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Molecular diagnosis of rejection is emerging in kidney, heart, and lung transplant biopsies and could offer insights for liver transplant biopsies. We measured gene expression by microarrays in 235 liver transplant biopsies from 10 centers. Unsupervised archetypal analysis based on expression of previously annotated rejection-related transcripts identified 4 groups: normal "R1 normal " (N = 129), T cell-mediated rejection (TCMR) "R2 TCMR " (N = 37), early injury "R3 injury " (N = 61), and fibrosis "R4 late " (N = 8). Groups differed in median time posttransplant, for example, R3 injury 99 days vs R4 late 3117 days. R2 TCMR biopsies expressed typical TCMR-related transcripts, for example, intense IFNG-induced effects. R3 injury displayed increased expression of parenchymal injury transcripts (eg, hypoxia-inducible factor EGLN1). R4 late biopsies showed immunoglobulin transcripts and injury-related transcripts. R2 TCMR correlated with histologic rejection although with many discrepancies, and R4 late with fibrosis. R2 TCMR , R3 injury , and R4 late correlated with liver function abnormalities. Supervised classifiers trained on histologic rejection showed less agreement with histology than unsupervised R2 TCMR scores. No confirmed cases of clinical antibody-mediated rejection (ABMR) were present in the population, and strategies that previously revealed ABMR in kidney and heart transplants failed to reveal a liver ABMR phenotype. In conclusion, | 2157 MADILL-THOMSEN ET AL. 1 | INTRODUC TI ON Diagnosis of rejection in liver transplantation remains an important issue in clinical management. 1-4 The current standard-of-care (SOC) for liver biopsy diagnoses is histology, generally following Banff guidelines. 5 Histology is based on pattern recognition by experts, and assessments differ between observers. 6-11 Reported kappa values for pathology related to T cell-mediated rejection (TCMR) are low to moderate (0.15-0.62 12) especially when comorbidities are present, 7 leaving an unmet need for improvement in precision. Moreover, the diagnosis and prevalence of antibody-mediated rejection (ABMR) in liver transplants remain controversial. 5,13-15 Liver transplants present unique challenges because of their tolerogenic properties, inviting clinicians to consider reducing immunosuppression. 16-20 However, this practice requires a precise and accurate system for diagnosing rejection. 21-25 Liver function test abnormalities are associated with rejection but cannot distinguish TCMR from other diseases such as steatohepatitis. 26,27 Molecular measurement of gene expression using microarrays coupled with machine learning has the potential to improve the assessment of transplant biopsies by overcoming the limitations of conventional diagnostics. 28 We previously developed the Molecular Microscope ® Diagnostic System (MMDx) for kidney, 29-32 heart, 33,34 and lung transplants. 35-37 A number of factors argue that MMDx testing is more accurate than histology 29 : for example, use of continuous quantitative measurements, 29 low samplin...

BackgroundCombination of the University of California, San Francisco (UCSF) and the up-to-7 criteria with alpha-fetoprotein (AFP) cutoff of 100 ng/ml was proposed as the Warsaw expansion of the Milan criteria in selection of hepatocellular cancer (HCC) patients for liver transplantation. The purpose of this retrospective study was to validate this proposal.MethodsA total of 240 HCC patients after liver transplantation were included. Recurrence-free survival and overall survival at 5 years were set as the primary and secondary outcome measures, respectively.ResultsThe Warsaw expansion increased transplant eligibility rate by 20.3 %. AFP >100 ng/ml significantly increased the recurrence risk in patients within the Milan criteria (p = 0.025) and in those beyond, yet within either the UCSF or the up-to-7 criteria (p < 0.001). Recurrence-free survival at 5 years was 90.8 % for patients within the Milan criteria, 100.0 % in patients within the Warsaw expansion, 54.9 % in patients beyond the Warsaw expansion but within either the UCSF or the up-to-7 criteria, and 45.1 % in patients beyond both the UCSF and the up-to-7 criteria (p < 0.001). The corresponding overall survival rates were 71.6, 82.4, 64.3, and 55.3 %, respectively (p = 0.027).ConclusionsThe Warsaw expansion of the Milan criteria substantially increases the recipient pool without compromising outcomes.