Aberrant c‐Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c‐Met inhibition may have therapeutic potential. However, clinical trials of ...nonselective kinase inhibitors with c‐Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c‐Met status, and the prevalent off‐target activity of these agents, which may indicate that c‐Met inhibition is incomplete. In contrast, selective c‐Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c‐Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c‐Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child‐Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c‐Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c‐Met status. Thus, c‐Met inhibition continues to be an active area of research in HCC, with well‐designed trials in progress to investigate the benefit of selective c‐Met inhibitors. (Hepatology 2018;67:1132–1149)
Aims
Immunotherapies represent a new alternative therapeutic approach for hepatocellular carcinomas (HCCs), and have shown promising results when used in combination therapy. The aim of this study ...was to evaluate the potential of transarterial chemoembolisation (TACE) to modulate programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression profiles in a cohort of surgically treated HCCs.
Methods and results
A total of 82 surgically treated HCCs from patients who had undergone (n = 32) or not undergone (n = 50) preoperative TACE were included in the study. Immunohistochemical expression of PD‐1 and of PD‐L1 were analysed and compared according to TACE treatment. Pretreatment biopsies, which were available for 30 cases (20 with TACE and 10 without), were similarly analysed. Follow‐up data were retrieved from patients' charts. PD‐1 expression (≥1%) in intratumoral inflammatory cells (ICs) was observed in 46% of HCCs, and PD‐L1 expression (≥1%) in ICs and PD‐L1 expression in tumour cells (TCs) were observed in 46% and 16% of HCCs, respectively. A low level of PD‐1 expression (<1%) was associated with strong and diffuse glutamine synthetase overexpression (8% versus 27%, P = 0.024). HCCs from patients with TACE pretreatment showed significantly higher PD‐L1 expression in TCs than those from patients without TACE pretreatment (2% versus 0.4%, P = 0.027). PD‐1 expression in ICs and PD‐L1 expression in both ICs and TCs were higher in TACE‐resected tumours than in corresponding pre‐TACE biopsies (respectively: 1.8% versus 8.1%, P = 0.034; 0.8% versus 7.1%, P = 0.032; and 0% versus 2.4%, P = 0.043).
Conclusion
Our results, showing increases in PD‐1 expression and PD‐L1 expression in HCCs following TACE, support the use of TACE in combination with immunotherapy in selected cases to optimise tumour response.
Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a novel morphological subtype of HCC associated with early relapse after resection or percutaneous ablation, independently of classical ...clinical and radiological prognostic factors. The aim of the present study was to identify immunohistochemical markers of MTM-HCC, to ease its diagnosis and implementation into clinical practice.
To identify potential biomarkers of MTM-HCC, we first analyzed gene expression profiling data from The Cancer Genome Atlas study and further selected two candidate biomarkers. Performance of both biomarkers for diagnosis of MTM-HCC was further tested by immunohistochemistry in two independent series of 67 and 132 HCC biopsy samples.
Analysis of RNA sequencing data showed that MTM-HCC was characterized by a high expression of neoangiogenesis-related genes. Two candidate biomarkers, Endothelial-Specific Molecule 1 (ESM1) and Carbonic Anhydrase IX (CAIX), were selected. In the discovery series, sensitivity and specificity of ESM1 expression by stromal endothelial cells for the detection of MTM-HCC were 97% (28/29), and 92% (35/38), respectively. Sensitivity and specificity of CAIX were 48% (14/29) and 89% (34/38). In the validation set, sensitivity and specificity of ESM1 for the identification of MTM-HCC were 93% (14/15) and 91% (107/117), respectively. Interobserver agreement for ESM1 assessment was good in both series (Cohen Kappa 0.77 and 0.76).
Using a molecular-driven selection of biomarkers, we identified ESM1 as a reliable microenvironment immunohistochemical marker of MTM-HCC. The results represent a step toward the implementation of HCC morpho-molecular subtyping into clinical practice.
Objectives
To evaluate the diagnostic performance of liver surface nodularity (LSN) for the assessment of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD).
Methods
We ...retrospectively analysed patients with pathologically proven NAFLD who underwent liver MRI. Demographic, clinical, and laboratory data (including FIB-4 scores) were gathered. The SAF score was used to assess NAFLD. MRI-proton density fat fraction (PDFF) and LSN were determined on pre-contrast MR sequences. ROC curve analysis was performed to evaluate the diagnostic performance of MRI-LSN for the diagnosis of advanced (F3-F4) liver fibrosis.
Results
The final population included 142 patients. Sixty-seven (47%) patients had non-alcoholic steatohepatitis (NASH), and 52 (37%) had advanced fibrosis. The median MRI-PDFF increased with the grades of steatosis: 8.1%, 18.1%, and 31% in S1, S2, and S3 patients, respectively (
p
< 0.001). The area under the ROC curve (AUC) of MRI-LSN ≥ 2.50 was 0.838 (95%CI 0.767–0.894, sensitivity 67.3%, specificity 88.9%, positive and negative predictive values 77.8% and 82.5%, respectively) for the diagnosis of advanced fibrosis. Combining FIB-4 and MRI-LSN correctly classified 103/142 (73%) patients. This was validated in an external cohort of 75 patients.
Conclusions
MRI-LSN has good diagnostic performance in diagnosis of advanced fibrosis in NAFLD patients. A combination of FIB-4 and MRI-LSN derived from pre-contrast MRI could be helpful to detect advanced fibrosis.
Key Points
•
MRI-LSN
≥
2.5 was accurate for the diagnosis of advanced hepatic fibrosis in NAFLD patients.
•
The combination of FIB-4 and MRI-LSN improved the detection of advanced fibrosis.
•
MRI-LSN can be easily derived by unenhanced MRI sequences that are routinely acquired.
Background: Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis. First-line sorafenib has been the standard of care for a decade, but the treatment landscape is expanding. ...This review provides a practical overview of current and future systemic treatment options for advanced HCC and their place in clinical practice. Summary: First-line sorafenib and lenvatinib have shown to improve the survival of patients with advanced HCC. In the second line, regorafenib provides benefit for patients who previously tolerated sorafenib. Anti-PD1 antibodies, nivolumab and pembrolizumab, recently became available for second-line use in the US. Ramucirumab (for patients with α-fetoprotein AFP levels ≥400) and cabozantinib present potential future second-line treatment options. Combinations of systemic and locoregional treatment, such as radiofrequency ablation or selective internal radiotherapy, require further research. Precision medicine has not yet been translated into clinical practice, as the most common driver mutations (TERT promoter, CTNNB1, TP53, and ARID1A mutations) have not yet been shown to be suitable therapeutic targets. However, our growing understanding of signaling pathways and efforts in drug development are expected to pave the way for precision medicine in HCC in the future. Evaluating the place for the current and novel systemic treatment options in clinical practice can be challenging due to the diverse toxicity profiles of the treatment options and characteristics of the patient population. Sorafenib data elucidate the effect patient characteristics (such as the performance score, Child-Pugh class, AFP, etiology of the underlying disease, and level of macrovascular invasion and extrahepatic spread) may have on outcomes in advanced stages. Key Messages: Lenvatinib is expected to join sorafenib as a preferred first-line treatment in advanced HCC. In the second line, the treatment of choice, regorafenib, is soon expected to be accompanied by cabozantinib and ramucirumab in patients with AFP ≥400 ng/mL, whereas nivolumab and pembrolizumab present second-line alternatives in the US.
Objective
The aim of this study was to assess the prognostic value of liver surface nodularity (LSN) and sarcopenia from preoperative computed tomography (CT) in patients with resectable metabolic ...syndrome (MS)-related hepatocellular carcinoma (HCC).
Methods
Patients with MS undergoing hepatectomy for HCC between 2006 and 2018 at a single center were retrospectively analyzed. LSN and sarcopenia were assessed on preoperative CT scans, and their association with severe (Clavien–Dindo grade 3–5) postoperative complications was analyzed on multivariate analysis. The influence of LSN and sarcopenia on overall survival (OS) and recurrence-free survival (RFS) was assessed.
Results
Overall, 110 patients (92 men 84%, mean 67.7 ± 7.7 years of age) were analyzed. Severe postoperative complications occurred in 34/110 (31%) patients. Patients with severe complications had a significantly higher LSN score (area under the receiver operating characteristic curve 0.68 ± 0.05, optimal cut-off > 2.50) and were more frequently sarcopenic (47% vs. 13% without major complications,
p
< 0.001). Multivariate analysis identified sarcopenia (odds ratio OR 6.51, 95% confidence interval CI 2.08–20.39;
p
< 0.001), LSN > 2.50 (OR 7.05, 95% CI 2.13–23.35;
p
< 0.001), and preoperative portal vein embolization (PVE; OR 6.06, 95% CI 1.71–21.48;
p
= 0.005) as independent predictors of severe complications. LSN and sarcopenia had no influence on OS. Stratification according to a combination of LSN > 2.50 and sarcopenia predicted the risk of severe postoperative complications from 7% (no sarcopenia and LSN ≤2.50) to 71% (sarcopenia and LSN > 2.50;
p
< 0.001), as well as RFS from 61 months (95% CI 40–82) to 17 months (95% CI 9–25;
p
= 0.033). Results remained significant in 52 patients without advanced fibrosis.
Conclusions
The combination of LSN and sarcopenia derived from routine preoperative CT seems to help predict severe postoperative complications and stratification of RFS in patients with MS and resectable HCC.
Background:
In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapeutic sequence is still unclear and no second-line agent has ...proven its efficacy.
Objectives:
The aim of this retrospective multicenter real-world cohort study was to provide an evaluation of the efficacy and safety of the use of second-line tyrosine kinase inhibitors (TKIs) in this population.
Methods:
All patients with advanced HCC, treated in first-line setting by atezolizumab–bevacizumab, and who received at least one dose of treatment with TKI were included in this study. All the data were retrospectively collected from medical records. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall global survival (OGS), and safety. A total of 82 patients were included in this study.
Results:
Patients were assigned to the regorafenib group (n = 29, 35.4%) or other TKI (sorafenib n = 41, lenvatinib n = 8, or cabozantinib n = 4) group (n = 53). PFS was not significantly different between the two groups 2.6 versus 2.8 months, HR 1.07 (95% CI: 0.61–1.86), p = 0.818. Median PFS rates were 2.6, 4.4, and 2.8 months in sorafenib-, lenvatinib-, and cabozantinib group, respectively. OS was statistically different between the regorafenib group and other TKI group 15.8 versus 7.0 months, HR 0.40 (95% CI: 0.20–0.79), p = 0.023. When adjusting on confounding factors, there was still a difference in OS favoring the regorafenib group (adjusted hazard ratio 0.35, p = 0.019). OGS of patients who received regorafenib was improved compared to other TKI 18.6 versus 15.0 months, HR 0.42 (95% CI: 0.22–0.84), p = 0.036. Twenty percent of patients had grade 3 and none had grade 4 or 5 adverse events. In patients who experienced disease progression and fit for a third-line treatment, 80% and 50% received cabozantinib in regorafenib group and other TKI group, respectively.
Conclusion:
Efficacy of any TKI in the second-line setting was not affected by atezolizumab–bevacizumab treatment as first-line therapy. The safety profile in the second-line setting was consistent with the results shown in pivotal studies. PFS rates of patients were similar, regardless of TKI type. Regorafenib was associated with better OS and OGS rates compared to other TKI. These data need to be confirmed in prospective comparative studies.
The histopathological subtypes of hepatocellular carcinoma (HCC) are associated with distinct clinical features and prognoses. This study aims to report Liver Imaging Reporting and Data System ...(LI-RADS)-defined imaging features of different HCC subtypes in a cohort of resected tumours and to assess the influence of HCC subtypes on computed tomography (CT)/magnetic resonance imaging (MRI) LI-RADS categorisation in the subgroup of high-risk patients.
This retrospective institutional review board-approved study included patients with resected HCCs and available histopathological classification. Three radiologists independently reviewed preoperative CT and MRI exams. The readers evaluated the presence of imaging features according to LI-RADS v2018 definitions and provided a LI-RADS category in patients at high risk of HCC. Differences in LI-RADS features and categorisations were assessed for not otherwise specified (NOS-HCC), steatohepatitic (SH-HCC), and macrotrabecular-massive (MTM-HCC) types of HCCs.
Two hundred and seventy-seven patients (median age 64.0 years, 215 77.6% men) were analysed, which involved 295 HCCs. There were 197 (66.7%) NOS-HCCs, 62 (21.0%) SH-HCCs, 23 (7.8%) MTM-HCCs, and 13 (4.5%) other rare subtypes. The following features were more frequent in MTM-HCC: elevated α-foetoprotein serum levels (p <0.001), tumour-in-vein (p <0.001 on CT, p ≤0.052 on MRI), presence of at least 1 LR-M feature (p ≤0.010 on CT), infiltrative appearance (p ≤0.032 on CT), necrosis or severe ischaemia (p ≤0.038 on CT), and larger size (p ≤0.006 on CT, p ≤0.011 on MRI). SH-HCC was associated with fat in mass (p <0.001 on CT, p ≤0.002 on MRI). The distribution of the LI-RADS major features and categories in high-risk patients did not significantly differ among the 3 main HCC subtypes.
The distribution of LI-RADS major features and categories is not different among the HCC subtypes. Nevertheless, careful analysis of tumour-in-vein, LR-M, and ancillary features as well as clinico-biological data can provide information for the non-invasive diagnosis of HCC subtypes.
In high-risk patients, the overall distribution of LI-RADS major features and categories is not different among the histological subtypes of hepatocellular carcinoma, but tumour-in-vein, presence of LR-M features, and ancillary features can provide information for the non-invasive diagnosis of hepatocellular carcinoma subtypes.
Display omitted
•The distribution of the major features and categories of LI-RADS is not different among the HCC histological subtypes.•MTM-HCC was associated with TIV, ≥1 LR-M feature, infiltrative appearance, necrosis or severe ischaemia, and larger size.•Steatohepatitis-related HCC was associated with fat in mass on CT and on MRI.
Purpose
Steatohepatitic hepatocellular carcinoma (SH-HCC) is characterized by intratumoral fat with > 50% inflammatory changes. However, intratumoral fat (with or without inflammation) can also be ...found in not-otherwise specified HCC (NOS-HCC). We compared the imaging features and outcome of resected HCC containing fat on pathology including SH-HCC (> 50% steatohepatitic component), NOS-HCC with < 50% steatohepatitic component (SH-NOS-HCC), and fatty NOS-HCC (no steatohepatitic component).
Material and methods
From September 2012 to June 2021, 94 patients underwent hepatic resection for fat-containing HCC on pathology. Imaging features and categories were assessed using LIRADS v2018. Fat quantification was performed on chemical-shift MRI. Recurrence-free and overall survival were estimated.
Results
Twenty-one patients (26%) had nonalcoholic steatohepatitis (NASH). The median intra-tumoral fat fraction was 8%, with differences between SH-HCC and SH-NOS-HCC (9.5% vs. 5%
p
= 0.03). There was no difference in major LI-RADS features between all groups; most tumors were classified as LR-4/5. A mosaic architecture on MRI was rare (7%) in SH-HCC, a fat in mass on CT was more frequently depicted (48%) in SH-HCC. A combination of NASH with no mosaic architecture on MRI or NASH with fat in mass on CT yielded excellent specificity for diagnosing SH-HCC (97.6% and 97.7%, respectively). The median recurrence-free and overall survival were 58 and 87 months, with no difference between groups (
p
= 0.18 and
p
= 0.69).
Conclusion
In patients with NASH, an SH-HCC may be suspected in L4/LR-5 observations with no mosaic architecture at MRI or with fat in mass on CT. Oncological outcomes appear similar between fat-containing HCC subtypes.
Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line ...treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV
cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study.
Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously.
Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials.
NCT05528952.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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