Clinical factors affecting rejection rates in liver transplantation.

BACKGROUND: With improvements in survival, liver transplant recipients now suffer more morbidity from long-term immunosuppression. Considerations were given to develop individualized immunosuppression based on their risk of rejection. METHOD: We retrospectively analyzed the data of 788 liver transplants performed during the period from October 1991 to December 2011 to study the relationship between acute cellular rejection (ACR) and various clinical factors. RESULTS: Multivariate analysis showed that older age (P=0.04, OR=0.982), chronic hepatitis B virus infection (P=0.005, OR= 0.574), living donor liver transplantation (P=0.02, OR=0.648) and use of interleukin-2 receptor antagonist on induction (P<0.001, OR=0.401) were associated with fewer ACRs. Patients with fulminant liver failure (P=0.004, OR=4.05) were more likely to develop moderate to severe grade ACR. CONCLUSIONS: Liver transplant recipients with older age, chronic hepatitis B virus infection, living donor liver transplantation and use of interleukin-2 receptor antagonist on induction have fewer ACR. Patients transplanted for fulminant liver failure are at higher risk of moderate to severe grade ACR. These results provide theoretical framework for developing individualized immunosuppression.

Durability of small-for-size living donor allografts.

Our aim was to study the long-term outcomes of living donor liver transplantation using small-for-size (SFS) grafts. From July 2002 to July 2009, 233 patients received a right liver graft with a middle hepatic vein from a living donor in our center. Recipients were stratified according to the graft weight to recipient standard liver volume (GW/SLV) ratio into 4 groups: >50% (n = 89), >40% to 50% (n = 85), >35% to 40% (n = 38), and ≤ 35% (n = 21). They were compared in terms of graft survivals, biliary stricture rates, renal function in terms of estimated glomerular filtration rate (eGFR), platelet counts, and graft function in terms of serum bilirubin and international normalized ratio (INR). The 5-year graft survivals for patients with GW/SLV of >50%, >40% to 50%, >35% to 40% and ≤ 35% were 88.8%, 88.2%, 81.5%, and 81.0%, respectively. Transplantation for hepatocellular carcinoma affected graft survivals (P = 0.02), but graft size did not (P = 0.66). There were no differences in frequency of biliary stricture (21.3% versus 17.1% versus 21.1% versus 28.6%; P = 0.75). At each year after transplant, their platelet counts (P = 0.12-0.65), eGFR (P = 0.49-0.91), bilirubin (P = 0.14-0.51), and INR (P = 0.20-0.98) remained comparable. SFS grafts with GW/SLV ≤ 35% and >35% to 40% had comparable long-term outcomes with larger liver grafts. Graft size did not affect long-term graft survivals.

The friendly incidental portal vein thrombus in liver transplantation.

Improved outcomes have been shown in liver transplantation (LT) with portal vein thrombosis (PVT). However, PVT is still discovered incidentally during surgery despite careful preoperative imaging. Data are limited comparing the outcomes of incidental PVT with PVT diagnosed via preoperative imaging before LT. This study aims to compare the overall outcomes of patients with PVT. From 2008 to 2012, 369 patients had LT, and 58 patients with PVT were identified. They were divided into those with non-PVT (group 0; n = 311), preoperatively identified PVT (group 1; n = 28), and incidental PVT (group 2; n = 30). The demographics, characteristics, preoperative assessment, and postoperative outcomes were compared. A survival analysis was also performed. Baseline characteristics and preoperative evaluations of all 3 groups were comparable (P > 0.05) except for Model for End-Stage Liver Disease score, tumor status, platelet levels, and serum bilirubin. A multivariate analysis only showed a high serum bilirubin level to be a predictor of PVT (P = 0.004; odds ratio, 3.395; 95% confidence interval, 1.467-7.861). Postoperative outcomes were also comparable (P > 0.05). Compared to group 2, group 1 had more patients with a Yerdel classification of 3 or 4 with more extensive surgical intervention required (P = 0.02). The survival analysis in all 3 groups was comparable with 5-year survival rate of 87.4%, 84.6%, and 91.8% in group 0, 1, and 2, respectively (P = 0.66). In conclusion, recipients with PVT undergoing LT can have similar outcomes as the non-PVT patients even if PVTs were discovered incidentally. Discovery of incidental PVT only requires thrombectomy with no substantial change of treatment strategy, and the outcome is not adversely affected because most incidental PVTs are of a lower Yerdel grade. Preoperative imaging is useful to identify those with a higher Yerdel grade to allow planning of surgical strategy during transplantation.

Section 3. Current status of downstaging of hepatocellular carcinoma before liver transplantation.

Liver transplantation (LT) is a well-established option of cure for hepatocellular carcinoma (HCC). Milan criteria is recognized as standard for selection of patients and set the baseline of survival to be achieved. It has been shown that tumor biology including differentiation, vascular invasion, and serum α-fetoprotein (AFP) predict posttransplant recurrence and survival better than morphology. Downstaging by locoregional therapies of HCC before LT, with the response to treatments and progression within observation period, serves as a selection tool rather than modulation of tumor biology. It selects those patients outside standard criteria at presentation but good tumor biology and high chance of good outcome to receive transplantation. The definition of downstaging should be differentiated from neo-adjuvant therapy, and the objectives in surgical and pretransplant candidates also differ.Published studies in this area showed variation in inclusion criteria, downstaging protocol and assessment of successful downstaging. Tumor biology predownstaging and postdownstaging was not incorporated. Posttransplant outcome were not clearly stated with regard to intention-to-treat survival, disease-free survival, and comparison against those originally within criteria. Meta-analysis of these results was impossible. Nevertheless, majority had reasonable protocol and were able to select patients whom likely to have good outcome. At present, there is no evidence that downstaged patients have a poorer prognosis than those presenting within the Milan criteria. Patients with tumors outside Milan criteria should be offered downstaging therapies. Those who are successfully downstaged to within Milan criteria should be eligible to liver transplant as same as those initially fit the criteria. In the last decade, various extended criteria of HCC for LT have been proposed and reported satisfactory survival. That makes downstaging technically unnecessary.To refine and validate the role of downstaging, it needs collaborative and prospective study with significant sample size, adequate preoperative staging, standardized protocol of selection of patients, and approaches to downstaging. Selection criteria should include histopathological data on tumor biology and serum AFP. There should be standardized definition of successful downstaging. Posttransplant disease-free survival should be reported in detail and compared with those who fit the standard criteria initially. A consistent immunosuppressant protocol is important to avoid bias.

Rescue Living-donor Liver Transplantation for Liver Failure Following Hepatectomy for Hepatocellular Carcinoma.

Liver failure following major hepatectomy for hepatocellular carcinoma is a known but uncommon mode of early treatment failure. When post-hepatectomy liver failure becomes progressive, the only effective treatment for rescuing the patient is liver transplantation. Deceased-donor liver transplantation in this situation is often not feasible because of the shortage of deceased-donor liver grafts. Proceeding with living-donor liver transplantation is an ethical challenge because of the possibility of donor coercion. In addition, tumor status, as confirmed by histopathological examination of the resected specimen, may indicate aggressive cancer that warns against rescue transplantation because of the increased chance of tumor recurrence. Here we describe four cases of rescue living-donor liver transplantation for liver failure after hepatectomy for hepatocellular carcinoma. The patients all survived the transplantation and were free from tumor recurrence after follow-up periods ranging from 6 months to 9 years. Our experience has shown that rescue living-donor liver transplantation for post-hepatectomy liver failure is feasible. Tumor status should be considered carefully because large tumors and tumors with macrovascular invasion are strong contraindications to rescue living-donor liver transplantation.

Can positron emission tomography with the dual tracers [11 C]acetate and [18 F]fludeoxyglucose predict microvascular invasion in hepatocellular carcinoma?

Microvascular invasion is a poor prognostic indicator of the recurrence of hepatocellular carcinoma (HCC) after surgical treatment. Positron emission tomography (PET) with [(18) F]fludeoxyglucose ([(18) F]FDG) as a tracer has been employed to predict the prognosis before surgery for various kinds of tumors, but it has not been found to be sensitive enough for HCC. Thus, [(11) C]acetate has been adopted as an additional tracer. This study was designed to evaluate the ability of dual-tracer PET ([(18) F]FDG and [(11) C]acetate) to predict microvascular invasion before liver resection or transplantation. Fifty-eight HCC patients who were preoperatively examined with whole-body dual-tracer PET were studied. Twenty-five patients were [(18) F]FDG-positive, and 56 were [(11) C]acetate-positive. The sensitivity of [(18) F]FDG in detecting primary HCC was 43%, and the sensitivity of [(11) C]acetate was 93%. Twenty-nine patients had HCC with microvascular invasion according to the final pathological examination. The sensitivity, specificity, positive predictive value, and negative predictive value of [(18) F]FDG PET in predicting microvascular invasion were 55.2%, 69%, 64%, and 60.6%, respectively; the corresponding rates for [(11) C]acetate PET were 93.1%, 0%, 48.2%, and 0%. The factors associated with HCC recurrence, which included multifocal involvement, a large tumor size, microsatellite lesions, poor HCC differentiation, and an advanced stage of disease, were analyzed and compared with positive PET results. A tumor size greater than 5 cm was significantly associated with positive [(18) F]FDG PET results; [(11) C]acetate was not associated with poor prognostic indicators. Preoperative [(18) F]FDG PET may predict microvascular invasion. The addition of [(11) C]acetate improves the overall sensitivity of PET, but it has no incremental value in predicting microvascular invasion.

Bile duct anastomotic stricture after adult-to-adult right lobe living donor liver transplantation.

Duct-to-duct anastomosis (DDA) and hepaticojejunostomy (HJ) are options for biliary reconstruction in patients undergoing adult-to-adult right lobe living donor liver transplantation (ARLDLT), after which biliary anastomotic stricture (BAS) is common as a complication. The risk factors for BAS are not clearly defined. We aimed to determine the rate of post-ARLDLT BAS in our center and its associated factors. In 265 ARLDLT recipients, 55 (20.8%) developed postoperative BAS. The diagnosis was based on clinical, biochemical, histological, and radiological results. The BAS rates were 21.4% (43/201) for recipients undergoing DDA during transplantation, 18.9% (10/53) for recipients undergoing HJ, and 18.2% (2/11) for recipients undergoing both procedures. BAS and non-BAS patients had comparable demographics. The number of graft bile duct openings (P = 0.516) and the size of the graft's smallest bile duct (5 versus 5 mm, P = 0.4) were not significantly different between BAS and non-BAS patients. Univariate analysis showed that the factors associated with postoperative BAS were the recipient warm ischemia time (55 versus 51 minutes, P = 0.026), graft cold ischemia time (120 versus 108 minutes, P = 0.046), stent use (21.8% versus 7.1%, P = 0.001), postoperative acute cellular rejection (29.1% versus 11.0%, P = 0.001), and University of Wisconsin solution use (21.8% versus 7.1%, P = 0.001). Multivariate analysis showed that the cold ischemia time (odds ratio = 1.012, 95% confidence interval = 1.002-1.023, P = 0.014) and acute rejection (odds ratio = 3.180, 95% confidence interval = 1.606-6.853, P = 0.002) were significant factors. The graft survival rates of BAS and non-BAS patients were comparable. One patient required retransplantation for secondary biliary cirrhosis. In conclusion, BAS remains common after ARLDLT regardless of DDA or HJ. The graft cold ischemia time and postoperative acute cellular rejection are significantly associated with postoperative BAS.