Hepatocellular carcinoma (HCC) is an increasingly common indication for liver transplantation (LT) in the United States and in many parts of the world. In the last decade, significant work has been done to better understand how to risk stratify LT candidates for recurrence of HCC following transplant using a combination of biomarker and imaging findings. However, despite the high frequency of HCC in the LT population, guidance regarding posttransplant management is lacking. In particular, there is no current evidence to support specific post‐LT surveillance strategies, leading to significant heterogeneity in practices. In addition, there are no current recommendations regarding recurrence prevention, including immunosuppression regimen or secondary prevention with adjuvant chemotherapy. Finally, guidance on treatment of disease recurrence is also lacking and there is significant controversy about the use of immunotherapy in transplant recipients due to the risk of rejection. Thus, outcomes for patients with recurrence are poor. This paper therefore provides a comprehensive review of the current literature on post‐LT management of patients with HCC and identifies gaps in our current knowledge that are in urgent need of further investigation.
Differentiating tumor versus bland portal vein thrombosis (PVT) is essential in determining liver transplantation (LT) candidacy for patients with hepatocellular carcinoma (HCC). We aimed to evaluate radiographic and clinical features that could noninvasively distinguish tumor PVT from bland PVT in HCC patients. Of 467 patients with HCC listed for LT from 2004 to 2011, 59 (12.6%) had PVT and 12 of 59 (20.3%) were deemed malignant. When comparing tumor versus bland PVT, thrombus enhancement was seen in 100% versus 8.5%; venous expansion was seen in 91.7% versus 10.6%; neovascularity was seen in 58.3% versus 2.1%; and being adjacent to HCC or prior treatment site was seen in 100% versus 21.3% (all P < 0.001). Combining these 4 imaging characteristics with alpha‐fetoprotein (AFP) >1000 ng/dL, the presence of ≥3 criteria best characterized tumor PVT with 100% sensitivity, 93.6% specificity, 80% positive predictive value, and 100% negative predictive value. No LT recipients with presumed bland PVT had macrovascular invasion on explant. There were no differences in post‐LT survival or HCC recurrence with bland PVT versus no PVT. In conclusion, we proposed noninvasive criteria that could accurately differentiate tumor PVT from bland PVT called A‐VENA, which is based on the presence of ≥3 of the following: AFP >1000 ng/dL; venous expansion; thrombus enhancement; neovascularity; and adjacent to HCC. Use of the A‐VENA criteria can assist in standardizing the evaluation of PVT in patients with HCC being considered for LT.
The beneficial effects of high-density lipoprotein (HDL) on atherosclerosis have largely been attributed to its major protein, apolipoprotein A-I (apoA-I). Used as a therapeutic intervention, apoA-I is a large protein that requires venous administration, and is both difficult and expensive to manufacture. Because of these problems with apoA-I, the generation of smaller, easier to manufacture apoA-I mimetic peptides has become a target for pharmacologic development in the therapeutic management of human atherosclerosis. A potent apoA-I mimetic peptide, 4F, was found to have significant activity in various inflammatory states in both mice and monkeys. The anti-inflammatory and antiatherogenic effects of 4F include increased pre-beta HDL formation, increased cholesterol efflux, the conversion of pro-inflammatory HDL to anti-inflammatory HDL, and reduced lipoprotein oxidation. In addition, improved arterial vasoreactivity is another important function of 4F. In a rat model of diabetes, D-4F increased arterial concentrations of heme oxygenase-1 (HO-1) and superoxide dismutase, decreased superoxide levels, reduced levels of circulating endothelial cells, decreased endothelial cell fragmentation, and restored arterial vasoreactivity to normal. In a mouse model of systemic sclerosis, D-4F functioned to improve vasodilation and angiogenic potential, while reducing myocardial inflammation and oxidative stress. With respect to mouse models of heart transplant-associated atherosclerosis, D-4F induced HO-1. In addition, D-4F was shown to improve cognitive performance in low-density lipoprotein-receptor null mice with Western diet-induced cognitive decline. D-4F also reduced the kidney content of oxidized phospholipids in a mouse model of hyperlipidemia-induced renal inflammation. In early human studies in patients with significant cardiovascular risk, a single dose of oral D-4F was found to safely improve the anti-inflammatory index of HDL. L-4F is also being studied in clinical trials as a potential treatment modality for obesity and the metabolic syndrome.
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