Everolimus vs Mycophenolate Mofetil in Combination With Tacrolimus: A Propensity Score-matched Analysis in Liver Transplantation.

BACKGROUND: No trial has investigated the long-term outcome of everolimus (EVR)-incorporating immunosuppression vs tacrolimus (TAC) and mycophenolate mofetil (MMF) after liver transplantation. MATERIALS AND METHODS: With a propensity score methodology, 178 recipients on TAC and MMF were compared to 178 patients on TAC and EVR. RESULTS: At a median (interquartile range) follow-up of 45 (46.3) months, the probability of treated biopsy-proven acute rejection, graft loss, and death was 36.6% for MMF and 28.1% for EVR (P = .0891). Treated biopsy-proven acute rejection was numerically lower for EVR (3.3% vs 7.3%, P = .09), while adverse events (70.2% vs 58.9%, P = .02) and drug discontinuations (21.3% vs 11.8%, P = .01) were significantly higher with regard to hypercholesterolemia (P = .001), thrombocytopenia (P = .0062), and edema (P = .0107). Patients on MMF showed more hypertension (P = .0315), tremor (P = .0006), cytomegalovirus infection (P = .0165), and malignancies (P = .0175). EVR was associated with lesser deterioration in mean (SD) renal function at the latest follow-up (-2.2 (1.8) vs -5.1 (3.2) mL/min/1.73 m2, t = 3.6, P = .005). CONCLUSIONS: The efficacy of the combination of TAC and EVR is comparable to that of TAC and MMF. Drug discontinuations and adverse events were higher for patients on EVR, but these latter showed less hypertension, cytomegalovirus infection, and renal dysfunction. The observed reduction in posttransplant malignancies for EVR requires longer follow-up to be confirmed.

Alcohol drinking after liver transplantation is associated with graft injury.

AIM: This was a single-center, mixed-design, cross-sectional and retrospective study to assess the performance of the 4-item, self-reported CAGE (Cut down, Annoyed, Guilty, Eye-opener) questionnaire in predicting histology-proven alcohol-related liver graft injury (ARLGI). METHODS: A total of 316 liver transplant (LT) patients between six months and five years were enrolled. Based on previous research, problem alcohol drinking (PAD) was defined as any score ≥ 1 on the CAGE, while a cut-off of 2 was assumed for alcohol dependence (AD). RESULTS: Responders were 195, 45 (23.1%) had a CAGE score ≥ 1 and 30 (15.3%) scored ≥ 2. After controlling for confounders, PAD was associated with hyperlipidemia (P=0.01), while AD with a male gender (P=0.01), hyperlipidemia (P=0.03) and alcohol as native diagnosis (P=0.03). PAD and AD were both associated with a significantly higher prevalence of ARLGI, i.e. 53.3% and 63.3%, respectively (P<0.0001). Hepatitis C virus (HCV) patients with PAD showed more steatosis (P=0.04), portal infiltrate (P=0.03), and pericellular/perivenular fibrosis (P=0.02). The likelihood ratios for CAGE scores ranging from 0 to 4 in predicting ARLGI were 0, 5.2, 7.8, 7.8, and 100, respectively. CONCLUSION: By use of a self-report instrument we found a 23.1% prevalence of PAD and a 15.3% prevalence of AD among LT patients between six months and five years. A variable degree of ARLGI was present in 53.3% of PAD and 63.3% of AD, respectively. HCV patients with PAD had more steatosis, portal inflammation, and pericellular fibrosis. Transplant physicians might improve their ability to predict the probability for ARLGI using the CAGE.

The impact of everolimus on renal function in maintenance liver transplantation.

We retrospectively investigated the impact on renal function (RF) of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) monotherapy in orthotopic liver transplant (OLT) recipients. Between January 2006 and July 2007, 70 deceased donor OLT recipients including 51 men and 19 women of overall mean age of 55.9 +/- 11 years were enrolled into a program of conversion to EVL monotherapy at a mean interval of 45 +/- 35.9 months from transplantation (range, 7-192 months). The indication for conversion was deteriorating RF in 64 (91.4%). Efficacy failure was defined as the persistence of CNI, EVL discontinuation, death, graft loss, loss to follow-up, or need for dialysis at 12 months. Twelve months after switching, 53 patients (75.7%) were on EVL monotherapy. Their mean change in creatinine clearance (CrCl) from baseline (day 1 before EVL introduction) to endpoint (12 months) was 5.8 +/- 13.1 mL/min. On univariate and multivariate analyses, the clinical variable correlated with the greatest probability of improvement was the baseline CrCl (P < .0001). Conversion from CNI to EVL monotherapy was successful in 75.7% of cases with improvement in RF correlated with baseline CrCl. These data supported preemptive minimization of CNI in the posttransplant course, seeking to delay the decline in RF.

The "You Are Not Alone" care program for liver transplantation.

Current clinical practice is based on the principles of efficacy, appropriateness, efficiency, quality, and safety. Compliance with these tenets requires experienced medical and nursing staff, and active participation of patients and their families in the planned therapeutic program. To match patients' expectations on quality and safety of care and spur active participation in the transplant care process, we set up an integrated, multiphase, multidisciplinary care program devoted to liver transplantation (LT) candidates, engrafted patients, and their families: the "Non Sei Solo" care program (You Are Not Alone). The basic principle of the care program was that, to provide efficient and effective education to their patients, health care professionals need to learn how to teach and what to teach, acquire successful communication skills, and monitor the process of education. The methodology encompassed 5 distinct phases: phase 1, exploration of patients' needs, by means of a questionnaire devoted to waitlisted and engrafted patients and their care givers; and phase 2, creation of 16 patient-oriented educational brochures directed to patients and their families. Once created, the educational brochures were presented, discussed, and amended during a consensus meeting involving all transplantation nurses and physicians (phase 3). To acquire the necessary skills and ease communication with patients, the transplantation nurses, physicians, surgeons, and anesthesiologists attended a 6-month counseling course under the tutorial of an expert counselor (phase 4). Finally, in June 2007 the program started officially with monthly meetings with patients and their families, guided hospital tours on patient request, and activation of a toll-free phone number to provide support to patients and answer their questions.

Immunochemical characterization of Glycine max L. Merr. var Raiden, as a possible hypoallergenic substitute for cow's milk-allergic patients.

BACKGROUND: Cows' milk allergy (CMA) is the most common cause of food allergy in infancy. The only proven treatment is the complete elimination of cows' milk proteins (CMPs) from the diet by means of hypoallergenic formulas. Soybean-based formulae are widely used although intolerance to soy has been reported to occur in 15-40% of infants with CMA. OBJECTIVE: The aim of this work was to analyse the in vitro reactivity of the soybean cultivar Raiden, which naturally lacks glycinin A(4)A(5)B(3), to evaluate whether this genotype could be a safe CMP substitute for CMA patients. METHODS: The reactivity of conventional soybean (CS) and Raiden soybean (RS) genotypes and also recombinant glycinin A(4)A(5)B(3) and alphabeta-conglycinin with casein-specific monoclonal antibodies and CMP-specific polyclonal serum was evaluated by immunoblotting and ELISA. A sequential competitive ELISA with the polyclonal antiserum and different soluble inhibitors was performed. In addition, an indirect ELISA with sera of atopic children with CMA was carried out to analyse the IgE-binding capacity of the different soybean components. RESULTS: We have shown that CS contains four components that cross-react with CMP, while RS has only one. The remaining cross-reactive component in RS was identified as alpha-subunit beta-conglycinin. By means of inhibitory ELISA, we demonstrated that CS, RS and the alpha-subunit beta-conglycinin extracts inhibited the binding of CMP-specific antibodies to the CMP-coated solid phase. Finally, we showed that CS, RS and the recombinant proteins were recognized by human CMP-specific IgE antibodies. CONCLUSION: This work shows that although Raiden has fewer cross-reactive components than conventional soybean, it still has a residual cross-reactive component: the alpha-subunit beta-conglycinin. This reactivity might make this genotype unsuitable to treat CMA and also explains adverse reactions to soybean in CMA infants.

Switch to everolimus for sirolimus-induced pneumonitis in a liver transplant recipient--not all proliferation signal inhibitors are the same: a case report.

We report a 62-year-old female liver transplant patient who presented with sirolimus (SIR)-related pneumonitis (SIP) treated with a switch to everolimus (EVER). At 13-month follow-up, the patient is on EVER monotherapy with no recurrence of SIP. Despite common mechanisms of action, the safety profile of EVER is different from SIR, and a switch from SIR to EVER should be contemplated in cases of SIP to allow patients to benefit from the antifibrotic properties of antiproliferative immunosuppressants.

[Quality of central venous catheter management protocols in Oncology centres of an Italian region]. / La qualità dei protocolli per la gestione dei cateteri venosi centrali.

The aim of this study was to evaluate the quality of central venous catheter (Port-a-cath, Groshong and Hohn) management protocols in Oncology centres in an Italian region. A retrospective study was performed in 25 hospitals, only 10 of which provided evidence that they utilized a central venous catheter management protocol. The submitted protocols were evaluated in terms of completeness and of adherence to manufacturers' indications and to recommendations of the Centre for Diseases Control. Study results show that overall, there is poor adherence to the basic quality requirements considered and only two of the ten protocols examined were found to be complete. Also, there is wide variability between the protocols with significant differences in the type of instructions provided in the different hospitals.

Cost analysis of tumor downsizing for hepatocellular carcinoma liver transplant candidates.

We report the results of a prospective, intent-to-treat (ITT) trial on the costs of selective tumor downsizing (DS) before liver transplantation (LT) for patients affected with hepatocellular carcinoma (HCC). The trial started in January 1997 including adult patients with nodular-type HCC within and beyond the Milan criteria. Patients were downsized with transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI) and/or radiofrequency ablation (RFA) according to clinical predictors. TACE and RFA were performed as inpatient procedures, while PEI was performed on an outpatient basis. Costs of DS were obtained according to the Tuscany Health Reimbursement Fee Catalog adjusted to yearly inflation rates from 1997 through 2005. Data analysis was performed at 1 year after the last enrollment of 198 patients, including 161 (81.3%) who were transplanted: 34 (17.2%) dropped out and 3 (1.5%) were still on the waiting list. One hundred and fifty-two patients (76.7%) underwent DS for a total of 201 procedures: 159 TACE, 39 PEI, and 3 RFA. Overall costs in Euros (euro) of waitlisting were 861,801.24 euro: 548,460 euro (63.7%) for pretransplantation evaluation; 197,994.84 euro (22.9%) for control visits and hospitalizations; and 115.346.4 euro (13.4%) for DS. Mean costs of DS were 758.58 euro +/- 270 euro per downstaged patient (747.53 euro +/- 257.1 euro Milan; 774.01 euro +/- 287.71 euro non-Milan); 582.85 euro +/- 398.87 euro per waitlisted patient (520.28 euro +/- 406.23 euro Milan; 520.28 +/- 364.48 euro non-Milan); and 716.4 euro per transplanted patient (580.67 euro Milan; 1026.76 euro non-Milan; +76.8%). A selective policy of tumor DS increased the costs of LT waitlisting by 13.4%, but due to higher dropout rates among non-Milan patients, the cost utility of DS was 76.8% higher in the Milan group.

Switch to tacrolimus for cyclosporine-induced gynecomastia in liver transplant recipients.

We report herein on two male liver transplant (LT) recipients who presented with cyclosporine (CsA)-related gynecomastia 6 and 10 months after transplantation. The clinical workup showed increased luteinizing hormone (LH), associated with a slight reduction in testosterone blood levels in one patient and increased prolactin levels in the other. After excluding concomitant primary endocrine and/or malignant disease, conversion to tacrolimus (TAC) was performed resulting in clinical improvement of gynecomastia and return of hormone blood levels to normal range within 3 months. Our report confirms a putative role of CsA in post-LT gynecomastia, reversible however upon conversion to TAC.

Gamma-glutamyltransferase in fine-needle liver biopsies of subjects with chronic hepatitis C.

Serum gamma-glutamyltransferase (GGT) is considered as a sensitive but rather nonspecific marker of hepatobiliary disease, including chronic hepatitis C virus (HCV) infection. Although its increase in HCV infection is associated with poor response to interferon-alpha (IFN-alpha) and poor prognosis, there is little knowledge of the reasons of its increase during disease. Immunohistochemistry and enzyme histochemistry were performed on fine-needle biopsies of subjects with HCV infection. GGT was detected in the lumen of bile ducts and in bile canaliculi. Furthermore, in subjects with elevated serum GGT, immunoreactive and catalytically active GGT was also detected on the sinusoidal surface of hepatocytes and diffuse cytoplasmic positivity appeared in isolated hepatocytes and hepatocellular foci. Antigen unmasking procedures showed the presence of GGT in the cytoplasm of mature and immature bile cells and of inflammatory cells. These results suggest that during chronic HCV infection there is a general enhancement of GGT activity within the liver. As the activity of several inflammatory mediators, such as leukotrienes, nitric oxide, and interleukins is modulated by GGT activity, the present findings suggest a direct relationship between serum GGT, enhanced intrahepatic GGT activity and prognosis and therapeutic outcome of chronic HCV infection.

Transcription factor RF2a alters expression of the rice tungro bacilliform virus promoter in transgenic tobacco plants.

The promoter from rice tungro bacilliform badnavirus (RTBV) is expressed only in phloem tissues in transgenic rice plants. RF2a, a b-Zip protein from rice, is known to bind to the Box II cis element near the TATA box of the promoter. Here, we report that the full-length RTBV promoter and a truncated fragment E of the promoter, comprising nucleotides -164 to +45, result in phloem-specific expression of beta-glucuronidase (GUS) reporter genes in transgenic tobacco plants. When a fusion gene comprising the cauliflower mosaic virus 35S promoter and RF2a cDNA was coexpressed with the GUS reporter genes, GUS activity was increased by 2-20-fold. The increase in GUS activity was positively correlated with the amount of RF2a, and the expression pattern of the RTBV promoter was altered from phloem-specific to constitutive. Constitutive expression of RF2a did not induce morphological changes in the transgenic plants. In contrast, constitutive overexpression of the b-ZIP domain of RF2a had a strong effect on the development of transgenic plants. These studies suggest that expression of the b-Zip domain can interfere with the function of homologues of RF2a that regulate development of tobacco plants.