor/recipient age, sex, panel reactive antibody (PRA), HLA mismatches, cold ischemia time, delayed graft function, acute rejection, blood pressure and its treatment, diabetes and anti-calcineurin use were also evaluated. Cox proportional hazard regression with time-dependent covariates to control for potentially confounding factors was used to analyze survival. The Kaplan-Meier product-limit estimate for survival according to urine protein excretion (< or = or >0.5 g/d) or Scr (< or = or >120 micromol/L) along with the log-rank test for all comparisons were computed. Statistical significance was set with p-value < 0.05. RESULTS: HSC is a prognostic factor of graft survival (HR: 2.54; 95% CI: 1.98-3.10; p < 0.01) only at five yr, but it does not predict mortality at any period. HP at three months (HR: 2.07; 95% CI: 1.70-2.43; p < 0.001) and at two yr 3.03 (2.54-3.51; p < 0.001) significantly predicts graft failure. HP at two yr is the prevailingly prognostic factor of patient survival in kidney transplantation (HR: 3.30; 95% CI: 1.94-5.62; p < 0.0001).

[Living donors for kidney transplantation: ethical and legal challenges]. / La transplantation rénale à partir de donneurs vivants: enjeux éthiques et juridiques.

Living donor kidney transplantation has developed very heterogeneously worldwide despite excellent results and without taking into account the context of global organ shortage. Such a heterogeneity highlights persistent ethical issues, whereas organ trafficking is emerging as an organized transplant tourism reinforcing the need for strong national legal frameworks. Despite its powerful regulation system, which ensures standardization, transparency and accountability of support for donation, France remains reluctant to enlarge the circle of legal donors, whereas it would be the first step to give a greater role to living organ donation.

Systemic Modelling in Bioethics.

We present here a new method for bioethics: systemic modelling. In this method, the complex phenomenon being studied (e.g. personalized medicine, genetic testing, gene therapy, genetically modified organisms) is modelled as a whole, to shed light on its organization and functioning, and major (bio)ethical issues and solutions for their resolution are then identified. This systemic modelling method is ideal for use in the identification of solutions, rather than their validation, with other methods then used to test the solutions found. We provide a description and reproducible instructions for the application of systemic modelling in bioethics, together with a brief example of the application of this method to the study of the impact of personalized medicine on French society.

Evidence that graft-site candidiasis after kidney transplantation is acquired during organ recovery: a multicenter study in France.

BACKGROUND: Infections of renal grafts with Candida species can induce life-threatening complications in the recipient. METHODS: A 9-year retrospective study involving all of the transplant centers in France was designed to determine the incidence, origin, characteristics, and outcome of graft-site candidiasis that occurred after kidney transplantation. Yeasts cultured from preservation or drainage solutions and graft specimens were recorded. RESULTS: Among 18,617 kidney grafts, 18 recipients corresponding to 12 donors developed culture-confirmed graft-site candidiasis (incidence, 1 case per 1000 grafts) a median of 25 days after the graft procedure. Clinical presentations included 14 cases of renal arteritis (13 were complicated by aneurysm), 1 urinoma, 2 graft site abscesses, and 1 surgical site infection. Candida albicans was involved in 13 cases. A unique C. albicans genotype or a single rare Candida species was involved in each episode. Together with the clinical history, these findings demonstrate that organ contamination followed by transmission to the recipient occurred during recovery. Therapeutic management varied from simple monitoring in 1 case to a combination of surgery (nephrectomy in 9 cases and arterial bypass in 9 cases) and antifungal therapy (14 cases). Overall, 3 of 18 kidney transplant recipients died, and 9 had their graft surgically removed. CONCLUSION: Graft-transmitted candidiasis that ends most often in fungal arteritis is associated with high morbidity and mortality after kidney transplantation and is related to organ contamination during recovery in the donor.

Effects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients.

Low serum levels of 25-hydroxy vitamin D frequently occur after renal transplantation, but few studies have evaluated the effects of normalizing this on serum parathyroid hormone and calcium levels or urinary calcium excretion. To determine this we compared the outcomes of 94 renal transplant patients with low 25-hydroxy vitamin D and normal serum calcium levels who were either treated or not with cholecalciferol every 2 weeks for 2 months (intensive phase) followed by an every other month maintenance phase. The biological characteristics of the two equally divided patient groups did not differ before treatment. After the intensive phase, serum 25-hydroxy vitamin D levels were normalized in all but 3 patients and the serum parathyroid hormone decreased and calcium levels increased with no severe adverse effects. During the maintenance phase, the serum 25-hydroxy vitamin D level decreased but remained significantly higher than in controls. In the control group, the serum 25-hydroxy vitamin D concentration increased slightly but became normal in only three patients. Serum 25-hydroxy vitamin D levels were significantly higher and parathyroid hormone levels were lower in treated patients compared to controls one year following transplant. Hence, cholecalciferol treatment significantly increased serum 25-hydroxy vitamin D and decreased parathyroid hormone levels with no adverse effects in 25-hydroxy vitamin D-deficient renal transplant patients.

Early conservative intervention for candida contamination of preservative fluid without allograft nephrectomy.

BACKGROUND: Fungal contamination of kidney allograft preservative fluid can lead to renal arteritis and arterial wall rupture. METHODS: We have evaluated a conservative management strategy based onearly antifungal therapy, rigorous morphological monitoring of the graft artery and surgical second look (SSL). Since November 2004, preservative fluid was routinely cultured on specific media for all kidney transplant recipients. RESULTS: In 8/474 cases, results were positive for Candida (albicans 5, glabrata 2, tropicalis 1). Two patients also had candida infection of drainage fluid leading to the diagnosis of operative site infection. Radiological and surgical examinations of the renal graft artery were normal in all cases and nephrectomy was not required. At 12 months, all patients were alive with a functioning allograft. CONCLUSION: Early antifungal therapy with microbiological and morphological follow-up should be recommended as soon as contamination is detected, but SSL is advised only in patients with risk factors for arterial anomalies.

[Renal transplantation: Procedure and early follow-up]. / Transplantation rénale : réalisation et suivi précoce.

More than fifty years after the success of the two first renal transplantations in Boston and in Necker hospital in Paris, renal transplantation became the treatment of choice of end stage renal failure, because it improves not only the quality of life of the patients but also their long-term survival. In France, more than 3,700 kidney transplantations are performed every year and more than 40,000 patients are living with a functioning kidney allograft. This treatment of end stage renal disease requires a fine-tuned pre-transplant evaluation and a multidisciplinary post-transplant care in order to prevent, to detect and to treat comorbidities and complications of immunosuppression. The ambition of this manuscript is not to describe in an exhaustive way all the aspects of renal transplantation but starting from the experience of a team, recently published data, and national and international guidelines, to try to provide a synthetic and chronological view of the early post-transplant monitoring.

[Can medical oncologists talk about cure to their patient after localized breast cancer treatment?] / Pouvons-nous à l'heure actuelle parler de guérison après le traitement d'un cancer du sein localisé ?

INTRODUCTION: Despite ongoing therapeutic advances in oncology, the use of the term cure in front of patients remains controversial. The word remission is often preferred in clinical practice. The purpose of this research is to explore how oncologists vary in their usage and definition of the word cure when talking to patients. METHODS: Qualitative and exploratory pilot study conducted by semi structured interviews with a group of French oncologists about a clinical vignette of localized breast cancer treated by surgery and complete adjuvant treatment. RESULTS: Thirteen oncologists participated in this study between January and March 2016. They were divided into two groups according to whether or not they use the term cure in their clinical practice. A first group of five doctors define the word cure as the lasting absence of relapse of the disease. Because of their duty of transparency and the uncertainty of post-therapeutic relapse, these five doctors tend to never use the word cure. The analysis of the second group of eight doctors, who do use of the word cure in their practice, highlighted an absence of consensus on its definition. However, all of them justify their use of it with the importance of expressing positive emotions such as hope to patients. DISCUSSION: Our findings confirm that there are divergent understandings of the concept of cure between oncologists and how they manage prognosis uncertainty. Medical language is thus influenced by scientific knowledge, but also by doctors' personal values and ways of thinking, perhaps influencing the doctor-patient relationship in turn. This exploratory study will be extended on a wider scale to explore the coexistence of other elements of diversity.

To biopsy or not to biopsy? Should we screen the histology of stable renal grafts?

Chronic allograft dysfunction is currently the main cause of late allograft failure. Recent encouraging evidence suggests that it may be possible to delay the development of graft damages if adequate management is initiated early in the course of the disease. These observations have renewed interest in the performance of protocol biopsies as routine follow-up procedure for the screening of renal transplants. In the present review, we summarize the available data from the literature to determine the pros and cons of protocol renal allograft biopsies. On the basis of this evidence, we discuss the ethical concerns raised by this procedure.

Impact of surgical procedures and complications on outcomes of third and subsequent kidney transplants.

BACKGROUND: Surgical procedures and complications have rarely been described in patients receiving a third or subsequent renal transplant. METHODS: Data from 61 consecutive third (n=56), fourth (n=4), and fifth (n=1) renal transplants performed during 1974 to 2005 were analyzed retrospectively. RESULTS: Actuarial graft survival was 91%, 74%, and 57% at one, five, and 10 years, respectively. Technical failure accounted for the loss of three grafts (5%). A transperitoneal approach was necessary in 41% of patients. Technical difficulties occurred in half of the procedures, mainly due to atheroma or vascular calcifications. Overall, there were 45 surgical complications in 30 patients, of urological (n=11), vascular (n=6), infectious (n=9), hemorrhagic (n=12), digestive (n=3), or wound origin (n=4). The rate of surgical revision was 16%. Univariate analysis showed that among surgical complications, only vascular complications were associated with a poor graft outcome (P=0.02). Urological complications did not influence long-term graft outcome. Multivariate analysis of all surgical procedures and complications that might have influenced graft survival showed that only vascular complications were associated with a poorer graft outcome (relative risk=6.13, P=0.015). CONCLUSIONS: Despite a high rate of surgical complications and revisions, third and subsequent kidney transplantations may be performed safely by experienced surgeons without surgical complications influencing long-term graft outcome.