Low-dose valganciclovir is efficacious and safe for prophylaxis of cytomegalovirus infection in kidney transplantation

Background: Optimal valganciclovir (VGC) dosage and duration for cytomegalovirus (CMV) prophylaxis in kidney transplant recipients remains controversial. This study aimed to determine GCV blood levels and efficacy/safety observed under low-dose oral VGC in kidney transplant recipients. Secondly, to quantify the variability of GCV blood levels, and its potential clinical impact. Methods: In this prospective study, each patient at risk for CMV undergoing kidney transplantation received low-dose VGC (450 mg qd) prophylaxis for 3 months, unless GFR was below 40 mL/min, in which case the dose was adapted to 450 mg every other day. GCV levels, at trough (Ctrough) and at peak (C3h) were measured monthly and CMV viremia was assessed during and after prophylaxis using real time quantitative Polymerase Chain Reaction. Adverse effects were recorded on each GCV sampling. Patients were followed up to one year after transplantation. Results: 38 kidney recipients (19 D+/R+, 11 D+/R-, 8 D-/R+) received 3-month VGC prophylaxis. Most patients (mean GFR of 59 mL/min) received 450 mg qd but the dose was reduced to 450 mg every other day in 6 patients with mean GFR of 22 mL/min. Average GCV C3h and Ctrough (regressed at 24h or 48h) were 3.9 mg/L (CV 33%, range: 1.3-8.2) and 0.4 mg/L (CV 111%, range 0.1-3.3). Population pharmacokinetic analysis showed a fair dispersion of the parameters mainly influenced by renal function. Despite this variability, patients remained aviremic during VGC prophylaxis. Neutropenia and thrombocytopenia (grade 2-4) were reported in 4% and 3% of patients respectively. During follow-up, asymptomatic CMV viremia was reported in 25% patients. One year after transplantation, 12% patients (all D+/R-) had developed a CMV disease, which was treated with a therapeutic 6-week course of oral VGC. Conclusion: Average GCV blood levels after oral administration of low-dose VGC in kidney transplant recipients were comparable to those previously reported with oral GCV prophylaxis, efficacious and well tolerated. Thus, a 3-month course of low-dose VGC is appropriate for the renal function of most kidney transplant recipients.

Emotional experience in patients awaiting lung transplantation: A qualitative analysis

Emotional reactions in the course of transplantation are often explored through negative emotions (e.g. stress, guilt) or depression and its evaluation. However the emotional reactions in the course of transplantation describing positive and negative emotional experiences have not been comprehensively described. Qualitative semi-structured interviews were conducted shortly after registration on the waiting list with 15 lung patients waiting for an organ coming from a deceased donor. In a qualitative analysis, focussing on the emotional experience of transplantation, a very rich discourse was underlined. The described emotions in the interviews of the patients were related to specific situations, stakes and existential questions. All these emotions help to describe more precisely the very intimate experience of a difficult and stressful situation while awaiting transplantation. It also helps to better understand the impact of the paradoxical situation of transplantation when a person is waiting for an organ, which will improve quality of life and will allow to survive, but which also depends on the end of the life of a donor.

Maladies inflammatoires cryptogéniques de l'intestin de novo après transplantation hépatique: rapport de quatre nouveaux cas et revue de la littérature [De novo inflammatory bowel diseases after liver transplantation: description of four new cases and a review of the literature]

Inflammatory bowel diseases are a result of an aberrant mucosal immune response to gut microflora. Several groups have reported newly diagnosed inflammatory bowel diseases following solid organ transplantation and subsequent immunosuppressive therapy. We describe four cases of newly diagnosed inflammatory bowel diseases following liver transplantation in a pool of 120 transplanted patients. These patients had no prior history of inflammatory bowel diseases or primary sclerosing cholangitis and were immunosuppressed. Two patients were transplanted for a hepatitis C related cirrhosis, one for alcoholic cirrhosis and one patient for autoimmune cirrhosis. Three patients were diagnosed with ulcerative colitis and one with Crohn's disease. These four patients were on a cyclosporin monotherapy when their inflammatory bowel diseases were diagnosed. These data suggest that cyclosporin monotherapy following solid organ transplantation does not prevent development of inflammatory bowel diseases.

Association between mannose-binding lectin deficiency and cytornegalovirus infection course after organ transplantation.

Background: Mannose binding lectin (MBL) is an innate humoral immune effector and MBL defi ciency has been suggested as a risk factor for the development of certain viral infections. However, there is no data about the possible association between MBL defi ciency and CMV, especially after organ transplantation. Methods: We measured MBL levels in 16 kidney transplant recipients with highrisk CMV serostatus (D+/R-) who received valganciclovir prophylaxis for 3 months (Study 1). In addition, MBL levels were retrospectively assayed in 55 recipients from a previous study of organ transplant recipients managed preemptively (Study 2). In Study 2, protracted CMV infection was associated with recipient CMV seronegativity, increasing age, and high viral load during the initial episode. In both studies, MBL defi ciency was diagnosed if MBL levels were <500 ng/ml. Results: In Study 1, after a follow-up of 12 months, 7 out of 16 patients developed CMV disease, 4 patients developed asymptomatic CMV infection, and 5 patients never developed any sign of CMV replication. Overall, 9/16 patients (56%) had MBL defi ciency: 5/7 (71%) of patients with CMV disease, 4/4 (100%) of patients with asymptomatic CMV infection, and 0/5 (0%) of patients without CMV infection (p=0.005, between CMV infection/disease versus no infection). Median MBL concentrations were higher in patients without CMV infection than in those with CMV infection (p<0.005). In Study 2, among 30 patients with CMV infection, 9/25 (36%) patients without MBL defi ciency had a protracted course, while 4/5 (80%) with MBL defi ciency did so (p=0.07). Conclusion: Data from two separate patient populations suggest that MBL defi ciency may be a signifi cant risk factor for late CMV disease/infection after prophylaxis, and protracted infection after preemptive treatment. This suggests a role for MBL in the control of CMV infection after organ transplantation.

Low levels of human leukocyte antigen donor-specific antibodies detected by solid phase assay before transplantation are frequently clinically irrelevant.

Since new technologies based on solid phase assays (SPA) have been routinely incorporated in the transplant immunology laboratory, the presence of pretransplantation donor-specific antibodies (DSA) against human leukocyte antigen (HLA) molecules has generally been considered as a risk factor for acute rejection (AR) and, in particular, for acute humoral rejection (AHR). We retrospectively studied 113 kidney transplant recipients who had negative prospective T-cell and B-cell complement-dependent cytotoxicity (CDC) crossmatches at the time of transplant. Pretransplantation sera were screened for the presence of circulating anti-HLA antibody and DSA by using highly sensitive and HLA-specific Luminex assay, and the results were correlated with AR and AHR posttransplantation. We found that approximately half of our patient population (55/113, 48.7%) had circulating anti-HLA antibody pretransplantation. Of 113 patients, 11 (9.7%) had HLA-DSA. Of 11 rejection episodes post-transplant, only two patients had pretransplantation DSA, of whom one had a severe AHR (C4d positive). One-year allograft survival was similar between the pretransplantation DSA-positive and -negative groups. Number, class, and intensity of pretransplantation DSA, as well as presensitizing events, could not predict AR. We conclude that, based on the presence of pretransplantation DSA, post-transplantation acute rejections episodes could not have been predicted. The only AHR episode occurred in a recipient with pretransplantation DSA. More work should be performed to better delineate the precise clinical significance of detecting low titers of DSA before transplantation.

Transplantation of a human mammary carcinoma cell line (BT 20) into nude mice.

Cell suspensions of a human mammary carcinoma cellline (BT 20), wh en injected subcutaneously into nude athymie mice (BALB/c NujNu), produced tumor nodules at the injection site. Subsequent seriai transM plantations also gave rise to neoplastic nodules after latency periods averaging 3 weeks. The nodules displayed morphologie and functional characteristics comparable to those of the original tumor cells. Metastases, however, were not observed in any of the tumor-bearing mice.

Potential and limitations of regulatory T-cell therapy in solid organ transplantation.

Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS: In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.

Schwann cell strip for peripheral nerve repair.

Many strategies have been investigated to provide an ideal substitute to treat a nerve gap injury. Initially, silicone conduits were used and more recently conduits fabricated from natural materials such as poly-3-hydroxybutyrate (PHB) showed good results but still have their limitations. Surgically, a new concept optimising harvested autologous nerve graft has been introduced as the single fascicle method. It has been shown that a single fascicle repair of nerve grafting is successful. We investigated a new approach using a PHB strip seeded with Schwann cells to mimic a small nerve fascicle. Schwann cells were attached to the PHB strip using diluted fibrin glue and used to bridge a 10-mm sciatic nerve gap in rats. Comparison was made with a group using conventional PHB conduit tubes filled with Schwann cells and fibrin glue. After 2 weeks, the nerve samples were harvested and investigated for axonal and Schwann cell markers. PGP9.5 immunohistochemistry showed a superior nerve regeneration distance in the PHB strip group versus the PHB tube group (> 10 mm, crossed versus 3.17+/- 0.32 mm respectively, P<0.05) as well as superior Schwann cell intrusion (S100 staining) from proximal (> 10 mm, crossed versus 3.40+/- 0.36 mm, P<0.01) and distal (> 10 mm, crossed versus 2.91+/- 0.31 mm, P<0.001) ends. These findings suggest a significant advantage of a strip in rapidly connecting a nerve gap lesion and imply that single fascicle nerve grafting is advantageous for nerve repair in rats.

Les discordances du moi : une lecture critique du débat philosophique contemporain sur l'identité personnelle au regard de la transplantation d'organes

La présente recherche analyse le concept mental d'identité personnelle et en propose une interprétation critique, qui se développe à partir des cas de troubles psychologiques se manifestant chez certains patients transplantés. Nous pensons que l'étude de ces cas offre la possibilité de repenser, et par là critiquer, certains présupposés qui conditionnent le débat philosophique contemporain sur l'identité personnelle de matrice essentiellement analytique. Nous proposons de ce concept mental une interprétation inusuelle, reposant sur une certaine compréhension de l'être (humain), que nous caractérisons par la formule «identité personnelle transductive ». Cette expression véhicule l'idée d'une «ontologie autre » ; autre que l'ontologie classique qui pense l'être comme déterminité, à l'instar d'un individu substantiel, stable et persistant. Nous nous éloignons ainsi de la conception de la déterminité telle qu'elle se développe depuis l'Antiquité grecque, parce que nous croyons que le changement ou le devenir réside dans la nature des choses. Nous avons ainsi essayé de présenter une interprétation de l'être différente, en empruntant à Gilbert Simondon la notion de « transductivité » -dans le sens d'« individuation en progrès »que cet auteur lui attribue. En comparant les témoignages des patients transplantés avec les cas imaginaires de transplantation de cerveau qui dominent les discussions philosophiques, nous avons montré la nécessité de refonder l'ontologie sur laquelle reposent les théories contemporaines de l'identité personnelle. Cette tentative répond à l'exigence de résoudre et tempérer les apories qui se font jour au sein des conceptions déterministes de la personne -soient-elles réductionnistes (à l'instar des partisans du critère de continuité psychologique et physique) ou non réductionnistes (à l'instar des conceptions simples ou Théories de l'ego basées sur une approche à la première personne, où la personne, comprise comme persistance substantielle d'un sujet, se fonde d'elle-même). Au coeur de notre démarche se trouve la notion d'« image du corps », véritable outil d'unification épistémologique et de renouvellement ontologique. Cette notion s'est révélée extrêmement utile non seulement pour comprendre et démêler les composantes qui interviennent dans le surgissement des troubles psychologiques lors des transplantations d'organes, ainsi que la variabilité des réactions individuelles, mais aussi, plus fondamentalement, pour rendre manifeste l'opération de «transduction perpétuée »qui est à la base de l'ontogenèse de l'être humain en tant que personne, donc du moi. La notion d'image du corps nous a donc permis de mettre en évidence ce que l'expérience de la transplantation d'organes bien comprise pourrait ou devrait apporter à la théorie de l'identité personnelle. C'est ainsi que, par approximation, s'est précisée l'idée d'une identité personnelle transductive, où le moi (la personne), étant interprété comme l'aspect subjectif d'une opération d'«individuation perpétuée », se donne sous le signe de la discordance.

Treatment of extended skin defects with autologous composite cultured skin grafts in a patient with epidermolysis bullosa

Rationale: The purpose of this article is to demonstrate the use of homologous culture cells in treating an advanced coccon formation of the hand and three extended squamous cell carcinomas of the lower and upper limb in a patient with recessive dystrophic epidermolysis bullosa. The preparation and application of these cells in the operation room are being described. Methods: A number of surgical approaches have been described to correct these deformities in order to improve function.We propose a new therapeutic approach of treating loss of motion and independent digital function as well as coverage of large skin defects in a patient with recessive dystrophic epidermolysis bullosa by using autologous culture cells. Surgical treatment of these patients is really difficult because of the existing skin fragility. Furthermore, surgical wounds do not easily heal because of recurrent blisters and erosions as well as due to the patients' poor nutricial status. Results: We report our experience of mutiple extended cutaneous squamous cell carcinomas arising in our patient which were successfully managed using autologous composite cultured skin grafts. The cocoon hand deformity was also treated with the limb becoming functional. Conclusion: The use of autologous keratinocytes and fibroblasts in epidermolysis bullosa is hereby outlined for the fist time.

LIGHT/HVEM/LTβR interaction as a target for the modulation of the allogeneic immune response in transplantation.

The exchange of information during interactions of T cells with dendritic cells, B cells or other T cells regulates the course of T, B and DC-cell activation and their differentiation into effector cells. The tumor necrosis factor superfamily member LIGHT (homologous to lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) is transiently expressed upon T cell activation and modulates CD8 T cell-mediated alloreactive responses upon herpes virus entry mediator (HVEM) and lymphotoxin β receptor (LTβR) engagement. LIGHT-deficient mice, or WT mice treated with LIGHT-targeting decoy receptors HVEM-Ig, LTβR-Ig or sDcR3-Ig, exhibit prolonged graft survival compared to untreated controls, suggesting that LIGHT modulates the course and severity of graft rejection. Therefore, targeting the interaction of LIGHT with HVEM and/or LTβR using recombinant soluble decoy receptors or monoclonal antibodies represent an innovative therapeutic strategy for the prevention and treatment of allograft rejection and for the promotion of donor-specific tolerance.