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Preoperative immune landscape predisposes adverse outcomes in hepatocellular carcinoma patients with liver transplantation.

ABSTRACT: Immune class in hepatocellular carcinoma (HCC) has been shown to possess immunogenic power; however, how preestablished immune landscapes in premalignant and early HCC stages impact the clinical outcomes of HCC patients remains unexplored. We sequenced bulk transcriptomes for 62 malignant tumor samples from a Korean HCC cohort in which 38 patients underwent total hepatectomy, as well as for 15 normal and 47 adjacent nontumor samples. Using in silico deconvolution of expression mixtures, 22 immune cell fractions for each sample were inferred, and validated with immune cell counting by immunohistochemistry. Cell type-specific immune signatures dynamically shifted from premalignant stages to the late HCC stage. Total hepatectomy patients displayed elevated immune infiltration and prolonged disease-free survival compared to the partial hepatectomy patients. However, patients who exhibited an infiltration of regulatory T cells (Tregs) during the pretransplantation period displayed a high risk of tumor relapse with suppressed immune responses, and pretreatment was a potential driver of Treg infiltration in the total hepatectomy group. Treg infiltration appeared to be independent of molecular classifications based on transcriptomic data. Our study provides not only comprehensive immune signatures in adjacent nontumor lesions and early malignant HCC stages but also clinical guidance for HCC patients who will undergo liver transplantation.

SUBMITTER: Yoon SH

PROVIDER: S-EPMC7997876 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Preoperative immune landscape predisposes adverse outcomes in hepatocellular carcinoma patients with liver transplantation

Project description:Immune class in hepatocellular carcinoma (HCC) has been shown to possess immunogenic power; however, how preestablished immune landscapes in premalignant and early HCC stages impact the clinical outcomes of HCC patients remains unexplored. We sequenced bulk transcriptomes for 62 malignant tumor samples from a Korean HCC cohort in which 38 patients underwent total hepatectomy, as well as for 15 normal and 47 adjacent nontumor samples. Using in-silico deconvolution of expression mixtures, 22 immune cell fractions for each sample were inferred, and validated with immune cell counting by immunohistochemistry. Cell type-specific immune signatures dynamically shifted from premalignant stages to the late HCC stage. Total hepatectomy patients displayed elevated immune infiltration and prolonged disease-free survival compared to the partial hepatectomy patients. However, patients who exhibited an infiltration of regulatory T cells (Tregs) during the pretransplantation period displayed a high risk of tumor relapse with suppressed immune responses, and pretreatment was a potential driver of Treg infiltration in the total hepatectomy group. Treg infiltration appeared to be independent of molecular classifications based on transcriptomic data. Our study provides not only comprehensive immune signatures in adjacent nontumor lesions and early malignant HCC stages but also clinical guidance for HCC patients who will undergo liver transplantation.

2021-03-15 | GSE148355 | GEO

Preoperative immune landscape predisposes adverse outcomes in hepatocellular carcinoma patients with liver transplantation

Project description:Preoperative immune landscape predisposes adverse outcomes in hepatocellular carcinoma patients with liver transplantation

| PRJNA624047 | ENA

Liver transplantation and cirrhotomimetic hepatocellular carcinoma: classification and outcomes.

Project description:Liver transplantation has become the standard-of-care treatment for hepatocellular carcinoma (HCC) that falls within certain size and numerical criteria for patients with cirrhosis. Cirrhotomimetic (CMM) HCC is an uncommon growth pattern that infiltrates cirrhotic parenchyma, can become extensive in size, and can evade detection via radiological studies. Liver transplant outcomes for this type of HCC are not well reported but generally are considered to be poor. We wished to better describe this variant of HCC in explanted livers, derive a classification system for this tumor type, and assess the outcomes of liver transplantation for this tumor variant. All patients undergoing transplantation for HCC at a single center in 1996-2009 (358 patients) were retrospectively analyzed, and 26 patients exhibiting a CMM growth pattern were identified. We developed a classification system for this tumor growth pattern variant and determined patient and tumor-specific outcomes. We derived a classification schema for CMM HCC based on the tumor extent and cellular histopathology, with a clear cell pathology being associated with favorable outcomes. We noted 100.0% 3-year recurrence-free survival and 58.3% 5-year recurrence-free survival after transplantation for those patients with tumors confined to 1 lobe that had a clear cell pathology and 16.2% 3- and 5-year recurrence-free survival for those patients who did not meet these criteria. In conclusion, CMM HCC features were noted in 7% of the patients undergoing transplantation for HCC at our center, with favorable outcomes observed for inpatients with clear cell histology and growth involving less than or equal to 50% of the liver.

| S-EPMC4146426 | biostudies-literature

Liver transplantation for hepatocellular carcinoma: Improving eligibility without compromising outcomes.

Project description:BackgroundIn the context of liver transplantation for hepatocellular carcinoma (HCC), traditional transplant criteria appear restrictive. The objective of the current study was to determine risk factors for recurrence and improve transplant eligibility in patients with HCC.Materials and methodsThis was a retrospective study of patients who underwent living donor liver transplant (LDLT) for HCC (n = 219). Largest tumor diameter, tumor number, AFP and neutrophil to lymphocyte ratio were assessed. Multivariate analysis was performed to develop risk scores. The new model was compared with seven previously published transplant criteria using receiver operator curves.ResultsLargest tumor size >3.7 cm [HR:2.6, P = 0.02], and AFP > 600 ng/ml [HR:4.7, P = 0.001] were independent predictors of recurrence. Patients with risk scores of 0, 1-3, 4-6 and 7-9 had recurrence rate of 5.9%, 12.5%, 25% and 58.4% respectively. When compared with Milan criteria, Metro ticket 2.0, AFP model and Samsung criteria; transplant eligibility increased by 31.5%, 22.9%, 8.7%, and 7% respectively. Recurrence rate with the current model was 16/199 (8%) (P < 0.0001) and was comparable with other transplant criteria (6.9-9.1%). On ROC analysis, only Milan criteria (AUC = 0.7, P = 0.001) and the current model (AUC = 0.66, P = 0.01) showed significance for recurrence. All patients with high risk scores within Milan criteria had recurred at 3 years (P = 0.03).ConclusionsLow AFP can be used to select patients for LDLT outside traditional criteria for HCC, with comparable recurrence rates.

| S-EPMC8281598 | biostudies-literature

Liver transplantation for hepatocellular carcinoma.

Project description:BACKGROUND: Orthotopic liver transplantation (OLT) is the best available option for early hepatocellular carcinoma (HCC), although its application is limited by stringent selection criteria, costs, and deceased donor graft shortage, particularly in Asia, where living donor liver transplant (LDLT) has been developed. METHODS: This article reviews the present standards for patient selection represented by size-and-number criteria with particular references to Milan Criteria and novel prediction models based on results achieved in patients exceeding those limits, with consideration of the expanded indication represented by the UCSF Criteria. RESULTS: The expected outcomes after deceased donor liver transplant (DDLT) or LDLT are favorable if predetermined selection criteria are applied. However, selection bias, difference in waiting time, and ischemia-regeneration injuries of the graft among DDLT vs LDLT may influence long-term results. In the article, the differences between East and West in first-line treatments for HCC (resection vs transplantation), indications, and ethics for the donor, are summarized as well as possible novel predictors of tumor biology (especially DNA mutation and fractional allelic loss, FAI) to be considered for better outcome prediction. CONCLUSIONS: Liver transplantation remains the most promising product of modern surgery and represents a cornerstone in the management of patients with HCC.

| S-EPMC2266786 | biostudies-other

Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma.

Project description:Tumor-infiltrating immune cells are highly relevant for prognosis and identification of immunotherapy targets in hepatocellular carcinoma (HCC). The recently developed CIBERSORT method allows immune cell profiling by deconvolution of gene expression microarray data. By applying CIBERSORT, we assessed the relative proportions of immune cells in 41 healthy human livers, 305 HCC samples and 82 HCC adjacent tissues. The obtained immune cell profiles provided enumeration and activation status of 22 immune cell subtypes. Mast cells were evaluated by immunohistochemistry in ten HCC patients. Activated mast cells, monocytes and plasma cells were decreased in HCC, while resting mast cells, total and naïve B cells, CD4+ memory resting and CD8+ T cells were increased when compared to healthy livers. Previously described S1, S2 and S3 molecular HCC subclasses demonstrated increased M1-polarized macrophages in the S3 subclass with good prognosis. Strong total immune cell infiltration into HCC correlated with total B cells, memory B cells, T follicular helper cells and M1 macrophages, whereas weak infiltration was linked to resting NK cells, neutrophils and resting mast cells. Immunohistochemical analysis of patient samples confirmed the reduced frequency of mast cells in human HCC tumor tissue as compared to tumor adjacent tissue. Our data demonstrate that deconvolution of gene expression data by CIBERSORT provides valuable information about immune cell composition of HCC patients.

| S-EPMC5906687 | biostudies-literature

Analysis of preoperative circulating tumor cells for recurrence in patients with hepatocellular carcinoma after liver transplantation.

Project description:BackgroundLiver transplantation (LT) is an effective option for hepatocellular carcinoma (HCC) and end-stage liver cirrhosis. However, organ shortage and tumor recurrence are the main obstacles limiting its popularization and application in HCC patients. Testing for circulating tumor cells (CTCs) would be a valuable strategy to predict the recurrence and metastasis of HCC after LT. Various CTCs detection methods have different advantages and disadvantages. This study aims to investigate the predictive value of testing for CTCs based on immunofluorescence in situ hybridization of peripheral blood cells in patients with HCC after LT.MethodsA total of 50 patients who received testing for CTCs and then underwent LT were enrolled in this study. Negative enrichment and immunofluorescence in situ hybridization (imFISH) methods were introduced to detect CTCs.ResultsTwenty-six (52%) patients were CTC-positive, and 24 (48%) patients were CTC-negative. The results showed that CTCs result was correlated with tumor size (ꭓ2=5.773, P=0.016), AFP level (ꭓ2=5.454, P=0.020), tumor grade (ꭓ2=6.478, P=0.039) and Recurrence(ꭓ2=6.211, P=0.013).Twelve patients had recurrence after LT within one year. The results showed that the CTCs result (P=0.034) was the only independent factor impacting long-term survival. The 1-year disease-free survival rates of CTC-negative and CTC-positive patients were 91.6% and 61.5%, respectively (P=0.020). The 1-year overall survival of CTC-positive patients and CTC-negative was 88.5% and 91.7%, respectively (P=0.751).ConclusionsCTCs result was closely related to the early recurrence of patients with HCC after LT. CTC-positive patients had a worse prognosis after LT than the CTC-negative group.

| S-EPMC7575976 | biostudies-literature

Hypothyroidism is associated with worse outcomes of hepatocellular carcinoma patients after liver transplantation.

Project description:Background/aimsHypothyroidism has been associated with hepatocellular carcinoma (HCC) incidence; however, the relationship between hypothyroidism and HCC patient outcomes is unclear. We investigated the impact of hypothyroidism on outcomes after liver transplantation for HCC.Materials and methodsWe retrospectively studied HCC patients transplanted between January 2000 and December 2015. Hypothyroidism was defined as a thyroid-stimulating hormone (TSH) level continuously greater than 5 mIU/L, a documented history of hypothyroidism, or treatment with thyroid hormone replacement therapy. Multivariate Cox regression was used to assess the impact of hypothyroidism on overall survival (OS) and recurrence-free survival (RFS) adjusting for potential confounders. Subgroup analyses and interaction tests were conducted to compare the impact of hypothyroidism in different subgroups and assess for possible synergistic effects. Sensitivity analyses were performed among different cohorts to verify the stability of the results.ResultsA total of 343 HCC patients who underwent liver transplantation were included in the analysis. The primary analysis was conducted among 288 patients diagnosed with HCC prior to transplantation. Hypothyroidism was independently associated with worse OS and RFS, as was elevated TSH. The adjusted hazard ratio (AHR) of hypothyroidism was 2.45 (95% confidence interval [CI], 1.44-4.18) for OS and 5.54 (2.36, 13.01) for RFS. The AHR of TSH for OS was 1.05 (1.02, 1.09) and 1.08 (1.03, 1.13) for RFS. No interaction was found among different subgroups categorized by etiology and comorbidity. The results were stable to sensitivity analyses.ConclusionHypothyroidism is associated with poorer overall and recurrence-free survival of HCC patients receiving liver transplantation. These results require validation.

| S-EPMC6308061 | biostudies-literature

Hemojuvelin deficiency promotes liver mitochondrial dysfunction and predisposes mice to hepatocellular carcinoma.

Project description:Hemojuvelin (HJV) enhances signaling to the iron hormone hepcidin and its deficiency causes iron overload, a risk factor for hepatocellular carcinoma (HCC). We utilized Hjv-/- mice to dissect mechanisms for hepatocarcinogenesis. We show that suboptimal treatment with diethylnitrosamine (DEN) triggers HCC only in Hjv-/- but not wt mice. Liver proteomics data were obtained by mass spectrometry. Hierarchical clustering analysis revealed that Hjv deficiency and DEN elicit similar liver proteomic responses, including induction of mitochondrial proteins. Dietary iron overload of wt mice does not recapitulate the liver proteomic phenotype of Hjv-/- animals, which is only partially corrected by iron depletion. Consistent with these data, primary Hjv-/- hepatocytes exhibit mitochondrial hyperactivity, while aged Hjv-/- mice develop spontaneous HCC. Moreover, low expression of HJV or hepcidin (HAMP) mRNAs predicts poor prognosis in HCC patients. We conclude that Hjv has a hepatoprotective function and its deficiency in mice promotes mitochondrial dysfunction and hepatocarcinogenesis.

| S-EPMC8863832 | biostudies-literature

Thrombosis after liver transplantation for hepatocellular carcinoma.

Project description:The influence of thrombosis on the prognosis of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT) and the role of the commonest inherited thrombophilia abnormalities factor V Leiden and prothrombin G20210A in the development of thrombosis are unknown. We investigated a cohort of patients who underwent LT for HCC with the aim to estimate the incidence rate (IR) of thrombosis, its influence on mortality and re-transplantation rates and, in the frame of a nested case-control study, the role of thrombophilia in donors and recipients for the development of thrombosis. Four-hundred and thirty patients underwent LT and were followed for a median of 7.2 years. Twenty-six recipients (6%) developed thrombosis (IR 1.06 [95%CI: 0.71-1.53] per 100 pts-yr). Mortality rate after LT was 3.95 (95%CI: 3.22-4.79) per 100 pts-yr and was not influenced by thrombosis. Re-transplantation was planned for 33 patients and was more common in patients with thrombosis than in those without (HR 2.50 [95%CI: 0.87-7.17]). The risk of thrombosis was 4 times higher in recipients with thrombophilia than in those without (OR 4.23 [95%CI: 0.99-18.04]) and 6 times higher when the analysis was restricted to venous thrombosis (OR 6.26 [95%CI: 1.19-32.85]). The presence of inherited thrombophilia in the donors did not increase the risk of thrombosis of the recipient. In conclusion, thrombosis is a complication of 6% of patients transplanted for HCC and increases the risk of re-transplantation but not of mortality. The risk of thrombosis, particularly venous, is increased in the presence of thrombophilia abnormalities in the recipients.

| S-EPMC5658078 | biostudies-literature

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