Telomerase is a key enzyme for cell survival that prevents telomere shortening and the subsequent cellular senescence that is observed after many rounds of cell division. In contrast, inactivation of ...telomerase is observed in most cells of the adult liver. Absence of telomerase activity and shortening of telomeres has been implicated in hepatocyte senescence and the development of cirrhosis, a chronic liver disease that can lead to hepatocellular carcinoma (HCC) development. During hepatocarcinogenesis, telomerase reactivation is required to enable the uncontrolled cell proliferation that leads to malignant transformation and HCC development. Part of the telomerase complex, telomerase reverse transcriptase, is encoded by TERT, and several mechanisms of telomerase reactivation have been described in HCC that include somatic TERT promoter mutations, TERT amplification, TERT translocation and viral insertion into the TERT gene. An understanding of the role of telomeres and telomerase in HCC development is important to develop future targeted therapies and improve survival of this disease. In this Review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets.
Studies are needed to determine the long-term effects of bariatric surgery for patients with nonalcoholic steatohepatitis (NASH). We evaluated sequential liver samples, collected the time of ...bariatric surgery and 1 and 5 years later, to assess the long-term effects of bariatric surgery in patients with NASH.
We performed a prospective study of 180 severely obese patients with biopsy-proven NASH, defined by the NASH clinical research network histologic scores. The patients underwent bariatric surgery at a single center in France and were followed for 5 years. We obtained liver samples from 125 of 169 patients (76%) having reached 1 year and 64 of 94 patients (68%) having reached 5 years after surgery. The primary endpoint was the resolution of NASH without worsening of fibrosis at 5 years. Secondary end points were improvement in fibrosis (reduction of ≥1 stage) at 5 years and regression of fibrosis and NASH at 1 and 5 years.
At 5 years after bariatric surgery, NASH was resolved, without worsening fibrosis, in samples from 84% of patients (n = 64; 95% confidence interval, 73.1%-92.2%). Fibrosis decreased, compared with baseline, in samples from 70.2% of patients (95% CI, 56.6%-81.6%). Fibrosis disappeared from samples from 56% of all patients (95% CI, 42.4%-69.3%) and from samples from 45.5% of patients with baseline bridging fibrosis. Persistence of NASH was associated with no decrease in fibrosis and less weight loss (reduction in body mass index of 6.3 ± 4.1 kg/m2 in patients with persistent NASH vs reduction of 13.4 ± 7.4 kg/m2; P = .017 with resolution of NASH). Resolution of NASH was observed at 1 year after bariatric surgery in biopsies from 84% of patients, with no significant recurrence between 1 and 5 years (P = .17). Fibrosis began to decrease by 1 year after surgery and continued to decrease until 5 years (P < .001).
In a long-term follow-up of patients with NASH who underwent bariatric surgery, we observed resolution of NASH in liver samples from 84% of patients 5 years later. The reduction of fibrosis is progressive, beginning during the first year and continuing through 5 years.
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INTRODUCTION:
Severe alcohol-related hepatitis (AH) is associated with an increased risk of infection, but the impact of pneumonia has not been specifically analyzed in a specific cohort.
METHODS:
...All patients admitted for severe AH between 2002 and 2020 were prospectively included. Systematic screening for infection was performed at admission and renewed in the case of clinical suspicion.
RESULTS:
We included 614 patients (60.4% men, mean age 49.9 years, median model for end-stage liver disease MELD 25.2, bilirubin 18.1 mg/dL), 202 (32.9%) with infections at admission (73 lung infections). Encephalopathy (
P
= 0.006), MELD score (
P
= 0.0002), and tobacco exposure (past vs never smokers:
P
= 0.002 or active vs past smokers:
P
= 0.005) were associated with lung infection at admission on multivariate analysis. Factors independently associated with death before steroid initiation were encephalopathy (
P
= 0.003), MELD score (
P
= 0.05), and especially lung infection (
P
< 0.0001). Thus, patients with a lung infection had a lower probability of receiving steroids than those with other infections and noninfected patients: 54.8 vs 88.4 vs 98.1% (
P
< 0.0001). One hundred forty-six of the 558 patients who received corticosteroids developed infection, including 57 (39.04%) pneumonias. The risk of respiratory and nonrespiratory infection was higher in nonresponders to steroids (Lille score ≥0.45) than in responders: 13% vs 7.6%,
P
= 0.03 and 27.9% vs 10.6%,
P
< 0.001, respectively. The variables independently associated with 3-month mortality after steroid initiation were lung infection (
P
= 0.004), nonresponse to steroids (
P
< 0.0001), MELD score (
P
= 0.0003), ascites (
P
= 0.003), and encephalopathy (
P
= 0.018), whereas nonrespiratory infections were not (
P
= 0.91).
DISCUSSION:
Lung infection is frequent during severe AH and influences mortality at admission and after steroid initiation. These results emphasize the need for specific management of lung infection during the course of AH.
Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- ...cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA.
This study aimed to describe patient characteristics, treatment efficacy, and safety in patients with hepatocellular carcinoma (HCC) undergoing stereotactic body radiation therapy (SBRT). We ...retrospectively analyzed data of 318 patients with 375 HCC treated between June 2007 and December 2018. Efficacy (overall survival OS, relapse-free survival, and local control) and acute and late toxicities were described. The median follow-up period was 70.2 months. Most patients were treated with 45 Gy in three fractions. The median (range) PTV volume was 90.7 (2.6–1067.6) cc. The local control rate at 24 and 60 months was 94% (91–97%) and 94% (91–97%), respectively. Relapse-free survival at 12, 24, and 60 months was 62% (55–67%), 29% (23–36%), and 13% (8–19%), respectively. OS at 12, 24, and 60 months was 72% (95%CI 67–77%), 44% (38–50%), and 11% (7–15%), respectively. Approximately 51% and 38% experienced acute and late toxicity, respectively. Child-Pugh score B-C, high BCLC score, portal thrombosis, high GTV volume, and higher PTV volume reported on total hepatic volume ratio were significantly associated with OS. SBRT is efficient for the management of HCC with a favorable toxicity profile. The outcome is highly related to the natural evolution of the underlying cirrhosis.
Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based ...chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37–1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43–1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23–3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31–9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08–4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27–3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44–3.49, p = 0.67). Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.
To validate cancer screening programs, experts recommend estimating effects on case fatality rates (CFRs) and cancer‐specific mortality. This study evaluates hepatocellular carcinoma (HCC) screening ...in patients with cirrhosis for those outcomes using a modeling approach. We designed a Markov model to assess 10‐year HCC‐CFR, HCC‐related, and overall mortality per 100,000 screened patients with compensated cirrhosis. The model evaluates different HCC surveillance intervals (none, annual 12 months, semiannual 6 months, or quarterly 3 months) and imaging modalities (ultrasound US or magnetic resonance imaging MRI) in various annual incidences (0.2%, 0.4%, or 1.5%). Compared to no surveillance, 6‐month US reduced the 10‐year HCC‐CFR from 77% to 46%. With annual incidences of 0.2%, 0.4%, and 1.5%, the model predicted 281, 565, and 2059 fewer HCC‐related deaths, respectively, and 187, 374, and 1356 fewer total deaths per 100,000 screened patients, respectively. Combining alpha‐fetoprotein screening to 6‐month US led to 32, 63, and 230 fewer HCC‐related deaths per 100,000 screened patients for annual incidences of 0.2%, 0.4%, and 1.5%, respectively. Compared to 6‐month US, 3‐month US reduced cancer‐related mortality by 14%, predicting 61, 123, and 446 fewer HCC‐related deaths per 100,000 screened patients with annual incidences of 0.2%, 0.4%, and 1.5%, respectively. Compared to 6‐month US, 6‐month MRI (−17%) and 12‐month MRI (−6%) reduced HCC‐related mortality. Compared to 6‐month US, overall mortality reductions ranged from −0.1% to −1.3% when using 3‐month US or MRI. A US surveillance interval of 6 months improves HCC‐related and overall mortality compared to no surveillance. A shorter US interval or using MRI could reduce HCC‐CFR and HCC‐related mortality, with a modest effect on overall mortality.
Telomerase activation is the earliest event in hepatocellular carcinoma (HCC) development. Thus, we aimed to elucidate the role of telomere length maintenance during liver carcinogenesis.
Telomere ...length was measured in the tumor and non-tumor liver tissues of 1,502 patients (978 with HCC) and integrated with TERT alterations and expression, as well as clinical and molecular (analyzed by genome, exome, targeted and/or RNA-sequencing) features of HCC. The preclinical efficacy of anti-TERT antisense oligonucleotides (ASO) was assessed in vitro in 26 cell lines and in vivo in a xenograft mouse model.
Aging, liver fibrosis, male sex and excessive alcohol consumption were independent determinants of liver telomere attrition. HCC that developed in livers with long telomeres frequently had wild-type TERT with progenitor features and BAP1 mutations. In contrast, HCC that developed on livers with short telomeres were enriched in the non-proliferative HCC class and frequently had somatic TERT promoter mutations. In HCCs, telomere length is stabilized in a narrow biological range around 5.7 kb, similar to non-tumor livers, by various mechanisms that activate TERT expression. Long telomeres are characteristic of very aggressive HCCs, associated with the G3 transcriptomic subclass, TP53 alterations and poor prognosis. In HCC cell lines, TERT silencing with ASO was efficient in highly proliferative and poorly differentiated cells. Treatment for 3 to 16 weeks induced cell proliferation arrest in 12 cell lines through telomere shortening, DNA damage and activation of apoptosis. The therapeutic effect was also obtained in a xenograft mouse model.
Telomere maintenance in HCC carcinogenesis is diverse, and is associated with tumor progression and aggressiveness. The efficacy of anti-TERT ASO treatment in cell lines revealed the oncogenic addiction to TERT in HCC, providing a preclinical rationale for anti-TERT ASO treatment in HCC clinical trials.
Telomeres are repeated DNA sequences that protect chromosomes and naturally shorten in most adult cells because of the inactivation of the TERT gene, coding for the telomerase enzyme. Here we show that telomere attrition in the liver, modulated by aging, sex, fibrosis and alcohol, associates with specific clinical and molecular features of hepatocellular carcinoma, the most frequent primary liver cancer. We also show that liver cancer is dependent on TERT reactivation and telomere maintenance, which could be targeted through a novel therapeutic approach called antisense oligonucleotides.
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•Age, sex, fibrosis and alcohol modulate liver telomere attrition.•Liver telomere length associates with variable HCC clinical and molecular subtypes.•HCC tumor telomere length is influenced by liver and tumor factors.•HCC cancer cells show actionable oncogenic addiction to TERT activation.
Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the ...Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration.
The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A.
In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication.
Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH.
Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.
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•Unregulated YAP activation is a key player in AH pathogenesis.•YAP activation in AH hepatocytes led to their transdifferentiation, with loss of the hepatocyte identity towards a cholangiocyte program.•In vivo unregulated YAP activation exacerbated hepatocyte transdifferentiation and impaired regeneration in a mouse model.•Therapeutic inhibition of YAP activity blocked the transdifferentiation of hepatocytes in patients with AH.
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