scholarly journals PD-1 expression in hepatocellular carcinoma predicts liver-directed therapy response and bridge-to-transplant survival

2021 ◽  
Author(s):  
Kelley G. Núñez ◽  
Tyler Sandow ◽  
Daniel Fort ◽  
Mina Hibino ◽  
Paige Wright ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Tumor Progression ◽  
Lymphocyte Count ◽  
Univariate Analysis ◽  
Transplant Survival ◽  
Bridge To Transplant ◽  
Incomplete Response ◽  
Advanced Tumor ◽  
Increased Risk

Abstract Background Hepatocellular carcinoma (HCC) patients undergo liver-directed therapy (LDT) to control tumor burden while awaiting liver transplantation with response impacting waitlist survival. In this study, we investigate the link between absolute lymphocyte count (ALC) and PD-1 expression with response to LDT and bridge-to-transplant survival. Methods Treatment-naïve HCC patients (n = 86) undergoing LDT were enrolled at a single center from August 2016–March 2020. Response to LDT was determined using mRECIST. Blood samples were collected on the day of LDT and at follow-up. Cells were analyzed for phenotype by flow cytometry. Outcomes were liver transplantation or tumor progression. Results Incomplete response to initial LDT was associated with tumor progression precluding liver transplantation (OR: 7.6, 1.7 – 33.3, P < 0.001). Univariate analysis of baseline T cell phenotypes revealed ALC (OR: 0.44, 0.24–0.85, P = 0.009) as well as intermediate expression of PD-1 on CD4 (OR: 3.3, 1.03–10.3, P = 0.034) and CD8 T cells (OR: 3.0, 0.99–8.8 P = 0.043) associated with incomplete response to LDT. Elevations in PD-1 expression were associated with increased risk of bridge-to-transplant tumor progression (HR: 3.2, 1.2–9.4). In patients successfully bridged to liver transplantation, pre-treatment peripheral PD-1 profile was associated with advanced tumor staging (P < 0.005) with 2/4 of patients with elevations in PD-1 having T3-T4 TNM staging compared to 0 with low PD-1 expression. Conclusion Low lymphocyte count or elevated expression of the PD-1 checkpoint inhibitor is associated with incomplete response to LDT and increased risk of bridge-to-transplant tumor progression. Patients with impaired T cell homeostasis may benefit from PD-1 immunotherapy to improve response to LDT and improve bridge-to-transplant outcomes.

scholarly journals Type III TGF-β Receptor Down-Regulation Promoted Tumor Progression via Complement Component C5a Induction in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1503
Author(s):  
Oscar Wai Ho Yeung ◽  
Xiang Qi ◽  
Li Pang ◽  
Hui Liu ◽  
Kevin Tak Pan Ng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Tumor Stage ◽  
Complement Component ◽  
Soluble Form ◽  
Advanced Tumor Stage ◽  
Down Regulation ◽  
Type Iii ◽  
Advanced Tumor ◽  
Β Receptor

Background and Aims—Transforming growth factor-beta (TGF-β) signaling orchestrates tumorigenesis and one of the family members, TGF-β receptor type III (TGFβR3), are distinctively under-expressed in numerous malignancies. Currently, the clinical impact of TGFβR3 down-regulation and the underlying mechanism remains unclear in hepatocellular carcinoma (HCC). Here, we aimed to identify the tumor-promoting roles of decreased TGFβR3 expression in HCC progression. Materials and Methods—For clinical analysis, plasma and liver specimens were collected from 100 HCC patients who underwent curative resection for the quantification of TGFβR3 by q-PCR and ELISA. To study the tumor-promoting mechanism of TGFβR3 downregulation, HCC mouse models and TGFβR3 knockout cell lines were applied. Results—Significant downregulation of TGFβR3 and its soluble form (sTGFβR3) were found in HCC tissues and plasma compared to healthy individuals (p < 0.01). Patients with <9.4 ng/mL sTGFβR3 exhibited advanced tumor stage, higher recurrence rate and shorter disease-free survival (p < 0.05). The tumor-suppressive function of sTGFβR3 was further revealed in an orthotopic mouse HCC model, resulting in 2-fold tumor volume reduction. In TGFβR3 knockout hepatocyte and HCC cells, increased complement component C5a was observed and strongly correlated with shorter survival and advanced tumor stage (p < 0.01). Interestingly, C5a activated the tumor-promoting Th-17 response in tumor associated macrophages. Conclusion—TGFβR3 suppressed tumor progression, and decreased expression resulted in poor prognosis in HCC patients through upregulation of tumor-promoting complement C5a.

scholarly journals Hepatocellular carcinoma in HCV-infected patients awaiting liver transplantation: Genes involved in tumor progression

2004 ◽  
Vol 10 (5) ◽  
pp. 607-620 ◽  
Author(s):  
Valeria R. Mas ◽  
Daniel G. Maluf ◽  
Richard Stravitz ◽  
Catherine I. Dumur ◽  
Bradly Clark ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Tumor Progression

scholarly journals Combined proteomic/transcriptomic signature of recurrence post-liver transplantation for hepatocellular carcinoma beyond Milan

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Mamatha Bhat ◽  
Sergi Clotet-Freixas ◽  
Cristina Baciu ◽  
Elisa Pasini ◽  
Ahmed Hammad ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Protein Expression ◽  
Univariate Analysis ◽  
Milan Criteria ◽  
Post Transplant ◽  
Gene And Protein Expression ◽  
Galectin 3 ◽  
Transcriptomic Signature ◽  
Hcc Recurrence

Abstract Background and aims Liver transplantation (LT) can be offered to patients with Hepatocellular carcinoma (HCC) beyond Milan criteria. However, there are currently limited molecular markers on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to derive a combined proteomic/transcriptomic signature on HCC explant predictive of recurrence post-transplant using unbiased, high-throughput approaches. Methods Patients who received a LT for HCC beyond Milan criteria in the context of hepatitis B cirrhosis were identified. Tumor explants from patients with post-transplant HCC recurrence (N = 7) versus those without recurrence (N = 4) were analyzed by mass spectrometry and gene expression array. Univariate analysis was used to generate a combined proteomic/transcriptomic signature linked to recurrence. Significantly predictive genes and proteins were verified and internally validated by immunoblotting and immunohistochemistry. Results Seventy-nine proteins and 636 genes were significantly differentially expressed in HCC tumors with subsequent recurrence (p < 0.05). Univariate survival analysis identified Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) gene (HR = 0.084, 95%CI 0.01–0.68, p = 0.0152), ALDH1A1 protein (HR = 0.039, 95%CI 0.16–0.91, p = 0.03), Galectin 3 Binding Protein (LGALS3BP) gene (HR = 7.14, 95%CI 1.20–432.96, p = 0.03), LGALS3BP protein (HR = 2.6, 95%CI 1.1–6.1, p = 0.036), Galectin 3 (LGALS3) gene (HR = 2.89, 95%CI 1.01–8.3, p = 0.049) and LGALS3 protein (HR = 2.6, 95%CI 1.2–5.5, p = 0.015) as key dysregulated analytes in recurrent HCC. In concordance with our proteome findings, HCC recurrence was linked to decreased ALDH1A1 and increased LGALS3 protein expression by Western Blot. LGALS3BP protein expression was validated in 29 independent HCC samples. Conclusions Significantly increased LGALS3 and LGALS3BP gene and protein expression on explant were associated with post-transplant recurrence, whereas increased ALDH1A1 was associated with absence of recurrence in patients transplanted for HCC beyond Milan criteria. This combined proteomic/transcriptomic signature could help in predicting HCC recurrence risk and guide post-transplant surveillance.

scholarly journals Segmental Distribution of Hepatocellular Carcinoma Correlates with Microvascular Invasion in Liver Explants Undergoing Transplantation

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Yasir Al-Azzawi ◽  
Eva Rouanet ◽  
Ryan J. Hendrix ◽  
Lidia Spaho ◽  
Hesham Malik ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Vascular Invasion ◽  
Retrospective Chart Review ◽  
Microvascular Invasion ◽  
Poor Prognostic Factor ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
Common Etiology ◽  
Segment 8

Introduction. Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients is a poor prognostic factor after liver transplantation and/or resection. Any correlation between MVI and segmental location of HCC has yet to be studied. Our aim is to evaluate the segmental location of HCC and any correlation with the presence of MVI, portal vein thrombosis (PVT) in explanted livers, and the recurrence of HCC after transplantation. Another objective of the study is to assess the treatment history (ablation or transarterial chemoembolization (TACE)) and size of the tumor with respect to the risk of MVI. Methods. A single center, retrospective chart review, including 98 HCC patients, aged 18 years and older who had liver transplantation in our institute between 2012 and 2017. We reviewed the radiological images of the HCC tumors, the pathological findings of the explanted livers, and the follow-up imaging after transplantation. Results. 98 patients with the diagnosis of HCC underwent liver transplantation between 2012 and 2017. The mean age of the cohort was 63 ± 8.2. Males represented 75% and Caucasian race represented 75% of the cohort. The most common etiology of cirrhosis was chronic hepatitis C virus infection followed by alcohol abuse and nonalcoholic steatohepatitis (NASH) with percentages of 50%, 23%, and 10%, respectively. Microvascular invasion was found in 16% of the patients while PVT and the recurrence of HCC were found in 17% and 6 % of the cohort, respectively. MVI was found in 10 single HCC and 6 multifocal HCC. Right lobe HCC had more MVI when compared to the left and multilobar HCC, with percentages of 11%, 2%, and 3%, respectively. Localization of HCC in segment 8 was associated with the highest percentage of MVI when compared to all other segments. The risk of MVI in segment 8 HCC was 3.5 times higher than the risk from the other segments (p=0.002) while no vascular invasion was found in segments 1, 3, and 5. The risk of vascular invasion in untreated HCC is 3 times the risk in treated HCC (P=0.03). Conclusion. Our data indicate that the risk of microvascular invasion is highest in tumors localized to segment 8. The size and number of HCC tumors were not associated with an increased risk of microvascular invasion.

scholarly journals Prognostic Relevance of a Complete Pathologic Response in Liver Transplantation for Hepatocellular Carcinoma

2019 ◽  
Vol 26 (13) ◽  
pp. 4556-4565 ◽  
Author(s):  
Michał Grąt ◽  
Marek Krawczyk ◽  
Jan Stypułkowski ◽  
Marcin Morawski ◽  
Maciej Krasnodębski ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Propensity Score ◽  
Neoadjuvant Treatment ◽  
Pathologic Response ◽  
Secondary Outcome ◽  
Complete Pathologic Response ◽  
Risk Of Recurrence ◽  
Increased Risk ◽  
Treatment Naïve

Abstract Background A complete pathologic response (CPR) after neoadjuvant treatment is reported to be associated with an exceptionally low risk of recurrence after liver transplantation for hepatocellular carcinoma (HCC). This study aimed to evaluate the prognostic role of CPR in liver transplantation for HCC. Methods This retrospective cohort study was based on 222 HCC transplant recipients. Incidence of recurrence and survival at 5 years were the primary and secondary outcome measures, respectively. Competing risk analyses were applied to evaluate recurrence incidence and its predictors. Propensity score matching was performed to compare the outcomes for patients after neoadjuvant treatment with and without CPR. Results Neoadjuvant treatment was performed for 127 patients, 32 of whom achieved CPR (25.2%). Comparison of baseline characteristics showed that the patients with CPR were at lowest baseline recurrence risk, followed by treatment-naïve patients and patients without CPR. Adjusted for potential confounders, CPR did not have any significant effects on tumor recurrence. No significant net reclassification improvement was noted after addition of CPR to existing criteria. Neoadjuvant treatment without CPR was associated with increased risk of recurrence in subgroups within the Milan criteria (p = 0.016), with alpha-fetoprotein concentration (AFP) model not exceeding 2 points (p = 0.021) and within the Warsaw criteria (p = 0.007) compared with treatment-naïve patients who were at risk similar to those with CPR. The 5-year incidences of recurrence in propensity score-matched patients with and without CPR were respectively 14.0% and 15.9% (p = 0.661), with corresponding survival rates of 73.2% and 67.4%, respectively (p = 0.329). Conclusions The findings showed that CPR is not independently associated with long-term outcomes after liver transplantation for HCC.

Sign in / Sign up

Export Citation Format

Share Document