Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: A multicenter, retrospective cohort study.

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.

An integrated proteomics and metabolomics approach to assess graft quality and predict early allograft dysfunction after liver transplantation: a retrospective cohort study.

BACKGROUND: Early allograft dysfunction (EAD) is a common complication after liver transplantation (LT) and is associated with poor prognosis. Graft itself plays a major role in the development of EAD. We aimed to reveal the EAD-specific molecular profiles to assess graft quality and establish EAD predictive models. METHODS: A total of 223 patients who underwent LT were enrolled and divided into training (n=73) and validation (n=150) sets. In the training set, proteomics was performed on graft biopsies, together with metabolomics on paired perfusates. Differential expression, enrichment analysis, and protein-protein interaction network were used to identify the key molecules and pathways involved. EAD predictive models were constructed using machine learning and verified in the validation set. RESULTS: A total of 335 proteins were differentially expressed between the EAD and non-EAD groups. These proteins were significantly enriched in triglyceride and glycerophospholipid metabolism, neutrophil degranulation, and the MET-related signaling pathway. The top 12 graft proteins involved in the aforementioned processes were identified, including GPAT1, LPIN3, TGFB1, CD59, and SOS1. Moreover, downstream metabolic products, such as lactate dehydrogenase, interleukin-8, triglycerides, and the phosphatidylcholine/phosphorylethanolamine ratio in the paired perfusate displayed a close relationship with the graft proteins. To predict the occurrence of EAD, an integrated model using perfusate metabolic products and clinical parameters showed areas under the curve of 0.915 and 0.833 for the training and validation sets, respectively. It displayed superior predictive efficacy than that of currently existing models, including donor risk index and D-MELD scores. CONCLUSIONS: We identified novel biomarkers in both grafts and perfusates that could be used to assess graft quality and provide new insights into the etiology of EAD. Herein, we also offer a valid tool for the early prediction of EAD.

Integrated chromosomal instability and tumor microbiome redefined prognosis-related subtypes of pancreatic cancer.

BACKGROUND: Pancreatic cancer is a common malignancy with poor prognosis and limited treatment. Here we aimed to investigate the role of host chromosomal instability (CIN) and tumor microbiome in the prognosis of pancreatic cancer patients. METHODS: One hundred formalin-fixed paraffin-embedded (FFPE) pancreatic cancer samples were collected. DNA extracted from FFPE samples were analyzed by low-coverage whole-genome sequencing (WGS) via a customized bioinformatics workflow named ultrasensitive chromosomal aneuploidy detector. RESULTS: Samples are tested according to the procedure of ultrasensitive chromosomal aneuploidy detector (UCAD). We excluded 2 samples with failed quality control, 1 patient lost to follow-up and 6 dead in the perioperative period. The final 91 patients were admitted for the following analyses. Thirteen (14.3%) patients with higher CIN score had worse overall survival (OS) than those with lower CIN score. The top 20 microbes in pancreatic cancer samples included 15 species of bacteria and 5 species of viruses. Patients with high human herpesvirus (HHV)-7 and HHV-5 DNA reads exhibited worse OS. Furthermore, we classified 91 patients into 3 subtypes. Patients with higher CIN score (n =13) had the worst prognosis (median OS 6.9 mon); patients with lower CIN score but with HHV-7/5 DNA load (n = 24) had worse prognosis (median OS 10.6 mon); while patients with lower CIN score and HHV-7/5 DNA negative (n = 54) had the best prognosis (median OS 21.1 mon). CONCLUSIONS: High CIN and HHV-7/5 DNA load were associated with worse survival of pancreatic cancer. The novel molecular subtypes of pancreatic cancer based on CIN and microbiome had prognostic value.

Development and validation of a nomogram model for predicting chronic kidney disease after liver transplantation: a multi-center retrospective study.

Chronic kidney disease (CKD) is a frequent complication after liver transplantation (LT) and associated with poor prognosis. In this study, we retrospectively analyzed 515 adult patients who underwent LT in our center. They were randomly divided into a training set (n = 360) and an internal test set (n = 155). Another 118 recipients in other centers served as external validation set. Univariate and multivariate COX regression analysis were used to determine risk factors. A nomogram model was developed to predict post-LT CKD. The incidence of post-LT CKD in our center was 16.9% (87/515) during a median follow-up time of 22.73 months. The overall survival of recipients with severe CKD (stage IV and V) were significantly lower than those with non or mild CKD (stage III) (p = 0.0015). A nomogram model was established based on recipient's age, anhepatic phase, estimated glomerular filtration rate and triglyceride levels at 30 days after LT. The calibration curves for post-LT CKD prediction in the nomogram were consistent with the actual observation in both the internal and external validation set. In conclusion, severe post-LT CKD resulted in a significantly reduced survival in liver recipient. The newly established nomogram model had good predictive ability for post-LT CKD.

Serum Exosome-Derived piRNAs Could Be Promising Biomarkers for HCC Diagnosis.

Background: Serum exosome-based liquid biopsy has significant advantages for screening and diagnosing hepatocellular carcinoma (HCC). P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are novel small silencing RNAs that have been identified to function in cancer-related signalling pathways. However, studies on the presence of piRNAs in serum exosomes from HCC patients and their diagnostic values in HCC are not well reported. Our aim is to validate serum exosome-derived piRNAs as the valuable component of liquid biopsy for diagnosing HCC. Methods: We used small RNA (sRNA) sequencing to profile piRNAs from serum exosomes and describe the base distribution characteristics of serum exosome-derived piRNAs. Serum exosomes from 125 HCC patients and 44 nontumor donors were included in this study. Results: We found that piRNAs were components of serum exosomes from HCC patients. A total of 253 differentially expressed serum exosome-derived piRNAs were screened from HCC compared with the piRNAs from nontumor donors. Serum exosome-derived piRNAs from HCC displayed a distinctive base distribution. To further confirm the potential diagnostic value of serum exosome-derived piRNAs in HCC, we detected the levels of the top 5 upregulated piRNAs in our Chinese cohort. The training set and validation set both showed that all 5 piRNAs were dramatically increased in the serum exosomes from HCC compared with the piRNAs from non-tumour donors. The piRNAs could strongly identify HCC patients from non-tumour donors according to the area under the receiver operating characteristic (AUROC) model. Additionally, the piRNAs could also present significant values for the diagnosis of HCC with low tumour burden. Conclusion: piRNAs enriched the components of serum exosomes from HCC and could serve as promising biomarkers for HCC diagnosis.

Immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, can we harness the power of immune checkpoint inhibitors?

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death globally and liver transplantation (LT) can serve as the best curative treatment option. However, HCC recurrence after LT remains the major obstacle to the long-term survival of recipients. Recently, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many cancers and provided a new treatment strategy for post-LT HCC recurrence. Evidence has been accumulated with the real-world application of ICIs in patients with post-LT HCC recurrence. Notably, the use of these agents as immunity boosters in recipients treated with immunosuppressors is still controversial. In this review, we summarized the immunotherapy for post-LT HCC recurrence and conducted an efficacy and safety evaluation based on the current experience of ICIs for post-LT HCC recurrence. In addition, we further discussed the potential mechanism of ICIs and immunosuppressive agents in regulating the balance between immune immunosuppression and lasting anti-tumor immunity.

Assessing Donor Liver Quality and Restoring Graft Function in the Era of Extended Criteria Donors.

Liver transplantation (LT) is the final treatment option for patients with end-stage liver disease. The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world. Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases, which significantly reduce recipient survival. Although several clinical factors have been demonstrated to impact donor liver quality, accurate, comprehensive, and effective assessment systems to guide decision-making for organ usage, restoration or discard are lacking. In addition, the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function. Moreover, such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment. Focusing on donors and grafts, we updated potential biomarkers in donor blood, liver tissue, or perfusates that predict graft quality following LT, and summarized strategies for restoring graft function in the era of extended criteria donors. In this review, we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.

Decoding Single-cell Landscape and Intercellular Crosstalk in the Transplanted Liver.

BACKGROUND: Liver transplantation (LT) is the most effective treatment for various end-stage liver diseases. However, the cellular complexity and intercellular crosstalk of the transplanted liver have constrained analyses of graft reconstruction after LT. METHODS: We established an immune-tolerated orthotopic LT mouse model to understand the physiological process of graft recovery and intercellular crosstalk. We employed single-cell RNA sequencing and cytometry by time-of-flight to comprehensively reveal the cellular landscape. RESULTS: We identified an acute and stable phase during perioperative graft recovery. Using single-cell technology, we made detailed annotations of the cellular landscape of the transplanted liver and determined dynamic modifications of these cells during LT. We found that 96% of graft-derived immune cells were replaced by recipient-derived cells from the preoperative to the stable phase. However, CD206 + MerTK + macrophages and CD49a + CD49b - natural killer cells were composed of both graft and recipient sources even in the stable phase. Intriguingly, the transcriptional profiles of these populations exhibited tissue-resident characteristics, suggesting that recipient-derived macrophages and natural killer cells have the potential to differentiate into 'tissue-resident cells' after LT. Furthermore, we described the transcriptional characteristics of these populations and implicated their role in regulating the metabolic and immune remodeling of the transplanted liver. CONCLUSIONS: In summary, this study delineated a cell atlas (type-proportion-source-time) of the transplanted liver and shed light on the physiological process of graft reconstruction and graft-recipient crosstalk.

The role of macrophage TAM receptor family in the acute-to-chronic progression of liver disease: From friend to foe?

Hepatic macrophages, the key cellular components of the liver, emerge as essential players in liver inflammation, tissue repair and subsequent fibrosis, as well as tumorigenesis. Recently, the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl and MerTK, was found to be a pivotal modulator of macrophages. Activation of macrophage TAM receptor signalling promotes the efferocytosis of apoptotic cells and skews the polarization of macrophages. After briefly reviewing the mechanisms of TAM receptor signalling in macrophage polarization, we focus on their role in liver diseases from acute injury to chronic inflammation, fibrosis and then to tumorigenesis. Notably, macrophage TAM receptor signalling seems to be a two-edged sword for liver diseases. On one hand, the activation of TAM receptor signalling inhibits inflammation and facilitates tissue repair during acute liver injury. On the other hand, continuous activation of the signalling contributes to the process of chronic inflammation into fibrosis and tumorigenesis by evoking hepatic stellate cells and inhibiting anti-tumour immunity. Therefore, targeting macrophage TAM receptors and clarifying its downstream pathways will be exciting prospects for the precaution and treatment of liver diseases, particularly at different stages or statuses.

Nomogram to predict primary non-response to infliximab in patients with Crohn's disease: a multicenter study.

BACKGROUND: Infliximab (IFX) is effective at inducing and maintaining clinical remission and mucosal healing in patients with Crohn's disease (CD); however, 9%-40% of patients do not respond to primary IFX treatment. This study aimed to construct and validate nomograms to predict IFX response in CD patients. METHODS: A total of 343 patients diagnosed with CD who had received IFX induction from four tertiary centers between September 2008 and September 2019 were enrolled in this study and randomly classified into a training cohort (n = 240) and a validation cohort (n = 103). The primary outcome was primary non-response (PNR) and the secondary outcome was mucosal healing (MH). Nomograms were constructed from the training cohort using multivariate logistic regression. Performance of nomograms was evaluated by area under the receiver-operating characteristic curve (AUC) and calibration curve. The clinical usefulness of nomograms was evaluated by decision-curve analysis. RESULTS: The nomogram for PNR was developed based on four independent predictors: age, C-reactive protein (CRP) at week 2, body mass index, and non-stricturing, non-penetrating behavior (B1). AUC was 0.77 in the training cohort and 0.76 in the validation cohort. The nomogram for MH included four independent factors: baseline Crohn's Disease Endoscopic Index of Severity, CRP at week 2, B1, and disease duration. AUC was 0.79 and 0.72 in the training and validation cohorts, respectively. The two nomograms showed good calibration in both cohorts and were superior to single factors and an existing matrix model. The decision curve indicated the clinical usefulness of the PNR nomogram. CONCLUSIONS: We established and validated nomograms for the prediction of PNR to IFX and MH in CD patients. This graphical tool is easy to use and will assist physicians in therapeutic decision-making.