A Case of Anti-Synthetase Syndrome Successfully Treated with Mycophenolate Mofetil and Rituximab but No Corticosteroids.

A patient with antisynthetase syndrome with pulmonary and muscular involvement was treated with immunosuppressive agents without corticosteroids. Rituximab was added to mycophenolate mofetil therapy with improvement in lung functional and imaging findings and normalization of creatine kinase levels. LEARNING POINTS: Antisynthetase syndrome associated with interstitial lung disease (ILD) and myopathy can be successfully treated without corticosteroids.A combination of several immunosuppressive agents can be a therapeutic alternative in case of refractory ILD.

Ex Vivo Fecal Fermentation of Human Ileal Fluid Collected After Wild Strawberry Consumption Modulates Human Microbiome Community Structure and Metabolic Output and Protects Against DNA Damage in Colonic Epithelial Cells.

SCOPE: Wild strawberries (Fragaria vesca) are richer in (poly)phenols than common commercial strawberry varieties, e.g., Fragaria × ananassa. (Poly)phenols and their microbiota-derived metabolites are hypothesized to exert bioactivity within the human gut mucosa. To address this, the effects of wild strawberries are investigated with respect to their bioactivity and microbiota-modulating capacity using both in vitro and ex vivo approaches. METHODS AND RESULTS: Ileal fluids collected pre- (0h) and post-consumption (8h) of 225 g wild strawberries by ileostomates (n = 5) and also in vitro digested strawberry varieties (Fragaria vesca and Fragaria × ananassa Duchesne) supernatants are collected. Subsequent fermentation of these supernatants using an in vitro batch culture proximal colon model reveals significant treatment-specific changes in microbiome community structure in terms of alpha but not beta diversity at 24 h. Nutri-kinetic analysis reveals a significant increase in the concentration of gut microbiota catabolites, including 3-(4hydroxyphenyl)propionic acid, 3-(3-hydroxyphenyl)propanoic acid, and benzoic acid. Furthermore, post-berry ileal fermentates (24 h) significantly (p < 0.01) decrease DNA damage (% Tail DNA, COMET assay) in both HT29 cells (∼45%) and CCD 841 CoN cells (∼25%) compared to untreated controls. CONCLUSIONS: Post berry consumption fermentates exhibit increased overall levels of (poly)phenolic metabolites, which retains their bioactivity, reducing DNA damage in colonocytes.

Injection drug use before and after liver transplantation: a retrospective multicenter analysis on incidence and outcome.

BACKGROUND AND AIMS: Injecting drug use (IDU) before and after liver transplantation (LT) is poorly described. The aim of this study was to quantify relapse and survival in this population and to describe the causes of mortality after LT. METHODS: Past injection drug users were identified from the LT listing protocols from four centers in Switzerland and France. Data on survival and relapse were collected and used for uni- and multivariate analysis. RESULTS: Between 1988 and 2006, we identified 59 patients with a past history of IDU. The mean age at transplantation was 42.4 yr and the majority of patients were men (84.7%). The indication for LT was for the vast majority viral cirrhosis accounting for 91.5% of cases, while alcoholic cirrhosis was 5.1%. There were 16.9% of patients who had a substitution therapy before and 6.8% who continued after LT. Two patients (3.4%) relapsed into IDU after LT and died at 18 and 41 months. The mean follow-up was 51 months. Overall survival was 84%, 66%, and 61% at 1, 5, and 10 yr after transplantation. CONCLUSIONS: Documented IDU was rare in liver transplanted patients. Past IDU was not associated with poorer survival after LT, and relapse after LT occurred in 3.4%.

CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients.

Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype; n = 8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P < 0.05) and required significantly higher daily doses per weight (P < 0.01) than the nonexpressors (*3/*3 genotype; n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437C>T influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P < 0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.

[Liver transplantation: new organ allocation system in Switzerland]. / Transplantation hépatique: introduction en Suisse d'un nouveau système d'allocation des organes.

This article describes the new organ allocation system for liver transplantation introduced in Switzerland on July 1, 2007. In its newly adopted transplantation law, Switzerland chose the MELD score (Model for end-stage liver disease), based on three laboratory values: total bilirubin, serum creatinine and INR. Advantages and limitations of the MELD score are discussed. Finally the West Switzerland joint liver transplantation program is briefly introduced.

[The pivotal role of the pathologist in transplantation]. / Rôle du pathologiste en transplantation.

The management of rejection has recently become more complex, in particular since the identification of antibody-mediated rejection in addition to the full-established pictures of cellular rejection. The pathologist who reads graft biopsies must solve these problems in order to arrive at a clear histopathological diagnosis. The diagnosis will then have to be discussed in a multidisciplinary approach with the clinical persons, in order to decide upon the optimal treatment approach. Protocol biopsies may detect subclinical rejection and, hence help adjust the immunosuppressive treatment for an extended allograft survival. Finally, allograft biopsies performed with the purpose of "staging" may yield helpful informations concerning the condition of the organ, and may thus help to anticipate a possible future re-transplantation.

Microwave Ablation in Intermediate Hepatocellular Carcinoma in Cirrhosis: An Italian Multicenter Prospective Study.

Background and Aims: To report long-term results in treatment of intermediate hepatocellular carcinoma (HCC) in cirrhotics using new high-powered microwaves (MWS) ablation alone. Methods: This multicenter study included 215 cirrhotics (age range: 67-84 years; 137 males; 149 Child A, 66 Child B) who underwent percutaneous ultrasound-guided high-powered MWS ablation instead of transarterial chemoembolization. Among the patient population, 109 had a single nodule (Ø 5.3-8 cm) [group A], 70 had 2 nodules (Ø 3-6 cm) [group B] and 36 had 3-5 nodules (Ø 1.5-6.8 cm) [group C]. MWS ablation efficacy was evaluated using enhanced-computed tomography and/or magnetic resonance imaging. Primary end-point was 5-year cumulative overall survival (OS). Results: On enhanced-computed tomography and/or magnetic resonance imaging, complete ablation rates were 100% for 1.5-3.5 cm nodules. In nodules >3.5-5 cm, it was 89% for the first ablation and 100% for the second. For lesions >5-8 cm, ablation was up to 92%. Overall, 1-, 3- and 5-year survival rates were 89, 60, and 21%, respectively. The cumulative OS rate of group A was 89%, 66% and 34% at 1, 3 and 5 years. The cumulative OS rate of group B was 88%, 60% and 11% at 1, 3 and 5 years. The cumulative OS rate of group C was 86%, 55% and 0%. The 5-year survival rate was significantly different among the groups (p <0.001). One patient died from rupture of HCC. Upon multivariate analysis, preablation total bilirubin >1.5 mg/dL was an independent factor for predicting lower survival. Conclusions: Percutaneous MWS ablation of intermediate HCC is safe and effective in inducing large volume of necrosis in intermediate HCC nodules, providing long-term survival rates similar to transarterial chemoembolization. Preablation total bilirubin >1.5 mg/dL as expression of liver function reserve is the main factor predicting a worse outcome.

Efficacy and safety of universal valganciclovir prophylaxis combined with a tacrolimus/mycophenolate-based regimen in kidney transplantation.

BACKGROUND: Immunosuppressive and antiviral prophylactic drugs are needed to prevent acute rejection and infection after transplantation. We assessed the efficacy and safety of the introduction of universal valganciclovir prophylaxis in combination with a tacrolimus/mycophenolate-based regimen in kidney transplantation at our centre. METHODS: We reviewed all consecutive patients who underwent kidney transplantation over a 5.5-year period. Patients transplanted from January 2000 to March 2003 (period 1) were compared to patients from April 2003 to July 2005 (period 2). In period 1 patients were treated with basiliximab, cyclosporine, steroids and mycophenolate (or azathioprine). Prophylaxis with valacyclovir was prescribed in cytomegalovirus (CMV) D+/R- patients, while any R+ patients were managed with a preemptive approach. In period 2, immunosuppression consisted of basiliximab or thymoglobulin induction, tacrolimus, steroids and mycophenolate. Three-month CMV prophylaxis with valganciclovir was used in all at-risk patients. RESULTS: Data analysis included 73 patients (period 1) and 70 (period 2). Acute rejection was more frequent in period 1 than in period 2 (42% vs 7%, p <0.001). Overall, 30% of patients in period 1 were diagnosed with CMV infection/disease requiring antiviral treatment, compared with 11.4% in period 2 (p = 0.003). Late-onset CMV disease remained a problem in D+/R- patients in both periods. There was no difference in incidence of BK virus nephropathy, fungal infections, PTLD, graft loss or mortality. However, 4 cases (5.7%) of delayed transient asymptomatic agranulocytosis were observed in period 2. CONCLUSIONS: The present analysis indicates that the combined regimen introduced in period 2 improved clinical results with a significant decrease in acute rejection and in CMV infection/disease incidence. However, a unique syndrome of delayed transient agranulocytosis probably due to drug myelotoxicity was observed in a subset of patients.

[Management of chronic viral hepatitis]. / Prise en charge des hépatites virales chroniques.

This review highlights recent progress in the management of chronic hepatitis B, C and D. New nucleoside and nucleotide analogs have recently been approved and are currently being evaluated for the treatment of chronic hepatitis B. At the same time, resistance is becoming an increasingly common clinical problem. Efforts are currently being made to individualize treatment regimens for patients with chronic hepatitis C, with the aim of enhancing efficacy and improving tolerability. Finally, recent studies using pegylated interferon-alpha have shown promising results for the treatment of chronic hepatitis D.

Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients.

OBJECTIVE: The expression on lymphocytes of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene, might influence cyclosporine intracellular concentration. METHODS: ABCB1 genotypes, cyclosporine intracellular and blood concentrations were determined in 64 stable renal, liver or lung transplant recipients. RESULTS: Cyclosporine intracellular concentration correlated moderately with blood concentration (r=0.30, P<0.00005). The ABCB1 1199A carriers presented a 1.8-fold decreased cyclosporine intracellular concentration (P=0.04), whereas the 3435T carriers presented a 1.7-fold increase (P=0.02) as well as a 1.2-fold increased blood concentration (P=0.04). In contrast, ABCB1 61A>G, 1236C>T and 2677G>T polymorphisms did not influence cyclosporine intracellular and blood concentrations. CONCLUSION: This is the first report demonstrating that ABCB1 polymorphisms influence cyclosporine intracellular concentration. Interestingly, its influence on intracellular concentration is significantly higher than on blood concentration (P<0.002). This may therefore modulate cyclosporine immunosuppressive activity.

Prevention of cryoprecipitation during cardiopulmonary bypass in a patient with HIV-HCV co-infections.

BACKGROUND: There are no guidelines for the management of patients with cryoglobulins during cardiopulmonary bypass (CPB) necessitating core hypothermia. OBJECTIVE: To evaluate a simple, pragmatic protocol of in vitro temperature-dependent cryoprecipitation of serum in patients with cryoglobulinemia before elective cardiac surgery with CPB. METHODS: A 44-year-old female patient was known for chronic hepatitis C and type III cryoglobulinemia. Elective surgery was planned for an aortic arch aneurysm. A differential serum cryoprecipitation profile was established in vitro prior to surgery. RESULTS: Whereas, at temperatures < or = 15 degrees C, cryoglobulin levels were > or = 0.112 g/L (normal value < 0.05 g/L), at 20 degrees C and above, the precipitate was < or = 0.016 g/L. Accordingly, surgery was performed without any cryoglobulin-related complications at an extracorporeal circulation temperature of 22-24 degrees C, to minimise the risk of cryoprecipitation. CONCLUSION: In elective cases of surgery with CPB and hypothermia, temperature-dependent differential serum cryoprecipitation profile may be an easy and efficient way to assess a safe peroperative level of temperature to avoid complications due to cryoglobulins, without enhancing the patient's tissue ischemia risks.