Citations

As with any other intervention in health, liver transplantation (LT) entails a variety of risks, including donor-transmitted cancers (DTCs). At present, 2%–4% of used deceased organ donors are known to have a current or past history of malignancy. The frequency of DTCs is consistently reported at 3–6 cases per 10 000 solid organ transplants, with a similar frequency in the LT setting. A majority of DTCs are occult cancers unknown in the donor at the time of transplantation. Most DTCs are diagnosed within 2 y after LT and are associated with a 51% probability of survival at 2 y following diagnosis. The probability of death is greatest for DTCs that have already metastasized at the time of diagnosis. The International Liver Transplantation Society-Sociedad Española de Trasplante Hepático working group on DTC has provided guidance on how to minimize the occurrence of DTCs while avoiding the unnecessary loss of livers for transplantation both in deceased and living donor LT. The group endorses the Council of Europe classification of risk of transmission of cancer from donor to recipient (minimal, low to intermediate, high, and unacceptable), classifies a range of malignancies in the liver donor into these 4 categories, and recommends when to consider LT, mindful of the risk of DTCs, and the clinical condition of patients on the waiting list. We further provide recommendations to professionals who identify DTC events, stressing the need to immediately alert all stakeholders concerned, so a coordinated investigation and management can be initiated; decisions on retransplantation should be made on a case-by-case basis with a multidisciplinary approach.

Abstract Cholangiocarcinoma (CCA) represents the second‐most common primary liver malignancy after HCC and has risen in incidence globally in the past decades. Intrahepatic cholangiocarcinoma (iCCA) comprises 20% of all CCAs, with the rest being extrahepatic (including perihilar [pCCA] and distal CCA). Though long representing an absolute contraindication for liver transplantation (LT), recent analyses of outcomes of LT for iCCA have suggested that iCCA may be a potentially feasible option for highly selected patients. This has been motivated both by successes noted in outcomes of LT for other malignancies, such as HCC and pCCA, and by several retrospective reviews demonstrating favorable results with LT for a selected group of iCCA patients with small lesions. LT for iCCA is primarily relevant within two clinical scenarios. The first includes patients with very early disease (single tumor, ≤2 cm) with cirrhosis and are not candidates for liver resection (LR). The second scenario is patients with locally advanced iCCA, but where the extent of LR would be too extensive to be feasible. Preliminary single‐center reports have described LT in a selected group of patients with locally advanced tumors who have responded to neoadjuvant therapy and have a period of disease stability. Currently, there are three prospective trials underway that will help clarify the role of LT in iCCA. This review seeks to explore the available studies involving LT for iCCA, the challenges of ongoing trials, and opportunities for the future.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10‐5) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10‐6). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68Ga‐PSMA‐11 standardized uptake value: SUVmax (median [range] 9.2 [4.9‐28.4]), SUVmean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.

Abstract The burden of HCC is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process‐based measures and patient‐reported outcomes (PROs) along the HCC care continuum. We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13‐member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate PROs based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha‐fetoprotein [AFP]) every 6 months, need for surveillance in high‐risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging‐Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high‐risk population.

Background. As the number of donation after circulatory death (DCD) liver transplants (LTs) performed in the United States continues to increase annually, there has been interest by policy makers to develop a more robust exception point safety net for patients who develop ischemic cholangiopathy (IC) following DCD LT. As such, there is a need for better understanding of the clinical course and long-term outcomes in patients who develop IC, as well as determining if IC can be classified into distinct categories with distinctly different clinical outcomes. Methods. All DCD LT performed at Mayo Clinic Florida, Mayo Clinic Arizona, and Mayo Clinic Rochester from January 1999 to March 2020 were included (N = 770). Outcomes were compared between 4 distinct radiologic patterns of IC: diffuse necrosis, multifocal progressive, confluence dominant, and minor form. Results. In total, 88 (11.4%) patients developed IC, of which 42 (5.5%) were listed for retransplantation of liver (ReLT). Patients with diffuse necrosis and multifocal progressive patterns suffered from frequent hospital admissions for cholangitis in the first year following DCD LT (median 3 and 2), were largely stent dependent (100% and 85.7%), and almost universally required ReLT. Patients with confluence dominant disease were managed with multiple stents and frequently recovered, ultimately becoming stent free without need for ReLT. Patients with the minor form IC did well with limited need for stent placement or repeat procedures and did not require ReLT. Graft survival was different between the 4 distinct IC patterns ( P < 0.001). Conclusions. The present analysis provides a detailed analysis on the natural history and clinical course of IC. Patients developing IC can be classified into 4 distinct patterns with distinct clinical courses.

Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory disease of the biliary tract characterized by cellular senescence and periportal fibrogenesis. Specific disease features that are cell intrinsic and either genetically or epigenetically mediated remain unclear due in part to a lack of appropriate, patient‐specific, in vitro models. Recently, our group developed systems to create induced pluripotent stem cell (iPSC)‐derived cholangiocytes (iDCs) and biliary epithelial organoids (cholangioids). We use these models to investigate whether PSC cholangiocytes are intrinsically predisposed to cellular senescence. Skin fibroblasts from healthy controls and subjects with PSC were reprogrammed to pluripotency, differentiated to cholangiocytes, and subsequently grown in three‐dimensional matrigel‐based culture to induce formation of cholangioids. RNA sequencing (RNA‐seq) on iDCs showed significant differences in gene expression patterns, including enrichment of pathways associated with cell cycle, senescence, and hepatic fibrosis, that correlate with PSC. These pathways also overlapped with RNA‐seq analysis on isolated cholangiocytes from subjects with PSC. Exome sequencing on the subjects with PSC revealed genetic variants of unknown significance in the genes identified in these pathways. Three‐dimensional culture revealed smaller size, lack of a central lumen, and increased cellular senescence in PSC‐derived cholangioids. Congruent with this, PSC‐derived iDCs showed increased secretion of the extracellular matrix molecule fibronectin as well as the inflammatory cytokines interleukin‐6, and chemokine (C‐C motif) ligand 2. Conditioned media (CM) from PSC‐derived iDCs more potently activated hepatic stellate cells compared to control CM. Conclusion: We demonstrated efficient generation of iDCs and cholangioids from patients with PSC that show disease‐specific features. PSC cholangiocytes are intrinsically predisposed to cellular senescence. These features are unmasked following biliary differentiation of pluripotent stem cells and have functional consequences in epithelial organoids.