ABSTRACT
Long-term systemic immunosuppression is needed for vascularized composite allotransplantation (VCA). The high rate of acute rejection episodes in the first posttransplant year, the development of chronic rejection, and the adverse effects that come along with this treatment, currently prevent a wider clinical application of VCA. Opportunistic infections and metabolic disturbances are among the most observed side effects in VCA recipients. To overcome these challenges, local immunosuppression using biomaterial-based drug delivery systems (DDS) have been developed. The aim of these systems is to provide high local concentrations of immunosuppressive drugs while reducing their systemic load. This review provides a summary of recently investigated local DDS with different mechanisms of action such as on-demand, ultrasound-sensitive, or continuous drug delivery. In preclinical models, ranging from rodent to porcine and nonhuman primate models, this approach has been shown to reduce systemic tacrolimus (TAC) load and adverse effects, while prolonging graft survival. Localized immunosuppression using biomaterial-based DDS represents an encouraging approach to enhance graft survival and reduce toxic side effects of immunosuppressive drugs in VCA patients. Preclinical models using TAC-releasing DDS have demonstrated high local immunosuppressive effects with a low systemic burden. However, to reduce acute rejection events in translational animal models or in the clinical reality, the use of additional low-dose systemic TAC treatment may be envisaged. Patients may benefit through efficient graft immunosuppression and survival with negligible systemic adverse effects, resulting in better compliance and quality of life.
ABSTRACT
BACKGROUND & AIM: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has a poor prognosis, and the adjusted effect of different treatments on post-recurrence survival (PRS) has not been well defined. This study aims to evaluate prognostic and predictive variables associated with PRS. METHODS: This Latin American multicenter retrospective cohort study included HCC patients who underwent LT between the years 2005-2018. We evaluated the effect of baseline characteristics at time of HCC recurrence diagnosis and PRS (Cox regression analysis). Early recurrences were those occurring within 12 months of LT. To evaluate the adjusted treatment effect for HCC recurrence, a propensity score matching analysis was performed to assess the probability of having received any specific treatment for recurrence. RESULTS: From a total of 1085 transplanted HCC patients, the cumulative incidence of recurrence was 16.6% (CI 13.5-20.3), with median time to recurrence of 13.0 months (IQR 6.0-26.0). Factors independently associated with PRS were early recurrence (47.6%), treatment with sorafenib and surgery/trans-arterial chemoembolization (TACE). Patients who underwent any treatment presented "early recurrences" less frequently, and more extrahepatic metastasis. This unbalanced distribution was included in the propensity score matching, with correct calibration and discrimination (receiving operator curve of 0.81 [CI 0.72;0.88]). After matching, the adjusted effect on PRS for any treatment was HR of 0.2 (0.10;0.33); P < .0001, for sorafenib therapy HR of 0.4 (0.27;0.77); P = .003, and for surgery/TACE HR of 0.4 (0.18;0.78); P = .009. CONCLUSION: Although early recurrence was associated with worse outcome, even in this population, systemic or locoregional treatments were associated with better PRS.
