Giovanni Vennarecci

A pilot study on the safety and effectiveness of immunosuppression without prednisone after liver transplantation

BACKGROUND Corticosteroids are commonly used in the immunosuppression therapy after liver transplantation, yet are associated with considerable side effects. Retrospective studies have shown that corticosteroids can be safely withdrawn from months to years after transplant. We prospectively investigated the effects of early immunosuppression without the use of corticosteroids on graft outcome and transplant complications. METHODS Forty-five patients undergoing liver transplantation were randomized to receive immunosuppression composed of cyclosporine microemulsion and azathioprine with (n=22) or without prednisone (n=23), in conventional doses. In those patients who received prednisone, this was withdrawn within 3 months after transplant. The median follow-up of survivors was 14 months (range: 6-24). The study end points were to determine graft survival and function, infectious complications, including hepatitis C virus (HCV)-RNA levels in HCV-infected recipients, acute rejection, kidney function, and metabolic complications. RESULTS Eleven deaths occurred, 6 of which were in the prednisone group. Two-year survival did not differ between patients treated with or without prednisone (70.2% vs. 78.3%, P=0.83), nor did the causes of death. No differences were observed with regard to graft function, renal function, and infectious complications. In the subset of patients who received transplants for HCV-related cirrhosis, the dynamics of virus replication HCV-RNA was faster among those treated with prednisone. The incidence and severity of acute rejection was similar in the two groups. More than 80% of acute rejections in both groups were classified as mild or moderate and underwent spontaneous resolution. Only two patients in each group had severe acute rejection requiring additional treatment with high-dose steroids. Patients receiving prednisone tended to have greater biochemical signs of cholestasis, higher serum cholesterol and glucose levels, and more frequent insulin requirement than those treated without corticosteroids. CONCLUSIONS Liver transplantation can be performed safely without using corticosteroids in the early postoperative course, and there is no need for routine aggressive steroid treatment of established acute rejections.

The ALPPS procedure: a surgical option for hepatocellular carcinoma with major vascular invasion.

BackgroundHepatocellular carcinoma (HCC) tends to have a particular invasiveness toward the portal vein (PV) branches and hepatic veins. This situation can hamper major surgical resection with a risk of postoperative liver failure due to the small future liver remnant (FLR) in cirrhotic livers. These patients are then usually directed to palliative treatments with poor results. The associating liver partition and PV ligation (PVL) in staged hepatectomy (ALPPS) strategy is one of the main surgical innovations in recent years in the field of liver surgical oncology. The ALPPS approach could allow surgical resection in patients with HCC and associated major vascular invasion.MethodsAmong 1,143 liver resection performed in our center, the ALPPS approach was employed in order to induce rapid hypertrophy of the left FLR in patients with HCC and associated major vascular invasion. This strategy consists of combining the in situ splitting of the liver along the main portal scissura or on the right side of the falciform ligament and PVL in a strategy of staged hepatectomy.ResultsIn our experience the ALPPS approach allowed us to achieve a sufficient FLR in two cases of HCC with major vascular invasion, in which the classic two-stage strategy could not be applied. In both cases the patients could undergo major hepatectomies without mortality.ConclusionsThis novel strategy could expand the number of patients undergoing major liver resections that were previously considered non-resectable because of the risk of liver decompensation for an insufficient FLR.

Plasma Cytokines and Portopulmonary Hypertension in Patients With Cirrhosis Waiting for Orthotopic Liver Transplantation

Portopulmonary hypertension (PPHTN) is a rare complication in patients with portal hypertension. A role of endothelin 1 (ET-1) and other cytokines was demonstrated in primary pulmonary hypertension but not in PPHTN. We evaluated the possible role of ET-1, interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α) in the pathogenesis of PPHTN. Plasmatic concentrations of ET-1, IL-6, IL-1β, and TNF-α were measured in patients with pulmonary systolic arterial pressure (PAPs) >30 mm Hg and in patients with cirrhosis. In all, Six out of 11 patients with PAPs >30 mm Hg had PPHTN on right heart catheterization. The remaining 10 patients had an hyperdynamic circulation (HC). In PPHTN patients, ET-1 and IL-6 were significantly higher compared with HC and patients with cirrhosis. Endothelin 1 and IL-6 could be implicated in the pathogenesis of PPHTN. On the basis of these results, ET-1 receptor antagonists or anti-IL-6 could have a rationale in the treatment of PPHTN.

De novo malignancies following liver transplantation: results from a multicentric study in central and southern Italy, 1990-2008.

OBJECTIVE The objective of this study was to quantify incidence rates (IR) and risks of de novo tumors (except nonmelanoma skin cancers) in patients who underwent orthotopic liver transplantation (OLT) in central and southern Italy. METHODS Data were collected on 1675 patients (75.5% males) who underwent OLT in six Italian transplantation centers in central and southern Italy (1990-2008). The time at risk of cancer (person years [PY]) was computed from OLT to the date of cancer diagnosis, death, or last follow-up, whichever occurred first. The number of observed cancer cases were compared with the expected one using data from population-based cancer registries. We computed gender- and age-standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS During 10,104.3 PYs (median follow-up, 5.2 years), 98 patients (5.9% of the total) were diagnosed with a de novo malignancy (for a total of 100 diagnoses). Twenty-two of these cancers were post-transplantation lymphoproliferative disorders (PTLD; 18 non-Hodgkin lymphoma [NHL] and 2 Hodgkins lymphoma [HL]), 6 were Kaposis sarcoma (KS), and 72 were solid tumors (19 head and neck [H&N], 13 lung, 11 colon-rectum, 6 bladder, and 4 melanoma). The overall incidence was 9.9 cases/10(3) PYs, with a 1.4-fold significantly increased SIR (95% CI, l.2-1.7). Significantly increased SIRs were observed for KS (37.3), PTLD (3.9), larynx (5.7), melanoma (3.1), tongue (7.1), and H&N (4.5) cancers. CONCLUSIONS These results confirmed that OLT patients are at greater risk for cancer, mainly malignancies either virus-associated or related to pre-existent factors (eg, alcohols). These observations point to the need to improve cancer surveillance after OLT. The on-going enrollment of patients in the present cohort study will help to elucidate the burden of cancer after OLT and better identify risk factors associated with its development.

Portal vein aneurysm: What to know.

Portal vein aneurysm is an unusual vascular dilatation of the portal vein, which was first described by Barzilai and Kleckner in 1956 and since then less than 200 cases have been reported. The aim of this article is to provide an overview of the international literature to better clarify various aspects of this rare nosological entity and provide clear evidence-based summary, when available, of the clinical and surgical management. A systematic literature search of the Pubmed database was performed for all articles related to portal vein aneurysm. All articles published from 1956 to 2014 were examined for a total of 96 reports, including 190 patients. Portal vein aneurysm is defined as a portal vein diameter exceeding 1.9 cm in cirrhotic patients and 1.5 cm in normal livers. It can be congenital or acquired and portal hypertension represents the main cause of the acquired version. Surgical indication is considered in case of rupture, thrombosis or symptomatic aneurysms. Aneurysmectomy and aneurysmorrhaphy are considered in patients with normal liver, while shunt procedures or liver transplantation are the treatment of choice in case of portal hypertension. Being such a rare vascular entity its management should be reserved to high-volume tertiary hepato-biliary centres.

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.

Immunosuppression without prednisone after liver transplantion is safe and associated with normal early graft function: preliminary results of a randomized study.

Abstract Prednisone has been commonly considered the mainstay of immunosuppressive therapy after liver transplantation. Recent data suggest that prednisone withdrawal late after transplant reduces complications without affecting graft function. We report here the preliminary results of an open‐label, randomized study aimed at investigating whether prednisone therapy can be completely avoided during the first 3 months after transplantation. Twenty‐seven consecutive patients were randomized to receive double (group A: cyclosporine and azathioprine) or triple (group B: prednisone, cyclosporine, and azathioprine) immunosuppressive therapy after liver transplantation. Six patients died within the first 3 weeks in each group and were excluded from the calculations. The present results refer to 10 patients in group A and 11 in group B. The actuarial 1‐year survival did not differ between the two groups (90.9 % vs 88.8 %). There were no differences with respect to infectious complications or episodes of histological acute graft rejections. Only one severe acute rejection occurred in group A and two in group B. During the first month after transplant, liver and kidney functions tended to be better in the group of patients treated without prednisone, although there were no differences in the mean cyclosporine blood levels. These data, though preliminary, indicate that early immunosuppression without the use of prednisone is safe and tends to be associated with improved liver and renal functions compared to conventional triple therapy.

Successful Use of Extended Criteria Donor Grafts With Low to Moderate Steatosis in Patients With Model for End-Stage Liver Disease Scores Below 27

Liver transplantation may be performed using extended criteria donor grafts (ECDg). The characteristics of ECDg include age >60 years, long intensive care unit (ICU) stay, history of malignancy or steatosis. Grafts are often discarded due to steatosis, which can be macrovesicular (MaS) or microvesicular (MiS). MaS is the variety most frequently involved with unfavorable outcomes due to primary nonfunction (PNF) or primary dysfunction (PDF). As of January 2000, all livers referred to our institution were considered potentially transplantable. Steatosis was defined as the presence of fat droplets in more than 5% of hepatocytes. We observed 35 steatotic grafts. Grafts were stratified according to MaS and MiS as follows: low steatosis (5%-15%), mild steatosis (16%-30%), moderate steatosis (31%-60%), or severe steatosis (>60%). Fifteen grafts with moderate (n = 2) or severe (n = 13) MaS were discarded. Twenty grafts were harvested: 18 of them were transplanted at our institution, the remaining 2, discarded by our donor team, were transplanted by other Italian centers. Low MaS was detected in 10 grafts (50%), mild MaS in 4 (20%), and moderate MaS in 2 (10%). Low MiS was detected in 8 grafts (40%), mild MiS in 5 (25%), and moderate MiS in 1 (5%). Steatotic grafts were transplanted only into recipients with model for end-stage liver disease (MELD) scores <27. The 6-month graft survival was 80%; the PNF rate was 10%; and the PDF rate was 15%. The careful use of ECDg with low to moderate steatosis is possible if particular care is taken to avoid additional risk factors related to the recipient.

Validation of the AFP model as a predictor of HCC recurrence in patients with viral hepatitis-related cirrhosis who had received a liver transplant for HCC

BACKGROUND & AIMS The AFP model was shown to be superior to the Milan criteria for predicting hepatocellular carcinoma (HCC) recurrence after liver transplantation in a French population. Our aim was to test the AFP model in a non-French, post-hepatitic cirrhosis-based population of HCC candidates. METHODS 574 patients transplanted for HCC in four Italian centers were studied. AFP score was assessed at the last evaluation before liver transplantation (LT). Probabilities of recurrence and survival were estimated by the log-rank test or competing risk analysis and compared according to the AFP model. RESULTS 24.7% patients were beyond Milan criteria. HCC complicated hepatitis C virus (HCV) and hepatitis B virus (HBV) cirrhosis in 58.7% and 24% of the cases, respectively. Five-year probabilities of recurrence differed according to AFP score ⩽2 vs. >2 in the whole population (13.2±1.8% vs. 49.8±8.7%, p<0.001, HR=4.98), in patients within Milan criteria (12.8±2.0% vs. 32.4±12.1%, p=0.009, HR=3.51), beyond Milan criteria (14.9±4.2% vs. 58.9±11.5%, p<0.001, HR=4.26), HCV patients (14.9±2.5% vs. 67.6±14.7%, p<0.001, HR=6.56) and HBV patients (11.6±3.4% vs. 34.3±12.5%, p=0.012, HR=3.49). By net reclassification improvement analysis AFP score significantly improved prediction of non-recurrence compared to Milan criteria. Overall five-year survival rates according to AFP score ⩽2 or >2 were 71.7±2.2% vs. 42.2±8.3% (p<0.001, HR=2.14). CONCLUSIONS The AFP model identifies HCC candidates at low risk of recurrence, otherwise excluded by Milan criteria in a population with a predominance of post-hepatitic-related HCC. The AFP score can be proposed for selection of HCC candidates in programs with a high proportion of viral/HCV-related cirrhosis. LAY SUMMARY Selection criteria for liver transplantation of patients affected with hepatocellular carcinoma (HCC) are based on the Milan criteria, which have been shown to be too restrictive, precluding access to liver transplantation for some patients who might be cured by this operation. Recently, a French group of researchers developed a new selection model called the AFP model, or AFP score, allowing some patients with HCC not meeting Milan criteria to be transplanted with excellent results. In the present work, the AFP score was tested in a population of non-French patients transplanted for HCC occurring mainly on post-hepatitic (HCV or HBV) cirrhosis. The results confirm that in this specific population, as in the original French population of patients, the AFP model better selects patients with HCC eligible for transplantation, compared to Milan criteria. We conclude that the AFP score, which has been officially adopted by the French organization for Organ Sharing for HCC patients, can also be implemented in countries with an important burden of HCC occurring on post-hepatitic cirrhosis.

Laparoscopic liver resections in normal and cirrhotic livers: a retrospective analysis in a tertiary hepato-biliary unit.

BACKGROUND Liver surgery in patients with underlying liver disease results in higher mortality and morbidity rates compared to patients without underlying liver disease. Laparoscopy seems to have good results in patients with normal liver in terms of postoperative outcomes, but is more challenging in cirrhotic patients. Aim of this study was to evaluate the feasibility of laparoscopic liver resection both in normal and cirrhotic livers, and secondary endpoint was to compare the surgical results. METHODS We retrospectively evaluated 105 patients who underwent laparoscopic liver resection between November 2001 and January 2012. Candidates for laparoscopic liver resection were divided into two groups according to the presence or absence of an underlying liver disease. RESULTS 105 patients (52.4% males, median age 56.1 years) were enrolled, and 37.1% had liver cirrhosis. Hepatocellular carcinoma in hepatitis C virus-related cirrhosis (89.7%) and liver metastases (57.6%) were the main indications for surgery in patients with cirrhosis and non-cirrhotic livers, respectively. None of the patients died post-operatively. Cirrhotic patients had greater blood loss (100 vs 50 ml; p<0.012) and longer hospital stays (6 vs 4 days; p<0.031) compared to non-cirrhotics. CONCLUSIONS Laparoscopic liver resections are safe and feasible procedures in both patients with cirrhotic and non-cirrhotic livers.