Silvio Nadalin

Right Portal Vein Ligation Combined With In Situ Splitting Induces Rapid Left Lateral Liver Lobe Hypertrophy Enabling 2-Staged Extended Right Hepatic Resection in Small-for-Size Settings

Objective:To evaluate a new 2-step technique for obtaining adequate but short-term parenchymal hypertrophy in oncologic patients requiring extended right hepatic resection with limited functional reserve. Background:Patients presenting with primary or metastatic liver tumors often face the dilemma that the remaining liver tissue may not be sufficient. Preoperative portal vein embolization has thus far been established as the standard procedure for achieving resectability. Methods:Two-staged hepatectomy was performed in patients who preoperatively appeared to be marginally resectable but had a tumor-free left lateral lobe. Marginal respectability was defined as a left lateral lobe to body weight ratio of less than 0.5. In the first step, surgical exploration, right portal vein ligation (PVL), and in situ splitting (ISS) of the liver parenchyma along the falciform ligament were performed. Computed tomographic volumetry was performed before ISS and before completion surgery. Results:The study included 25 patients with primary liver tumors (hepatocellular carcinoma: n = 3, intrahepatic cholangiocarcinoma: n = 2, extrahepatic cholangiocarcinoma: n = 2, malignant epithelioid hemangioendothelioma: n = 1, gallbladder cancer: n = 1 or metastatic disease [colorectal liver metastasis]: n = 14, ovarian cancer: n = 1, gastric cancer: n = 1). Preoperative CT volumetry of the left lateral lobe showed 310 mL in median (range = 197–444 mL). After a median waiting period of 9 days (range = 5–28 days), the volume of the left lateral lobe had increased to 536 mL (range = 273–881 mL), representing a median volume increase of 74% (range = 21%–192%) (P < 0.001). The median left lateral liver lobe to body weight ratio was increased from 0.38% (range = 0.25%–0.49%) to 0.61% (range = 0.35–0.95). Ten of 25 patients (40%) required biliary reconstruction with hepaticojejunostomy. Rapid perioperative recovery was reflected by normalization of International normalized ratio (INR) (80% of patients), creatinine (84% of patients), nearly normal bilirubin (56% of patients), and albumin (64% of patients) values by day 14 after completion surgery. Perioperative morbidity was classified according to the Dindo-Clavien classification of surgical complications: grade I (12 events), grade II (13 events), grade III (14 events, III a: 6 events, III b: 8 events), grade IV (8 events, IV a: 3 events, IV b: 5 events), and grade V (3 events). Sixteen patients (68%) experienced perioperative complications. Follow-up was 180 days in median (range: 60–776 days) with an estimated overall survival of 86% at 6 months after resection. Conclusions:Two-step hepatic resection performing surgical exploration, PVL, and ISS results in a marked and rapid hypertrophy of functional liver tissue and enables curative resection of marginally resectable liver tumors or metastases in patients that might otherwise be regarded as palliative.

Right living donor liver transplantation ; An option for adult patients ; Single institution experience with 74 patients

Objective: To present an institutional experience with the use of right liver grafts in adult patients and to assess the practicability and efficacy of this procedure by analyzing the results. Summary Background Data: Living donor liver transplantation (LDLT) for the pediatric population has gained worldwide acceptance. In the past few years, LDLT has also become feasible for adult patients due to technical evolution in hepatobiliary surgery and increased experience with reduced-size and split-liver transplants. Nevertheless, some graft losses remain unexplained and are possibly due to unrecognized venous outflow problems. Methods: From April 1998 to September 2002, we performed 74 right LDLTs (segments 5–8). The 74 donors were selected from 474 candidates according to standard protocol. The median age of the donors was 35 years (range 18–58 years) and 51 years (range 18–64 years) in recipients. Standard and extended indications for transplantation were considered. Over the period reported, technical modifications in the bile duct anastomosis (duct-to-duct, end-to-end, or end-to-side) and a new graft implantation technique that provides maximized venous outflow, leading to outcome improvement, were developed. Results: 64.9% of patients had liver cirrhosis and 35.1% had malignancy. While 44 donors (59.5%) presented an uneventful postoperative course, 27% minor (pleural effusion, pneumonia, venous thrombosis, wound infection, incisional hernia) and 13.5% major (biliary leakage, death of a donor due to unrecognized hereditary liver disease, and consecutive liver insufficiency) complications were documented. In recipients, 23% biliary complications and 6.8% hepatic artery thrombosis occurred. The overall patient and graft survival rate after 1 year was 79.4% and 75.3%, respectively. In cases with extended indication, the patient survival rate was 74% and the graft survival rate 68% at 12 months. Using technical modifications in the last 10 recipients, including 2 critically decompensated cirrhotics, the survival rate was 100% at a median follow-up of 3.5 months. Conclusions: In our transplant program, living donor liver transplantation has become a standard option in the adult patient population. The critical issue of this procedure is donor morbidity. Technical improvements in the harvesting and implantation of right grafts can also offer hope to patients with challenging forms of end-stage liver disease or malignant liver tumors.

Experience after the evaluation of 700 potential donors for living donor liver transplantation in a single center

Adequate selection of donors is a major prerequisite for living donor liver transplantation (LDLT). Few centers report on the entire number of potential donors considered or rejected for living donation. From April 1998 to July 2003, a total of 111 living donor liver transplantations were performed at our institution, with 622 potential donors for 297 adult recipients and 78 potential donors for 52 pediatric recipients evaluated. In the adult group, only 89 (14%) potential donors were considered suitable, with a total of 533 (86%) potential donors rejected. Of these, 67% were excluded either at initial screening or during the first and second steps of the evaluation procedure. In 31% of all cases, the evaluation of donors was canceled because of recipient issues. In the pediatric group, 22 (28%) donors were selected, with the other 56 (72%) rejected. Costs of the complete evaluation process accounted for 4,589 Euro (€) per donor. The evaluation of a potential living donor is a complex and expensive process. We present the results on the evaluation of the largest group of potential donors for adults reported in the literature. Only 14% of potential donors in our series were considered suitable candidates. It has not yet been established who should cover the expenses of the evaluation of all rejected donors. In conclusion, all efforts should be made in order to develop an effective screening protocol for the evaluation of donors with the aim of saving time and resources for a liver transplantation program. (Liver Transpl 2004;10:1087–1096.)

A Randomized, Controlled Study to Assess the Conversion From Calcineurin-Inhibitors to Everolimus After Liver Transplantation—PROTECT

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal‐sparing alternative. In this randomized 1‐year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post‐LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft‐Gault formula (−2.9 mL/min in favor of EVR, 95%‐CI: [−10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (−7.8 mL/min, 95%‐CI: [−14.366; −1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy‐proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI‐based to EVR‐based immunosuppression proved to be a safe alternative post‐LTx that deserves further investigation in terms of nephroprotection.

Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) in childhood is a rare disease associated with high morbidity and mortality. Most cases progress to end-stage renal failure. In approximately 50% of affected patients, mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway. This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells, particularly in the kidneys. Complement factor H (FH) heterozygosity induces unregulated activation of the membrane attack complex (MAC) C5b-9. Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis. Unfortunately, kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post-transplantation HUS recurrence, particularly in patients with FH mutation. Combined liver–kidney transplantation is also associated with poor outcome, mostly as a result of premature liver failure secondary to uncontrolled complement activation. Eculizumab is a complement C5 antibody that inhibits complement factor 5a (C5a) and the formation of the MAC. Thus, this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation. We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation.

Volumetric and functional recovery of the liver after right hepatectomy for living donation

Our objective was to study the kinetics of recovery of the liver volume and liver function after right hepatectomy (RH) for living donation, comparing conventional and quantitative liver function tests, i.e., galactose elimination capacity (GEC). A total of 27 donors underwent RH averaging 61% of the whole liver volume. The conventional and quantitative liver function tests, as well as magnetic resonance imaging volumetric studies, were performed preoperatively at postoperative day (POD) 10, 90, 180, and 360. Mean residual volume increased by 88% within 10 days from RH and thereafter did not show any significant variation. After 1 year, only 83% of the original volume was reached. GEC per milliliter of liver volume expressed in percent of initial value (GEC/mL) showed a decrease of 25% at POD10, an increase up to 125% at POD 180, and returned to normal values at POD 360. Liver biochemistries, International Normalized Ratio (INR), and bilirubin returned to normal in 10 days. Cholinesterase showed a similar course like GEC. In conclusion, within 10 days of 61% loss of its initial volume, the liver is capable of regenerating a volume necessary to its function, although it corresponds to only 74% of the initial one. It takes only 10 days to normalize liver biochemistries, while cholinesterase and albumin recover over 90 days. However, a direct measure of the cytosolic liver function obtained by GEC shows that functional recovery occurs much more gradually than the recovery of volume and liver biochemistries. (Liver Transpl 2004;10:1024–1029.)

Living-related liver transplantation from the view of the donor: A 1-year follow-up survey

Background. In the past, follow-up surveys for living-related liver transplantation (LRLT) mainly focused on the medical outcome of recipients and donors. In this survey the prevalence of personal, familial, or economic problems of the donors and changes of quality of life after donation were studied. Methods. Questionnaires were sent to 24 donors after right hepatectomy for LRLT (response 92%). The modified EUROTOLD (European Multicenter Study of Transplantation Using Living Donors) questionnaire was used to inquire about the decision-making process, family problems, and economic problems related to the donation. Global quality of life was measured with the SF-36 Health Survey. Results. For most donors the decision to donate was easy or not very difficult (21/22) and was made spontaneously (17/22). The amount of information about the risks of LRLT was limited at the time of decision but increased remarkably immediately before the operation. In 28%, family conflicts occurred (5/22). Retrospectively, all but two donors (91%) would donate again. On average, donors started working after 9 (±3.7) weeks and felt fully recovered after 13 (±7.3) weeks. Adverse financial affects were experienced by 41% of the donors (9/22) because of the donation, and four of those received a compensation. Importantly, quality of life did not differ between donors and nondonors. Conclusion. Donors viewed LRLT positively. Quality of life after donation did not change. However, donors had a prolonged period of physical rehabilitation, and 41% experienced financial disadvantages.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ⩽60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Current trends in live liver donation

The introduction of living donor liver transplantation (LDLT) has been one of the most remarkable steps in the field of liver transplantation (LT), able to significantly expand the scarce donor pool in countries in which the growing demands of organs are not met by the shortage of available cadaveric grafts. Although the benefits of this procedure are enormous, the physical and psychological sacrifice of the donors is immense, and the expectations for a good outcome for themselves, as well as for the recipients, are high. We report a current overview of the latest trends in live liver donation in its different aspects (i.e. donors selection, evaluation, operation, morbidity, mortality, ethics and psychology). This review is based on our centers personal experience with almost 200 LDLTs and a detailed analysis of the international literature of the last 7 years about this topic. Knowing in detail how to approach to the different aspects of living liver donation may be helpful in further improve donors safety and even recipients outcome.

Transforming Growth Factor-β (TGF-β)-mediated Connective Tissue Growth Factor (CTGF) Expression in Hepatic Stellate Cells Requires Stat3 Signaling Activation

Background: HSC-derived CTGF is an important mediator of liver fibrogenesis. Results: Stat3 is an essential factor for TGF-β mediated CTGF expression in activated HSCs. Conclusion: TGF-β is using a complex signaling network including Stat3 to trigger CTGF production in HSCs. Significance: Stat3 is defined for the first time as crucial TGF-β downstream signaling mediator to regulate extracellular matrix production in liver. In fibrotic liver, connective tissue growth factor (CTGF) is constantly expressed in activated hepatic stellate cells (HSCs) and acts downstream of TGF-β to modulate extracellular matrix production. Distinct from other cell types in which Smad signaling plays major role in regulating CTGF production, TGF-β stimulated CTGF expression in activated HSCs is only in part dependent on Smad3. Other signaling molecules like MAPKs and PI3Ks may also participate in this process, and the underlying mechanisms have yet to be clarified. In this study, we report involvement of Stat3 activation in modulating CTGF production upon TGF-β challenge in activated HSCs. Stat3 is phosphorylated via JAK1 and acts as a critical ALK5 (activin receptor-like kinase 5) downstream signaling molecule to mediate CTGF expression. This process requires de novo gene transcription and is additionally modulated by MEK1/2, JNK, and PI3K pathways. Cell-specific knockdown of Smad3 partially decreases CTGF production, whereas it has no significant influence on Stat3 activation. The total CTGF production induced by TGF-β in activated HSCs is therefore, to a large extent, dependent on the balance and integration of the canonical Smad3 and Stat3 signaling pathways.