Is everolimus linked to metabolic syndrome in liver transplant recipients?

BACKGROUND: As the mortality rates after liver transplantation (LT) have been reduced, the attention has shifted to additional conditions which still compromise the quality of life and the survival of these patients, such as the post-LT metabolic syndrome (MS). In order to determine the prevalence and the factors associated with the post-LT MS, we carried out the present study. METHODS: One hundred and six LT recipients, after completing at least 1 year follow up after LT, were included in the study. Data on clinical, laboratory parameters and immunosuppressive therapy before and after LT were recorded. MS was defined as per current diagnostic criteria. RESULTS: MS was prevalent in 47.2% (50 of 106 patients) and was not associated with the LT indications and the time period after LT. Univariate analysis showed that history of diabetes mellitus before (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.046-9.918, p = 0.042) and after LT (OR 6.03, 95% CI 2.18-16.67, p = 0.001), the age at the time of baseline visit (OR 1.077, 95% CI 1.033-1.124, p = 0.001) and the everolimus-based immunosuppression (OR 1.23, 95% CI 1.003-1.33, p = 0.019) were significantly associated with MS. Notably, everolimus administration was the only factor independently associated with the presence of post-LT MS (OR 1.026, 95% CI 1.004-1.047, p = 0.019). More specifically, everolimus was linked to the presence of arterial hypertension (OR 1.02, 95% CI 1.0-1.03, p = 0.05) and hyperlipidemia (OR 2.87, 95% CI 1.28-6.56, p = 0.011). CONCLUSIONS: Our study demonstrated for the first time that everolimus was independently associated with post-LT MS. Nevertheless, more robust studies are required to confirm these findings.

AGMA Score: A Novel Prognostic Score for Patients Undergoing Liver Transplant for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) in cirrhosis represents one of the leading indications for liver transplant. In an effort to expand the listing criteria, a variety of scoring systems have been suggested, mainly based on the tumor number/size criterion. The objective of our study was to evaluate the feasibility of proposing a transplant score for HCC excluding the tumor number/size criterion. PATIENTS AND METHODS: Data corresponding to patients who received transplants because of HCC were reviewed for the purposes of this study. Deceased donor and living donor liver transplants were included. Demographic, clinical and tumor-related parameters were evaluated. Uni- and multivariate regression analyses and survival analysis were performed. RESULTS: One hundred patients were included in the study. Fifty-five patients underwent deceased donor liver transplant, and 45 patients received living donor liver transplants. Tumor differentiation (G1/2 vs G3), alpha-fetoprotein levels (AFP), recipient age, and recipient laboratory Model for End-Stage Liver Disease Score (MELD) showed statistical significance. A scoring system was developed, with prognostic points assigned as follows: age 60 years or younger:age older than 60 years = 1:0 points, tumor grading well or moderate:tumor grading poor = 1:0 points, MELD score ≤22:MELD score >22 = 1:0 points, and AFP level ≤400 ng/mL:AFP level >400 ng/mL = 1:0 points. This stratification delineated 3 separate population samples corresponding to patients with scores of 4, 3, and 1 to 2, respectively. The calculated 5-year survival for scores 4, 3, and 1 to 2 was 76%, 47%, and 20%, respectively (P < .001). CONCLUSION: The AGMA score (age, grading, MELD, AFP) showed prognostic value in this single-center analysis and may find clinical implication avoiding the tumor number/size criterion.

Everolimus with or without mycophenolate mofetil in a liver transplantation setting: a single-center experience.

BACKGROUND: This study evaluated the efficacy, safety, and impact on renal function of everolimus in patients after liver transplantation (LT) with or without mycophenolate mofetil (MMF). METHODS: We evaluated LT recipients with calcineurin inhibitor (CNI)-related renal dysfunction after everolimus initiation. Laboratory data, including evaluation of renal function based on glomerular filtration rate (GFR) at baseline (i.e., everolimus initiation) and at the end of follow up, were analyzed. RESULTS: Fifty consecutive patients started taking everolimus at 30 months post-LT (range: 1-240), 6 as monotherapy and 44 in combination with MMF. After 30.5 months (range: 6-112), all patients were alive, without any biochemical evidence of a rejection episode or recurrence of hepatocellular carcinoma. The mean GFR, based on the Modification of Diet in Renal Disease equation, was 53±13 mL/min at baseline and 59±12 mL/min at the end of follow up (P=0.031). Eleven (22%) of the patients had GFR <60 mL/min at baseline but returned to GFR >60 mL/min by the end of follow up. In multivariate analysis, the time between the development of renal dysfunction and everolimus initiation was the only factor independently associated with GFR improvement (odds ratio [OR] 0.85, 95% confidence interval [95%CI] 0.76-0.96; P=0.007). Everolimus was stopped in 11 patients (22%) at the end of follow up because of adverse events. CONCLUSION: A CNI-free everolimus-based regimen was effective in LT recipients with renal dysfunction and was associated with an improvement in GFR.

Tubular Pyloric Gland Adenoma of the Left and Right Hepatic Ducts: Report of a Unique Case With Immunohistochemical and Molecular Studies.

Pyloric gland adenomas (PGAs) of the extrahepatic biliary system are rare lesions. We report a case of a tubular PGA that led to biliary obstruction. The tumor was located at the confluence of the right and left hepatic ducts, extending to the left hepatic duct. The tumor cells expressed MUC6 and MUC5AC. MUC1 and CD10 were focally positive. MUC2, p53, and CDX2 were not expressed. The Ki67 positivity was estimated at <15%. None of the KRAS, NRAS, BRAF, EGFR coding regions resulted in clinically relevant amino acid substitutions. SNP rs1050171 (EGFR p.Q787Q, silent mutation) corresponding to c.2361G>A transition in exon 20 was noticed. Awareness of this rare lesion is important for pathologists and clinicians alike, because it may cause significant morphologic and clinical difficulties, especially when presenting as an obstructive mass. Because of the possible risk of evolving malignancy, surgical resection is recommended whenever possible.

Pregnancy after liver transplantation. How safe? A retrospective case-series study in a large tertiary hospital.

OBJECTIVE: To study pregnancies achieved after liver transplantation in terms of obstetric complications, maternal, neonatal outcomes and post-pregnancy allograft function. METHODS: A retrospective study of prospectively collected data was conducted, enrolling women with a history of liver transplantation performed in the Transplantation Unit of our hospital that delivered in our department. Obstetric characteristics and antenatal complications were reviewed. Apgar score, admission to Neonatal Intensive Care Unit (NICU) and need for emergency intubation were analyzed. Outcomes of regular follow-up concerning all complications of allograft function observed after pregnancy were also studied. RESULTS: There were five cases of allograft recipients delivering their pregnancies during the study period. Mean maternal age was 32.2 ± 5 years. Interval from transplantation to delivery ranged from 40 to 219 months. Mean gestational week at delivery was 34.4 ± 2.5 weeks. Antenatal complications observed were pre-eclampsia (3 of 5 cases) and vaginal bleeding (1 of 5 cases). All preterm neonates were admitted to NICU, but no emergency intubation was demanded. One patient died a month after delivery, while three others were complicated by implant dysfunction up to 5 years after the delivery. CONCLUSION: Pregnancy in a liver transplant recipient is associated with complications for mother and infant.

Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a heterogeneous tumor with many factors implicated in its development, with chronic infection and cirrhosis by hepatitis B virus (HBV) being the most prevalent. Cirrhosis due to metabolic syndrome, alcohol consumption, viral infection with hepatitis C virus (HCV) is also involved in its development. Treatment of HCC remains unsatisfactory. Therapeutic management for HCC includes liver transplantation, liver resection, ablation, chemoembolization, which depend on the tumor stage, liver function, and patient performance status. The involvement of different signaling pathways in the initiation and modulation of HCC development based on clinical and research data provided a strong rationale for the development of anti-cancer agents targeting key components of the pathways. The complexity of the tumor prevents the major goal of this therapeutic approach, since sorafenib, a multi-kinase inhibitor, is the only successful drug so far that belongs to the target directed therapy in advanced stage HCC.

New nucleos(t)ide analogue monoprophylaxis after cessation of hepatitis B immunoglobulin is effective against hepatitis B recurrence.

New nucleos(t)ide agents (NAs) [entecavir (ETV) and tenofovir (TDF)] have made hepatitis B immunoglobulin (HBIG)-sparing protocols an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). Twenty-eight patients transplanted for HBV cirrhosis in our centre were prospectively evaluated. After LT, each patient received HBIG (1000 IU IM/day for 7 days and then monthly for 6 months) plus ETV or TDF and then continued with ETV or TDF monoprophylaxis. All patients had undetectable HBV DNA at the time of LT, and they were followed up with laboratory tests including glomerular filtration rate (GFR) after LT. All patients (11 under ETV and 17 under TDF) remained HBsAg/HBV DNA negative during the follow-up period [median: 21 (range 9-43) months]. GFR was not different between TDF and ETV groups of patients at 6 and 12 months and last follow-up (P value >0.05 for all comparisons). The two groups of patients were similar regarding their ratio of maximum rate of tubular phosphate reabsorption to the GFR (TmP/GFR). In conclusion, in this prospective study, we showed for the first time that maintenance therapy with ETV or TDF monoprophylaxis after 6 months of low-dose HBIG plus ETV or TDF after LT is highly effective and safe.

Everolimus-based immunosuppression in liver transplant recipients: a single-centre experience.

PURPOSE: Everolimus, a mammalian target of rapamycin inhibitor, has been shown to reduce growth factor-mediated cell proliferation, but data regarding its effectiveness and impact on renal function and recurrence of hepatocellular carcinoma (HCC) in liver transplant (LT) recipients are limited. METHODS: We evaluated LT recipients with a calcineurin inhibitor (CNI)-based immunosuppression regimen in whom everolimus treatment was initiated. The changes in laboratory data, including glomerular filtration rate (GFR), compared to the baseline (i.e. the day of everolimus conversion), were assessed. RESULTS: Totally, 44 consecutive patients (32 men, age 55 ± 7 years) were commenced on everolimus [indications: renal dysfunction post-LT (16 patients, group 1); prevention of HCC recurrence (21 patients) or others (7 patients), group 2] at 6 months (range 1-206) post-LT. After 48 (range 12-76) months, all patients were alive without any rejection episodes. Compared to group 2 patients, group 1 patients had significantly greater improvement in renal function (DGFR: 12 ± 5 vs. -0.4 ± 0.2 ml/min, p = 0.02). GFR at baseline (OR 0.08, p = 0.002) and the combination of everolimus + MMF (OR 0.14, p = 0.024) were the factors independently associated with improvement in renal function. Finally, HCC recurrence was observed less frequently in the everolimus group of patients (n = 21) compared to the CNI-historical control group (n = 22) with HCC before LT [0/21 (0 %) vs. 4/22 (18.5 %), log rank p = 0.055), although the two groups of recipients had similar baseline characteristics and follow-up. CONCLUSIONS: Everolimus is effective and is associated with low rates of HCC recurrence and improvement of renal function in LT recipients.

HCC influence on patient survival after liver transplantation for HDV cirrhosis.

BACKGROUND/AIMS: The effect of hepatocellular cancer (HCC) in patients transplanted for hepatitis B and D virus (HB/DV) cirrhosis is not well studied. Our aim was to study the long-term survival outcomes of patients who underwent liver transplantation for HB/DV cirrhosis with and without HCC. METHODOLOGY: A total of 231 primary, adult, single- organ liver transplants were performed from 1990 to 2007. HB/DV was the cause of cirrhosis in 36 patients. Nine patients died during the first 3 postoperative months from surgical complications. The study group comprised the remaining 27 patients. The median follow-up was 1515 days. RESULTS: The mean patient survival was 3760 days (95% CI: 3013-4507). Six patients were diagnosed with HCC. The mean patient survival was 3011 days (95% CI: 2344-3679) and 4036 days (95% CI: 3002-5070) for recipients without and with HCC, respectively. For the same groups, the incidence of microbial infections was 61.9% and 33.3%, respectively (p=0.219). HCC has not recurred in any of the six patients. CONCLUSIONS: The mean long-term survival after liver transplantation for HB/DV and HCC surpassed 11 years. The superior survival of HCC patients is difficult to explain. The increased number (almost double) of microbial infections in the non- HCC population might be held accountable.

Successful peritonitis management after 27 consecutive operations.

Hemorrhagic pancreatitis, especially in the setting of multiorgan dysfunction and generalized peritonitis, is characterized by a very high mortality rate. We herein describe the unique case of a patient who survived 27 consecutive laparotomies. This favourable outcome highlights the complexity of the underlying pathology as well as the challenges faced by the treating team.

Kidney transplantation in patients with diabetes mellitus: surgical complications.

BACKGROUND/AIMS: The aim of this study was to analyze the risk for surgical complications after kidney transplantation in patients with diabetes mellitus (DM) compared to patients without DM. METHODOLOGY: Between January 2002 and December 2005 270 consecutive kidney transplantations from deceased donors in adult recipients were performed. Data of these patients were analyzed on the presence of DM. Recipients with DM (n=32) were compared with patients without DM (n=238) concerning delayed graft function, wound infections, urinary leakage, postoperative bleeding and urinary infections. RESULTS: No statistically significant differences were found in the occurrence of delayed graft function, postoperative bleeding and urinary tract infections between both groups. Although the percentage of postoperative wound infections and urinary leakages was elevated in the DM group it was not statistical significant. CONCLUSION: In patients with terminal kidney insufficiency the presence of DM type II is a frequent co-morbidity and is per se not a contraindication for kidney transplantation. Because of the elevated cardiovascular risk profile patients with DM have to be evaluated very diligent before being listed for kidney transplantation. Nevertheless beside the additional short term risk caused by kidney transplantation it is the only modifiable risk with possible long term reduction for these patients.

Liver transplantation for hepatic metastases of neuroendocrine pancreatic tumors: a survival-based analysis.

BACKGROUND: Liver transplantation (LT) has been accepted as a treatment in selected cases of neuroendocrine tumors (NETs) with hepatic metastases. PATIENTS AND METHODS: A systematic review of the literature was conducted to evaluate long-term patient survival in the instances of LT for pancreatic NET. Univariate and multivariate regression analyses and survival analysis were performed. RESULTS: Fifty-three clinical studies were screened. Data from 20 studies encompassing 89 transplanted patients were included in the study. Most primary tumors were endocrine pancreatic tumors (n=69), with gastrinomas representing the most frequent diagnosis (n=21). There were 61 functioning pancreatic NET. Simultaneous LT and pancreatic NET resections were performed in 45 instances. Cumulative 1-, 3-, and 5-year survival was 71%, 55%, and 44%, respectively, with a calculated mean survival of 54.45±6.31 months. Vasoactive intestinal peptide (VIPomas) had the best overall survival. Recurrence-free survival at 1, 3, and 5 years was 84%, 47%, and 47%, respectively. Recipient age more than or equal to 55 years (P=0.0242) and simultaneous LT-pancreatic resection (P=0.0132) were found to be significant predictors of worse survival by both univariate and multivariate Cox proportional hazard analyses. A scoring system was developed, with prognostic points assigned as follows: age more than or equal to 55 years:age less than 55 years=1:0 points and simultaneous LT-pancreatic resection:LT alone=1:0 points. This stratification delineated three separate population samples corresponding to patients with scores of 0, 1, and 2, respectively. The calculated 5-year survival for scores 0, 1, and 2 was 61%, 40%, and 0%, respectively (P=0.0023). CONCLUSIONS: Despite the limitations of this retrospective analysis, good results can be achieved even for pancreatic NET primaries if the above-proposed scoring system is applied.

Laparoscopic versus open mesh repair for recurrent inguinal hernia: a meta-analysis of outcomes.

BACKGROUND: The objective of this study was to examine the outcomes of comparisons between laparoscopic and open mesh repairs in the setting of recurrent inguinal hernia. METHODS: The electronic databases MEDLINE, Embase, Pubmed, and the Cochrane Library were used to search for articles from 1990 to 2008. The present meta-analysis pooled the effects of outcomes of a total of 1,542 patients enrolled into 5 randomized controlled trials and 7 comparative studies, using classic and modern meta-analytic methods. RESULTS: Significantly fewer cases of hematoma/seroma formation were observed in the laparoscopic group in comparison with the Lichtenstein group (odds ratio, .38; .15-.96; P = .04). A matter of great importance is the higher relative risk of overall recurrence in the transabdominal preperitoneal group compared with the totally extraperitoneal group (relative risk, 3.25; 1.32-7.9; P = .01). CONCLUSIONS: Laparoscopic versus open mesh repair for recurrent inguinal hernia was equivalent in most of the analyzed outcomes.

Orthotopic liver transplantation: T-tube or not T-tube? Systematic review and meta-analysis of results.

BACKGROUND: The purpose of this study was to compare outcomes after duct-to-duct anastomoses with or without biliary T-tube in orthotopic liver transplantation. METHODS: We pooled the outcomes of 1027 patients undergoing choledocho-choledochostomy with or without T-tube in 9 of 46 screened trials by means of fixed or random effects models. RESULTS: The "without T-tube" and "with T-tube" groups had equivalent outcomes for: anastomotic bile leaks or fistulas, choledocho-jejunostomy revisions, dilatation and stenting, hepatic artery thromboses, retransplantation, and mortality due to biliary complications. The "without T-tube" group had better outcomes when considering "fewer episodes of cholangitis," "fewer episodes of peritonitis," and showed a favorable trend for "overall biliary complications." Although the "with T-tube" group showed superior result for "anastomotic and nonanastomotic strictures," the incidence of interventions was not diminished. CONCLUSIONS: Our systematic review and meta analysis favor the abandonment of T-tubes in orthotopic liver transplantation.

Corticosteroid-free immunosuppression in liver transplantation: a meta-analysis and meta-regression of outcomes.

To examine the impact of steroid withdrawal from the immunosuppression protocols in liver transplantation. The electronic databases Medline, Embase, Pubmed and the Cochrane Library were searched. Meta-analysis pooled the effects of outcomes of a total of 2590 patients enrolled into 21 randomized controlled trials (RCTs), using classic and modern meta-analytic methods. Meta-analysis of RCTs addressing patients transplanted for any indication showed no differences between corticosteroid-free immunosuppression and steroid-based protocols in most of the analyzed outcomes. More importantly, steroid-free cohorts appeared to benefit in terms of de novo diabetes mellitus development [R.R = 1.86 (1.43, 2.41)], Cytomegalovirus (CMV) infection [R.R = 1.47 (0.99, 2.17)], cholesterol levels [WMD = 19.71 (13.7, 25.7)], the number of patients that received the allocated treatment [O.R = 1.55 (1.17, 2.05)], severe acute rejection [R.R = 1.71 (1.14, 2.54)] and overall acute rejection [R.R = 1.31 (1.09, 1.58)] (when steroids were replaced in the steroid-free arm). Taking RCTs into account independently when steroids were not replaced, overall acute rejection was favoring the steroid-based arm [R.R = 0.75 (0.58, 0.98)]. Studies addressing exclusively transplanted HCV patients demonstrated a significant advantage of steroid-free protocols considering HCV recurrence [R.R = 1.15 (1.01, 1.13)], acute graft hepatitis [O.R = 3.15 (1.18, 8.40)], and treatment failure [O.R = 1.87 (1.33, 2.63)]. No unfavorable effects were observed after steroid withdrawal during short-term follow-up. On the contrary, significant advantages were documented.

Assessment of strangulated content of the spontaneously reduced inguinal hernia via hernia sac laparoscopy: preliminary results of a prospective randomized study.

This prospective randomized study aimed to evaluate the impact of hernia sac laparoscopy on the morbidity and mortality in cases with a spontaneous reduction of the strangulated hernia content before the assessment of its viability. Ninety-five patients underwent operation owing to incarcerated hernia. Forty-one patients, whose strangulated indirect inguinal hernia spontaneously reduced before the viability of the content was assessed, were included in this study. They were randomly assigned to 2 groups: group A (21 patients managed using hernia sac laparoscopy) and group B (20 patients managed without laparoscopy). The median hospital stay was 28 hours for group A and 34 hours for group B. Four patients of group B had major complications whereas there was none observed in the group A. Two unnecessary laparotomies and 2 deaths occurred in group B. Hernia sac laparoscopy seems to be an accurate and safe method allowing to prevent unnecessary laparotomy and especially in high-risk patients it contributes to decrease major morbidity.

The natural history of vascular access for hemodialysis: a single center study of 2,422 patients.

BACKGROUND: Our objective is to provide provision of primary and secondary patency rates data and incidence of complications. Despite the publication of some review articles and small prospective trials about vascular accesses, controversy still exists regarding the choice of the outflow conduit and especially the choice of the fistula to be formed in secondary and tertiary access procedures. METHODS: This is a retrospective study of 2,422 consecutive patients who underwent 3,685 vascular access procedures in a tertiary care hospital, including radial-cephalic (RCAVF), brachial-cephalic (BCAVF), brachial-basilic (BBAVF), and prosthetic graft (PTFE) fistulas. Maximum follow-up period was 20 years. Actuarial patency rates were obtained by Kaplan-Meier analysis. RESULTS: The median primary patency (days) of the most common 1st choices for vascular access were 712 (95% CI: 606, 818), 1,009 (95% CI: 823, 1,195), and 384 (95% CI: 273, 945) days for RCAVF, BCAVF, and PTFE, respectively. The median secondary patency was 1809 days (95% CI: 1,692, 1,926) for the RCAVF. The median primary patency of BBAVF (2nd or 3rd choice for vascular access) was 1,582 days (95% CI: 415, 2,749). The cumulative incidence of clinically important complications for the patients who received a RCAVF, BCAVF, BBAVF, and u-PTFE was 0.25, 0.57, 0.33, and 0.61 per patient-year, respectively. CONCLUSION: We advocate maximal use of autogenous conduits, except probably the case of the older diabetic patient, in whom access at the antecubital fossa should be the first choice. BBAVF is an excellent fistula and should probably be constructed before prosthetic graft placement.