Feasibility and effectiveness of using coronary stents in the treatment of hepatic artery stenoses after orthotopic liver transplantation: preliminary report.

OBJECTIVE: Our aim is to evaluate the feasibility, efficacy, and patency of using coronary stents for the treatment of hepatic artery stenosis after liver transplantation. CONCLUSION: Hepatic artery stenosis after liver transplantation can be treated using coronary stents. The low rate of complication, high technical success, and 1-year patency rates are encouraging.

Varicella Zoster Virus CNS disease in hematopoietic cell transplantation: A single center experience

Background: Varciella Zoster Virus (VZV) can lead to serious complications in Hematopoietic Cell Transplant (HCT) recipients. Central nervous system (CNS) VZV can be one of the most devastating infections in transplant recipients, yet little is known about this rare disease. Objectives: To describe CNS VZV in the post-transplant period and to define potential risk factors in the HCT population. Methods: We reviewed the course of all patients who received a first HCT at the Fred Hutchinson Cancer Center (FHCRC) in Seattle, WA from 1/1996 through 12/2007. Data were collected retrospectively using the Long-Term Follow-Up database, which includes on-site examinations, outside records, laboratory tests, and yearly questionnaires. Patients were classified as CNS VZV if they had laboratory confirmation of VZV in the cerebrospinal fluid (CSF), or had zoster with associated clinical and laboratory findings consistent with CNS disease. Results: A total of six patients developed VZV CNS disease during the evaluation period (table 1). Diagnosis was confirmed in 3/6 by detection of VZV in CSF by PCR. All other patients had a clinical diagnosis based on the presence of CNS symptoms, zoster, lymphocytic pleiocytosis, and response to IV acyclovir. Patients who developed CNS disease had a mean age of 42 years (range 34-51) at time of transplant. CNS disease developed at a mean of 9 months posttransplantation (range 0.5-24 months), and severity varied, ranging from meningitis (3/6) to encephalitis/myelitis (3/6). All had active graft-versus host disease (GHVD) and all were being treated with immunosuppressive therapy at time of diagnosis. Fever and headache were the most common symptoms, but patients who developed focal CNS findings or seizures (3/6) had a more complicated clinical course. While most patients presented with classic VZV/zoster skin lesions, 2/6 patients had no dermatologic findings associated with their presentation. Four (66%) of patients who developed VZV CNS disease died, two related to VZV complications despite aggressive antiviral therapy. Conclusions: In this cohort of HCT patients, VZV CNS disease was a rare complication. Mortality due to CNS VZV is high, particularly in patients who develop focal neurologic findings or seizures. Even in the absence of skin lesions, VZV CNS disease should be considered in patients who develop fevers and neurologic symptoms.

Influence of IFNL3/4 Polymorphisms on the Incidence of Cytomegalovirus Infection After Solid-Organ Transplantation.

BACKGROUND: Polymorphisms in IFNL3 and IFNL4, the genes encoding interferon λ3 and interferon λ4, respectively, have been associated with reduced hepatitis C virus clearance. We explored the role of such polymorphisms on the incidence of cytomegalovirus (CMV) infection in solid-organ transplant recipients. METHODS: White patients participating in the Swiss Transplant Cohort Study in 2008-2011 were included. A novel functional TT/-G polymorphism (rs368234815) in the CpG region upstream of IFNL3 was investigated. RESULTS: A total of 840 solid-organ transplant recipients at risk for CMV infection were included, among whom 373 (44%) received antiviral prophylaxis. The 12-month cumulative incidence of CMV replication and disease were 0.44 and 0.08 cases, respectively. Patient homozygous for the minor rs368234815 allele (-G/-G) tended to have a higher cumulative incidence of CMV replication (subdistribution hazard ratio [SHR], 1.30 [95% confidence interval {CI}, .97-1.74]; P = .07), compared with other patients (TT/TT or TT/-G). The association was significant among patients followed by a preemptive approach (SHR, 1.46 [95% CI, 1.01-2.12]; P = .047), especially in patients receiving an organ from a seropositive donor (SHR, 1.92 [95% CI, 1.30-2.85]; P = .001), but not among those who received antiviral prophylaxis (SHR, 1.13 [95% CI, .70-1.83]; P = .6). These associations remained significant in multivariate competing risk regression models. CONCLUSIONS: Polymorphisms in the IFNL3/4 region influence susceptibility to CMV replication in solid-organ transplant recipients, particularly in patients not receiving antiviral prophylaxis.

Sélection et suivi prétransplantation des patients candidats à la greffe cardiaque en Suisse romande [Selection and preoperative follow-up of heart transplantation candidates in the French part of Switzerland].

Heart transplantation (HTx) started in 1987 at two university hospitals (CHUV, HUG) in the western part of Switzerland, with 223 HTx performed at the CHUV until December 2010. Between 1987 and 2003, 106 HTx were realized at the HUG resulting in a total of 329 HTx in the western part of Switzerland. After the relocation of organ transplantation activity in the western part of Switzerland in 2003, the surgical part and the early postoperative care of HTx remained limited to the CHUV. However, every other HTx activity are pursued at the two university hospitals (CHUV, HUG). This article summarizes the actual protocols for selection and pre-transplant follow-up of HTx candidates in the western part of Switzerland, permitting a uniform structure of pretransplant follow-up in the western part of Switzerland.

Toward improved immunocompetence of adoptively transferred CD8+ T cells.

Adoptive transfer of autologous or allogenic T cells to patients is being used with increased frequency as a therapy for infectious diseases and cancer. However, many questions remain with regard to defining optimized procedures for preparation and selection of T cell populations for transfer. In a new study in this issue of the JCI, Gattinoni and colleagues used a TCR transgenic mouse model to examine in vitro-generated tumor antigen-specific CD8+ T cells at various stages of differentiation for their efficacy in adoptive immunotherapy against transplantable melanoma. The results confirm that CD8+ T cells progressively lose immunocompetence with prolonged in vitro cultivation and suggest that effector CD8+ T cells alone may be considerably less potent at protecting hosts with advanced tumors than are less differentiated T cells.

Effects of immunosuppressive drugs on HIV infection: implications for solid-organ transplantation.

With the advent of highly active antiretroviral therapy (HAART), HIV infection has become a chronic disease. Various end-stage organ failures have now become common co-morbidities and are primary causes of mortality in HIV-infected patients. Solid-organ transplantation therefore has been proposed to these patients, as HIV infection is not anymore considered an absolute contraindication. The initial results of organ transplantation in HIV-infected patients are encouraging with no differences in patient and graft survival compared with non-HIV-infected patients. The use of immunosuppressive drug therapy in HIV-infected patients has so far not shown major detrimental effects, and some drugs in combination with HAART have even demonstrated possible beneficial effects for specific HIV settings. Nevertheless, organ transplantation in HIV-infected patients remains a complex intervention, and more studies will be required to clarify open questions such as long-term effects of drug interactions between antiretroviral and immunosuppressive drugs, outcome of recurrent HCV infection in HIV-infected patients, incidence of graft rejection, or long-term graft and patient survival. In this article, we first review the immunological pathogenesis of HIV infection and the rationale for using immunosuppression combined with HAART. We then discuss the most recent results of solid-organ transplantation in HIV-infected patients.

Recurrent Hepatitis C After Liver Transplantation Experience of the First 21 Patients Treated in Lausanne

BACKGROUND AND AIM: Recurrent hepatitis C is a major cause of morbidity and mortality after liver transplantation (LT), and optimal treatment algorithms have yet to be defined. Here, we present our experience of the first 21 patients with recurrent hepatitis C treated in Lausanne. PATIENTS AND METHODS: Twenty-one patients with histologyproven recurrent hepatitis C after LT were treated since 2003. Treatment was initiated with pegylated interferon-α2a 135 μg per week and ribavirin 400 mg per day in the majority of patients, and subsequent doses were adapted individually based on on-treatment virological responses and clinical and/or biochemical side effects. RESULTS: On an intention-to-treat basis, sustained virological response (SVR) was achieved in 12/21 (57%) patients (5/11 [45%], 2/3 [67%], 4/5 [80%] and 1/2 [50%] of patients infected with genotypes 1, 2, 3 and 4, respectively). Two patients experienced relapse and 6 did not respond to treatment (NR). Treatment duration ranged from 24 to 90 weeks. It was stopped prematurely due to adverse events in 5/21 (24%) patients (with SVR achieved in 2 patients, NR in 2 patients, and death of one patient awaiting re-transplantation). Of note, SVR was achieved in a patient with combined liver and kidney transplantation. Importantly, SVR was achieved in some patients despite the lack of an early virological response or HCV RNA negativity at week 24. Darbepoetin α and filgrastim were used in 33% and 14%, respectively. CONCLUSION: Individually adapted treatment of recurrent hepatitis C can achieve SVR in a substantial proportion of LT patients. Conventional stopping rules do not apply in this setting so that prolonged therapy may be useful in selected patients.

Multi-layer amniotic membrane (MLAM) transplantation for non traumatic corneal perforations or descemetoceles

Purpose:To describe the indications, the surgical procedure and the clinical outcome of MLAM in the treatment of non traumatic corneal perforations and descemetoceles . Methods:A prospective, non comparative, interventional case series of eight consecutive patients (mean age 59 years old, 6 men and 2 women) with non traumatic corneal perforations or descemetoceles.The surgery consisted in a MLAM transplantation of a cryopreservated human amniotic membrane. The series included: three active herpetic keratitis, one rosacea, one perforation of an hydrops, one cicatricial pemphigoid, one perforation after an abcess in a corneal graft and one perforation after protonbeamtherapy. The clinical outcome included: the follow-up, the integrity of the eye, corneal epithelialization, inflammation and neovascularization, and the integration of the MLAM. Stromal thickness was followed precisely with the slit lamp. A corneal graft was performed at one patient after the MLAM, allowing microscopic investigation of the removed MLAM integrated in the cornea. Results:The mean follow-up was 8.78 months (range 3.57 to 30.17). Amniotic membrane transplantation was successful and reduced inflammation in 7 patients out of 8 ,after one procedure.One patient who presented a large herpetic keratitis epithelial defect with corneal anaesthesia had his MLAM dissolved after two weeks with an aqueous leakage. Epithelium healed within 3 weeks above 7 MLAM and remained stable at 3 months in 7 out of 8 patients. MLAM opacification gradually disappeared over a few months, however, stromal layers filling in the corneal perforations or above the descemetoceles remained stable. Conclusions:MLAM transplantation is a safe, effective and useful technique to cure non traumatic corneal perforations and descemetoceles. It can be performed in emergency despite the presence of an active inflammation or infection. By facilitating epithelialization, reducing inflammation and neovascularization, it allows corneal surface reconstruction in patients with persistent epithelial defects and corneal melting that usually ends in a perforation. For full visual rehabilitation, a delayed penetrating keratoplasty is required.

Psychological transformations in kidney transplantation: A prospective qualitative study

The aim of this IRB-approved study was to prospectively analyze psychological transformations in ESRD patients before and after transplantation (KT). Semi-structured interviews were conducted in 30 patients (mean age = 53±10) after their inclusion on the waiting-list (Gr. A). Follow-up interviews were performed 6 months later in 15 patients still awaiting KT (Gr. B6), and in 15 patients 6 months (Gr. C6) and 12 months (Gr. C12) after KT. Qualitative analysis was performed. Gr: A:All patients underlined loss of freedom, 87% devoted much energy to maintain normality, 57% modified medical directives. All reported emotional fragility related to dialysis and loss of quality of life (QOL), negative (43%) or suicidal thoughts (20%). Professional stigma was underlined (26%). Gr: B6:40% reported no change, 60% mentioned increase of illness intrusiveness, 46% dialysis side-effects, 40% communication problems, 33% tension with medical staff and waiting list handling. Fear of emotional breakdown (40%), couple problems (47%) and worsened professional difficulties (20%) were reported. Gr: C6:All patients mentioned improved QOL and freedom recovery (87%). All expressed concerns about possible acute rejection, 73% were anxious about laboratory results, 93% experienced dependence to immunosuppressants, 47% reported difficulties in handling medication, 21% feared to forget them, 47% were concerned about side-effects, 67% had resumed work but medical constraints led to professional tension (40%). Gr: C12:All mentioned recovered QOL. Medical controls were accepted as a routine (87%) and adherence to medication was mandatory (100%). All mentioned the limited long-term graft survival and 47% were anxious about possible return to dialysis, especially younger patients (27%). Positive identity and existential changes were reported (60%). This prospective qualitative study identifies psychological modifications in the course of KT. It provides a basis to adequately address concerns, but it shows also that KT is clearly associated with positive psychological transformations.

High Specificity of C4d/CD68 Staining for the Diagnosis of Late Antibody-Mediated Rejection in Heart Transplantation.

In heart transplantation (HTx), acute antibody-mediated rejection (AMR) is infrequent but carries high mortality and increased risk of graft vasculopathy. The diagnosis requires evidence of acute graft dysfunction, capillary lesions on endomyocardial biopsy (EMB), and immunopathological criteria of antibodymediated injury. Multiple markers of antibody-mediated injuries have been proposed, but there is ample debate on their usefulness. In kidney transplantation, C4d deposition in peritubular capillaries is a reliable marker of alloantibody-dependant graft injury. In this study, we prospectively screened all EMBs for C4d and CD68 in new HTx recipients, and correlated pathological fi ndings with immunological evidence of donor-specifi c antibodies (DSA) and graft dysfunction. Methods Between Nov 05 and Aug 08, we had 22 HTx, and 17 cases were analysed. All recipients received polyclonal rabbit anti-thymocytes globulin, calcineurin inhibitors, mycophenolate mofetil, and corticosteroids (weaning in 6 -12 months). They had EMB every 1-2 weeks in the fi rst 3 months, and then monthly for 9 months. C4d and CD 68 were assessed by immunochemistry. Echocardiography and DSA assessment or crossmatch (early phase) were realised if C4d or CD68 staining was positive. Results There was 1 early and 1 late AMR. Table 1 C4d and CD68 positive, at least 1 EMB 6 / 17; 35% 1 treated C4d and CD68 positive, at least 2 consecutive EMBs 3 / 17; 17.5% 1 treated C4d and CD68 positive, and graft dysfunction 1 / 17; 6% 1 treated C4d and CD68 positive, with DSA and crossmatch + 1 / 17; 6% 1 treated Table 2 C4d and CD68 positive, at least 1 EMB 1 / 17; 6% 1 treated C4d and CD68 positive, at least 2 consecutive EMBs 1 /17; 6% 1 treated C4d and CD68 positive and graft dysfunction 1 / 17; 6% 1 treated C4d and CD68 positive, and + DSA 1 / 17; 6% 1 treated Conclusion In this single-center experience, C4d / CD68 positive staining was frequent in the early phase and raised the question of false positive cases of AMR. However, these markers showed high specifi city for the diagnosis of AMR in the late phase. Of course these data need to be confi rmed in larger multi-center studies.

Internalization and homologous desensitization of the GLP-1 receptor depend on phosphorylation of the receptor carboxyl tail at the same three sites.

Homologous desensitization and internalization of the GLP-1 receptor correlate with phosphorylation of the receptor in a 33-amino acid segment of the cytoplasmic tail. Here, we identify the sites of phosphorylation as being three serine doublets located at positions 441/442, 444/445, and 451/452. The role of phosphorylation on homologous desensitization was assessed after stable expression in fibroblasts of the wild type or of mutant receptors in which phosphorylation sites were changed in various combinations to alanines. We showed that desensitization, as measured by a decrease in the maximal production of cAMP after a first exposure of the cells to GLP-1, was strictly dependent on phosphorylation. Furthermore, the number of phosphorylation sites correlated with the extent of desensitization with no, intermediate, or maximal desensitization observed in the presence of one, two, or three phosphorylation sites, respectively. Internalization of the receptor-ligand complex was assessed by measuring the rate of internalization of bound [125I]GLP-1 or the redistribution of the receptor to an endosomal compartment after agonist binding. Our data demonstrate that internalization was prevented in the absence of receptor phosphorylation and that intermediate rates of endocytosis were obtained with receptors containing one or two phosphorylation sites. Thus, homologous desensitization and internalization require phosphorylation of the receptor at the same three sites. However, the differential quantitative impairment of these two processes in the single and double mutants suggests different molecular mechanisms controlling desensitization and internalization.