Optimal Timing of Administration of Direct-Acting Antivirals for Patients with Hepatitis C-Associated Hepatocellular Carcinoma Undergoing Liver Transplantation

Objective: To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). Summary of Background Data: In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. Methods: The United States HCC LT Consortium (2015–2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). Results: Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0–3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0–3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). Conclusions: The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results

Chronically Retained Central Venous Catheter in Deceased Donor Liver Allograft

Central venous catheters (CVC) are commonly used across multiple medical specialties and are inserted for various reasons. A known, but rare, serious complication of CVC is fracture and retention of residual catheter. Here we describe a chronically retained catheter within the inferior vena cava (IVC) that was asymptomatic and neither diagnosed nor addressed until time of deceased donor liver donation. Prior to transplantation into the recipient, the retained catheter was removed, and a venoplasty of the suprahepatic IVC, middle hepatic vein, and left hepatic vein was performed with no significant issues after transplant in the recipient. With the persistent shortage of suitable organs for transplant leading to patients dying on the waiting list, every good quality organ should be carefully considered. Thus, even though a chronically retained, fractured CVC in a deceased organ donor presents a unique challenge, it can be managed surgically and should not be considered a contraindication to organ utilization

Costimulatory blockade with belatacept in clinical and experimental transplantation - a review

BACKGROUND: Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade. However, long-term follow-up has revealed that these agents are associated with troublesome side effects and chronic toxicity, contributing to graft loss and death. OBJECTIVES: Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation. Belatacept, a high-affinity chimeric fusion protein that binds to CD80/CD86 on antigen-presenting cells, has shown great promise in renal transplantation and is now in Phase III trials. METHODS: This review explores the development and efficacy of belatacept, compared with currently approved immunosuppressive agents used in transplantation. RESULTS: Belatacept seems to be an effective alternative to current maintenance immunosuppressive therapies, with no apparent end organ toxicity and a minimal side-effect profile. This agent works best when used in combination with therapies that target different pathways of T-cell activation, but the optimal regimen has not yet been identified. Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept-based combinatorial strategies

New approaches to the diagnosis of rejection and prediction of tolerance in liver transplantation

Immunosuppression after liver transplantation is essential for preventing allograft rejection. However, long-term drug toxicity and associated complications necessitate investigation of immunosuppression minimization and withdrawal protocols. Development of such protocols is hindered by reliance on current paradigms for monitoring allograft function and rejection status. The current standard of care for diagnosis of rejection is histopathologic assessment and grading of liver biopsies in accordance with the Banff Rejection Activity Index. However, this method is limited by cost, sampling variability, and interobserver variation. Moreover, the invasive nature of biopsy increases the risk of patient complications. Incorporating noninvasive techniques may supplement existing methods through improved understanding of rejection causes, hepatic spatial architecture, and the role of idiopathic fibroinflammatory regions. These techniques may also aid in quantification and help integrate emerging -omics analyses with current assessments. Alternatively, emerging noninvasive methods show potential to detect and distinguish between different types of rejection while minimizing risk of adverse advents. Although biomarkers have yet to replace biopsy, preliminary studies suggest that several classes of analytes may be used to detect rejection with greater sensitivity and in earlier stages than traditional methods, possibly when coupled with artificial intelligence. Here, we provide an overview of the latest efforts in optimizing the diagnosis of rejection in liver transplantation

Hepatic Epithelioid Hemangioendothelioma Presenting as an Enlarging Vascular Lesion within the Spleen

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm with variable malignant potential that most often presents within the liver. Many patients present with bilobar or extrahepatic disease, and the current treatment paradigm involves liver transplantation, with favorable long term results. Up to 25% of patients are diagnosed incidentally following imaging for other indications, and confirmation of diagnosis requires histologic analysis, as there are no classical imaging features to distinguish hepatic EHE (HEHE) from other solid hepatic lesions. Here we describe a case of microscopic HEHE that was diagnosed following splenectomy for an enlarging vascular tumor within the spleen. Due to the unexpected diagnosis of EHE within the spleen and coexisting but stable appearing liver hemangiomata, a left hepatic lobectomy was performed. Explant histology revealed benign hemangiomata and diffuse, microscopic HEHE. The patient ultimately underwent liver transplantation. HEHE can be a challenging diagnosis, and this case emphasizes that any enlarging vascular lesion, even within the spleen, should prompt a high index of suspicion for HEHE in the setting of known hemangiomata

Assessment of long-term outcomes post living liver donation highlights the importance of scientific integrity when presenting transplant registry data.

Living donor liver transplantation has expanded in recent years, particularly in North America. As experience with this procedure has matured over the last 25&nbsp;years, centers are increasingly faced with potential living donors who are more medically complex. As donors move through the evaluation process, completing the informed consent process continues to be challenged by a paucity of granular data demonstrating long-term outcomes and overall safety specifically in the otherwise "healthy" living liver donor population. Two recently published studies examined long-term outcomes post-living liver donation using Korean registry data and reported similar results, with excellent overall survival when compared to appropriately matched controls. However, the authors of these studies were presented differently, with one reporting an alarmist view based on one aspect of a suboptimal analysis approach using an inappropriate comparator group. Herein, the North American Living Liver Donor Innovation Group (NALLDIG) consortium discusses these two studies and their potential impact on living liver donation in North America, ultimately highlighting the importance of scientific integrity in data presentation and dissemination when using transplant registry data

The caspase selective inhibitor EP1013 augments human islet graft function and longevity in marginal mass islet transplantation in mice

OBJECTIVE: Clinical islet transplantation can provide insulin independence in patients with type 1 diabetes, but chronic graft failure has been observed. This has been attributed in part to loss of ≥ 60% of the transplanted islets in the peritransplant period, resulting in a marginal implant mass. Strategies designed to maximize survival of the initial islet mass are likely to have major impact in enhancing long-term clinical outcomes. EP1013 (N-benzyloxycabonyl-Val Asp-fluoromethyl ketone [zVD-FMK]), is a broad-spectrum caspase selective inhibitor with no observed toxicity in rodents. RESEARCH DESIGN AND METHODS: The therapeutic benefit of EP1013 was examined in a syngeneic rodent islet transplant model using deceased donor human islets to determine whether the amount of tissue required to restore euglycemia in diabetic animals could be reduced. RESULTS: EP1013 (combined pretransplant islet culture for 2 h and in vivo treatment for days 0-5 posttransplant) significantly improved marginal islet mass function following syngeneic islet transplantation in mice, even at lower doses, compared with previous studies using the pan-caspase inhibitor N-benzyloxycabonyl-Val Ala-Asp-fluoromethyl ketone (zVAD-FMK). EP1013 supplementation in vitro improved human islet yields following prolonged culture and reversed diabetes following implantation of a marginal human islet mass (80-90% reduction) into mice. CONCLUSIONS: Our data suggest that EP1013 therapy will markedly reduce the islet mass required in clinical islet transplantation, improving insulin independence rates following single-donor infusion

Vascular endothelial growth factor expression in hepatic epithelioid hemangioendothelioma: Implications for treatment and surgical management

Epithelioid hemangioendothelioma (EHE) is a low-grade, malignant vascular tumor that most commonly presents within the liver. Patients with hepatic EHE are often candidates for liver transplantation as the disease is usually multifocal at diagnosis. Although these patients achieve excellent early outcomes post-transplant, there are very few data regarding tumor markers that can further direct chemotherapy in hepatic EHE to prevent recurrent disease. The purpose of this study was to analyze the expression of the angiogenic factor vascular endothelial growth factor (VEGF) and its receptors in hepatic EHE. Six patients with hepatic EHE were assessed for liver transplantation at our center. Pathology specimens of primary and recurrent EHE were analyzed by hematoxylin and eosin staining and by immunofluorescence for VEGF, fetal liver kinase 1 (Flk-1), and fms-related tyrosine kinase 1 (Flt-1) expression. Five patients underwent liver transplantation, and 1 patient underwent liver resection. Biopsy-proven recurrent EHE occurred in 3 patients. VEGF expression was present in 100% of the EHE specimens examined, whereas Flt-1 expression was present in only 1 sample, and Flk-1 was not observed in any of the specimens. In 1 patient with recurrent hepatic EHE post-liver transplantation, a progressive increase in the VEGF fluorescence intensity and distribution was observed. In conclusion, in this series, VEGF expression was observed in all hepatic EHE specimens analyzed. These data suggest that anti-VEGF chemotherapeutic agents will be of use in patients with hepatic EHE, particularly as a means of reducing the tumor volume prior to resection, as a means of treating unresectable or metastatic disease, or as an adjuvant therapy in the setting of liver transplantation