N. Morelli

HLA class-I-soluble antigen serum levels in liver transplantation : a predictor marker of acute rejection

The serum levels of sHLA-I have been determined in 16 patients following liver transplantation. sHLA-I levels did not show remarkable variations in six patients without evidence of transplant-related complications. sHLA-I levels strongly increased in 10 patients undergoing acute rejection episodes. In these patients, an average 20% daily increase of sHLA-I levels was detected on the 6 days preceding and on the 2 days following the rejection episode. A fast decrease of sHLA-I levels was observed in seven patients following treatment of acute rejection with anti-CD3 mAb. The serum level of sHLA-I antigens positively correlated with ALT serum level and inversely correlated with PT. The determination of sHLA-I in serum may therefore be proposed as a useful marker in the monitoring of patients following liver transplantation. The increase of sHLA-I antigens may predict the onset of acute rejection whereas their decrease may be related to a good response of acute rejection to immunosuppressive treatment.

Sister Joseph's nodule in a liver transplant recipient: Case report and mini-review of literature

BackgroundUmbilical metastasis is one of the main characteristic signs of extensive neoplastic disease and is universally referred to as Sister Mary Josephs nodule.Case presentationA 59-years-old Caucasian female underwent liver transplant for end stage liver disease due to hepatitis C with whole graft from cadaveric donor in 2003. After transplantation the patient developed multiple subcutaneous nodules in the umbilical region and bilateral inguinal lymphadenopathy. The excision biopsy of the umbilical mass showed the features of a poorly differentiated papillary serous cystadenocarcinoma. Computed tomographic scan and transvaginal ultrasonography were unable to demonstrate any primary lesion. Chemotherapy was start and the dosage of the immunosuppressive drugs was reduced. To date the patient is doing well and liver function is normal.ConclusionsThe umbilical metastasis can arise from many sites. In some cases, primary tumor may be not identified; nonetheless chemotherapy must be administrated based on patients history, anatomical and histological findings.

Sirolimus therapy in liver transplant patients: an initial experience at a single center.

Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposis sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.

A prospective policy development to increase split-liver transplantation for 2 adult recipients: Results of a 12-year multicenter collaborative study

Objective:To analyze in a multicenter study the potential benefit of a new prospective policy development to increase split-liver procedures for 2 adult recipients. Background:Split-liver transplantation is an important means of overcoming organ shortages. Division of the donor liver for 1 adult and 1 pediatric recipient has reduced the mortality of children waiting for liver transplantation but the benefits or disadvantages to survival when the liver is divided for 2 adults (adult-to-adult split-liver transplant, AASLT) compared with recipients of a whole graft have not been fully investigated. Methods:We developed a computerized algorithm in selected donors for 2 adult recipients and applied it prospectively over a 12-year period among 7 collaborative centers. Patient and graft outcomes of this cohort receiving AASLT either as full right grafts or full left grafts were analyzed and retrospectively compared with a matched cohort of adults who received a conventional whole-liver transplant (WLT). Univariate and multivariate analysis was done for selected clinical variables in the AASLT group to assess the impact on the patient outcome. Results:Sixty-four patients who received the AASLT had a high postoperative complication rate (64.1% grade III and IV) and a lower 5-year survival rate than recipients of a WLT (63.3% and 83.1%) Conclusions:AASLT should be considered a surgical option for selected smaller-sized adults only in experimental clinical studies in experienced centers.

MELD score versus conventional UNOS status in predicting short-term mortality after liver transplantation*

The Model for End‐stage Liver Disease (MELD) provides a score able to predict short‐term mortality in patients awaiting liver transplantation (LT). In the early 2002, United Network for Organ Sharing (UNOS) has proposed to replace the conventional statuses 3, 2B, and 2A with a modified MELD score. However, the accuracy of the MELD model to predict post‐transplantation outcome is fairly elusive. In the present study we investigated the predictive value of the MELD score for short‐term patient and graft mortality in comparison with conventional UNOS status. Sixty‐nine patients listed at UNOS status 3 (n = 5), 2B (n = 55) or 2A (n = 9) who underwent LT were enrolled according to strict criteria. No donor‐related parameters affected 3‐month patient survival. Through univariate Cox regression, pretransplantation international normalized ratio (P = 0.049) and activated partial thromboplastin time (P = 0.032) were significantly associated with 3‐month patient survival, although not in the subsequent multivariate analysis. The overall MELD score was 17 ± 6.63 (median: 16, range: 4–34), increasing from UNOS Status 3 to 2A (r2 = 0.171, P = 0.0001). No significant difference occurred in the median MELD score between patients who underwent a second LT and those who did not (P =0.458). The inter‐rate agreement between UNOS status and MELD score after categorization for clinical urgency showed a fair agreement (κ = 0.244). The 3‐month patient and graft mortality was 15.94% and 20.29% respectively. The concordance statistic did not find significance between UNOS status and MELD score for 3‐month patient (P = 0.283) or graft mortality (P = 0.957), although the MELD score revealed a major sensitivity for short‐term patient mortality (0.637; 95%CI: 0.513–0.75). These findings suggest the need to implement MELD model accuracy for both inter‐rate agreement with UNOS Status and patient outcome.

http://www.D‐MELD.com, the Italian survival calculator to optimize donor to recipient matching and to identify the unsustainable matches in liver transplantation

Optimization of donor‐recipient match is one of the exciting challenges in liver transplantation. Using algorithms obtained by the Italian D‐MELD study (5256 liver transplants, 21 Centers, 2002–2009 period), a web‐based survival calculator was developed. The calculator is available online at the URL http://www.D‐MELD.com. The access is free. Registration and authentication are required. The website was developed using PHP scripting language on HTML platform and it is hosted by the web provider Aruba.it. For a given donor (expressed by donor age) and for three potential recipients (expressed by values of bilirubin, creatinine, INR, and by recipient age, HCV, HBV, portal thrombosis, re‐transplant status), the website calculates the patient survival at 90 days, 1 year, 3 years, and allows the identification of possible unsustainable matches (i.e. donor‐recipient matches with predicted patient survival less than 50% at 5 years). This innovative approach allows the selection of the best recipient for each referred donor, avoiding the allocation of a high‐risk graft to a high‐risk recipient. The use of the D‐MELD.com website can help transplant surgeons, hepatologists, and transplant coordinators in everyday practice of matching donors and recipients, by selecting the more appropriate recipient among various candidates with different prognostic factors.

Successful Simultaneous Pancreas Kidney Transplantation from Living‐Related Donor Against Positive Cross‐Match

A positive pretransplant flow cytometry cross‐match (FC‐XM) allows precise identification of high‐risk recipients vulnerable to hyperacute or accelerated rejection after transplantation. Living donor kidney transplant recipient candidates with positive cross‐match have been successfully treated with a combination of plasmapheresis (therapeutic plasma exchange, TPEX) and intravenous immunoglobulin (IVIG), achieving conversion to negative cross‐match and successful transplant. We report the first successful case of simultaneous pancreas kidney transplant (SPKT) from a living donor (LD) performed against an initially positive FC‐XM, converted to negative using a protocol based on TPEX and IVIG in combination with antiCD20 monoclonal antibody. This strategy of overcoming the cross‐match barriers in living donation may offer a chance of successful transplantation to highly sensitized candidates for SPKT, for whom cadaveric transplant is difficult to achieve.

Torque Teno Virus—Cause of Viral Liver Disease Following Liver Transplantation: A Case Report

Torque Teno Virus (TTV), a nonenveloped human virus of the Circoviridae family, is hepatotropic, causing liver damage, cirrhosis, and, rarely, fulminant hepatitis. It prevails in 10% to 75% of blood donors due to environmental differences, independent of chronic hepatitis B virus (HBV)/HCV hepatitis, cryptogenic cirrhosis, alcoholic cirrhosis, and in fulminant hepatitis non-A-G. Reports about the efficacy of clinical alpha interferon are rare. In July 2007, a 65-year-old man who was serologically negative for A-E viruses presented with acute liver failure due to a ruptured hepatic artery aneurysm and underwent orthotopic liver transplantation (OLT). Immunosuppression was based on cyclosporine and steroids. At postoperative day 20, there was persistent hypertransaminasemia with otherwise normal liver function. A percutaneous hepatic biopsy documented pattern suggestive of a viral etiology. Multiple tests for hepatotropic viruses in the donor and the recipient from the pre- and post-OLT periods remained negative. Only the TTV qualitative test, assessed by polymerase chain reaction (PCR) on patient sera, was positive. Immunosuppressive therapy was not changed; no antiviral therapy was undertaken. At 6 months posttransplantation, transaminase levels spontaneously normalized and the clinical situation was unchanged. No complications were observed; the patient is in good clinical condition. No graft rejection was observed. In histologically proven non-A-E viral hepatitis, it is important to consider TTV as an incidental pathogenic agent. It may be useful to extend virological tests to TTV among transplant recipients and donors and to gain further knowledge about this virus.

Preliminary Results of Liver Transplantation for Hepatocellular Carcinoma Among Allocation Organ Policy Strategies, Neoadjuvant Treatments, and Intention-to-Treat Analysis

We retrospectively evaluated the impact of our strategy for patients with hepatocellular carcinoma (HCC) according to an intention-to-treat analysis and drop-out probability. We evaluated only patients within the Milan criteria. We analyzed the outcomes of neoadjuvant strategies for HCC, organ allocation policy, and systematic application of strategies to increase the deceased donor pool as the current tendency to expand transplantability criteria for those patients. Kaplan-Meier survival probability rates at 1, 3, and 5 years according to an intention-to-treat analysis were 87.02%, 74.53%, and 65.93% for transplanted patients (n=108), and 50%, 14.29%, and 14.29% for the excluded or waiting list group (n=13), respectively (P< .0001). Drop-out risk at 3, 6, and 12 months was 2.40%, 8.59%, and 16.54%, respectively. During the same period, the mortality probability rates at 3, 6, and 12 months among patients without HCC awaiting orthotopic liver transplantation (OLT) were 3.60%, 9.50%, and 18.34%, respectively. Drop-out rate was lower among patients treated before OLT (P< .0001). On the basis of the neoadjuvant treatment results to reduce drop-out risk, we suggest avoiding the high priority for the HCC cohort, particularly within the first 6 months from entrance on the waiting list, because this approach can reduce the chances of patients with end-stage liver disease (ESLD) alone.

Laparoscopic bridging vs. anatomic open reconstruction for midline abdominal hernia mesh repair [LABOR]: single-blinded, multicenter, randomized, controlled trial on long-term functional results

BackgroundRe-approximation of the rectal muscles along the midline is recommended by some groups as a rule for incisional and ventral hernia repairs. The introduction of laparoscopic repair has generated a debate because it is not aimed at restoring abdominal wall integrity but instead aims just to bridge the defect. Whether restoration of the abdominal integrity has a real impact on patient mobility is questionable, and the available literature provides no definitive answer. The present study aims to compare the functional results of laparoscopic bridging with those of re-approximation of the rectal muscle in the midline as a mesh repair for ventral and incisional abdominal defect through an “open” access. We hypothesized that, for the type of defect suitable for a laparoscopic bridging, the effect of an anatomical reconstruction is near negligible, thus not a fixed rule.Methods and designThe LABOR trial is a multicenter, prospective, two-arm, single-blinded, randomized trial. Patients of more than 60 years of age with a defect of less than 10 cm at its greatest diameter will be randomly submitted to open Rives or laparoscopic defect repair. All the participating patients will have a preoperative evaluation of their abdominal wall strength and mobility along with volumetry, respiratory function test, intraabdominal pressure and quality of life assessment.The primary outcome will be the difference in abdominal wall strength as measured by a double leg-lowering test performed at 12 months postoperatively. The secondary outcomes will be the rate of recurrence and changes in baseline abdominal mobility, respiratory function tests, intraabdominal pressure, CT volumetry and quality of life at 6 and 12 months postoperatively.DiscussionThe study will help to define the most suitable treatment for small-medium incisional and primary hernias in patients older than 60 years. Given a similar mid-term recurrence rate in both groups, if the trial shows no differences among treatments (acceptance of the null-hypothesis), then the choice of whether to submit a patient to one intervention will be made on the basis of cost and the surgeon’s experience.Trial registrationCurrent Controlled Trials ISRCTN93729016