As hepatitis C virus (HCV) infection is now curable, HCV-positive donor organs have expanded the deceased donor pool. Using OPTN data, we identified adult kidney, liver, heart, and lung candidates listed between 2016-2025 and evaluated rates of consent to accept HCV antibody-positive (Ab+) and HCV viremic (NAT+) organs. Temporal trends were described, and multilevel modified Poisson regression with center-level random effects was used to estimate adjusted risk ratios for candidate factors and quantify center variation using median incidence rate ratios (MIRR). Rates of consent to accept both HCV Ab+ and NAT+ organs rose over time. By the end of follow-up, consent rates for HCV Ab+ organs were 63.1% for kidney, 80.6% for liver, 73.3% for heart, and 72.1% for lung candidates, and consent rates for NAT+ organs were 44.9%, 70.7%, 50.5%, and 46.1%, respectively. Associations between candidate characteristics and consent were small after adjustment for center, whereas center effects were large. For HCV Ab+ organs, MIRRs were 6.31 (kidney), 2.48 (liver), 2.90 (heart), and 4.36 (lung); for NAT+ organs, MIRRs were even higher, 9.65, 3.19, 4.00, and 7.30, respectively, indicating marked between-center variability. Our analyses suggest that access to HCV-positive organs is influenced more by center practices than patient characteristics.

The clinical management of hepatocellular carcinoma (HCC) has evolved significantly over the past decade. Key advances include the introduction of immune-based treatment options, which now serve as the foundation for systemic therapies. Additionally, innovations in surgical techniques, such as robotic surgery, have broadened the scope of resection to include selected patients previously deemed unsuitable due to factors like tumor location or the presence of portal hypertension. HCC downstaging has also gained recognition as a viable strategy in appropriately selected patients, demonstrating outcomes comparable to those achieved under conventional listing criteria. Consequently, the management of HCC has become increasingly complex, underscoring the critical importance of multidisciplinary collaboration and shared decision-making. In this review, we provide a concise overview of practical recommendations for HCC management, encompassing aspects such as risk stratification, early detection, diagnosis, and treatment strategies.

1Pediatric Liver Transplant Program, Children's Hospital of Los Angeles, Los Angeles, CA, USA 2USC Transplant Institute, Keck Medical Center of University of Southern California, Los Angeles, CA, USA 3NYU Langone Transplant Institute, NYU Langone Health, New York, NY,USA 4Ajmera Transplant Center, University Health Network, Toronto, Canada 5Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, Canada 6Transplant and Regenerative Medicine Center, The Hospital for Sick Children, Toronto, Canada Correspondence Blayne Amir Sayed, The Hospital for Sick Children, Division of General and Thoracic Surgery, 555 University Avenue, Toronto, Ontario, Canada M5G 1×8 Email: [email protected]

Artificial Intelligence (AI) can be a useful tool in the management of disease processes such as hepatocellular carcinoma (HCC) as treatment decisions are often complex and multifaceted. AI applications in medicine are expanding with the ongoing advances in AI including more sophisticated machine learning and deep learning processes. In preliminary studies, AI algorithms have demonstrated superiority in predicting the development of HCC compared with standard models. Radiomics, a quantitative method used to extract features from medical imaging, has been applied to numerous liver imaging modalities to aid in the diagnosis and prognostication of HCC. Deep learning methodologies can help us to identify patients at higher likelihood of disease progression and improve risk stratification. AI applications have expanded into the field of surgery as models not only help us to predict surgical outcomes but AI methodologies are also used intra-operatively, in real time, to help us to define anatomic structures and aid in the resection of complex lesions. In this review, we discuss promising applications of AI in the management of HCC. While further clinical validation is warranted to improve generalizability through the inclusion of larger and more diverse populations, AI is expected to play a central role in assisting clinicians with the management of complex disease processes such as HCC.

With the increasing incidence of hepatocellular carcinoma (HCC) in both the United States and globally, the role of liver transplantation in management continues to be an area of active conversation as it is often considered the gold standard in the treatment of HCC. The use of living donor liver transplantation (LDLT) and the indications in the setting of malignancy, both generally and in HCC specifically, are frequently debated. In terms of both overall survival and recurrence-free survival, LDLT is at least equivalent to DDLT, especially when performed for disease within Milan criteria. Emerging and compelling evidence suggests that LDLT is superior to DDLT in treating HCC as there is a significant decrease in waitlist mortality. As the oncologic indications for liver transplantation continue to expand and the gap between organ demand and organ availability continues to worsen, high volumes centers should consider using LDLT to shrink the ever-expanding waitlist.

Figure Legends for Figures S1-S8.

Kim, Jacqueline I.1; Torres-Hernandez, Alejandro1; Griesemer, Adam1,2 Author Information

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03322-8.

Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFαlow CD206hi phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.

The drivers and the specification of CD4 + T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T H -program. Specifically, CD11b + CD103 − DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 neg tumor-promoting IL-10 + IL-17 + IFNγ + regulatory CD4 + T cells. The balance between this distinctive T H program and canonical FoxP3 + T REGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T H -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b + CD103 − DC promote CD4 + T cell tolerance in PDA which may underscore its resistance to immunotherapy.

Background and Aims The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). Approach and Results We found that in SH, γδT cells are recruited to the liver by C‐C chemokine receptor (CCR) 2, CCR5, and nucleotide‐binding oligomerization domain‐containing protein 2 signaling and are skewed toward an interleukin (IL)‐17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand–dependent manner. γδT cells exhibit a distinct Vγ4+, PD1+, Ly6C+CD44+ phenotype in SH. Moreover, γδT cells up‐regulate both CD1d, which is necessary for lipid‐based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL‐17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet‐induced SH and accelerates disease resolution. Conclusions We demonstrate that hepatic γδT cells exacerbate SH, independent of IL‐17 expression, by mitigating conventional CD4+ T‐cell expansion and modulating their inflammatory program by CD1d‐dependent vascular endothelial growth factor expression.

Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease that is characterised by steatosis, chronic inflammation, and hepatocellular injury with or without fibrosis. The role and activation of macrophages in the pathogenesis of NASH is complex and is being studied for possible therapeutic options to help the millions of people diagnosed with the disease. The purpose of this review is to discuss the pathogenesis of NASH through the activation and role of Kupffer cells and other macrophages in causing inflammation and progression of NASH. Furthermore, this review aims to outline some of the current therapeutic options targeting the pathogenesis of NASH.

Abstract We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403–16. ©2018 AACR. See related commentary by Riquelme et al., p. 386. This article is highlighted in the In This Issue feature, p. 371