Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors has been approved as a first-line treatment for unresectable hepatocellular carcinoma ...(HCC), indicating a critical role of ICIs in the treatment of HCC. However, 20% of patients do not respond effectively to ICIs; mutations in the activation of the Wnt/β-catenin pathway are known to contribute to primary resistance to ICIs. From this point of view, non-invasive detection of Wnt/β-catenin activation should be informative for the management of advanced HCC. Wnt/β-catenin mutations in HCC have a dual aspect, which results in two distinct tumor phenotypes. HCC with minimal vascular invasion, metastasis, and good prognosis is named the "Jekyll phenotype", while the poorly differentiated HCC subset with frequent vascular invasion and metastasis, cancer stem cell features, and high serum Alpha fetoprotein levels, is named the "Hyde phenotype". To differentiate these two HCC phenotypes, a combination of the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and fluoro-2-deoxy-D-glucose-PET/CT may be useful. The former is applicable for the detection of the Jekyll phenotype, as nodules present higher enhancement on the hepatobiliary phase, while the latter is likely to be informative for the detection of the Hyde phenotype by showing an increased glucose uptake.
Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic ...alterations in oncogenic pathways such as Wnt/β-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/β-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field:
Although transcatheter arterial chemoembolization (TACE) is the standard of care for intermediate-stage hepatocellular carcinoma (HCC), this is a largely heterogeneous disease that includes a ...subgroup of patients who do not benefit from TACE. The treatment strategy for this subgroup of patients currently remains an unmet need in clinical practice. Here, we performed a proof-of-concept study that lenvatinib may be a more favorable treatment option over TACE as an initial treatment in intermediate-stage HCC patients with large or multinodular tumours exceeding the up-to-seven criteria. This proof-of-concept study included 642 consecutive patients with HCC initially treated with lenvatinib or conventional TACE (cTACE) between January 2006 and December 2018. Of these patients, 176 who received lenvatinib or cTACE as an initial treatment and met the eligibility criteria (unresectable, beyond the up-to-seven criteria, no prior TACE/systemic therapy, no vascular invasion, no extrahepatic spread and Child-Pugh A liver function) were selected for the study. Propensity score matching was used to adjust for patient demographics. After propensity-score matching, the outcome of 30 patients prospectively treated with lenvatinib (14 in clinical trials, one in an early access program and 15 in real world settings) and 60 patients treated with cTACE as the initial treatment was compared. The change of albumin-bilirubin (ALBI) score from baseline to the end of treatment were -2.61 to -2.61 for 30 patients in the lenvatinib group (
= 0.254) and -2.66 to -2.09 in the cTACE group (
< 0.01), respectively. The lenvatinib group showed a significantly higher objective response rate (73.3% vs. 33.3%;
< 0.001) and significantly longer median progression-free survival than the cTACE group (16.0 vs. 3.0 months;
< 0.001). Overall survival was significantly longer in the lenvatinib group than in the cTACE group (37.9 vs. 21.3 months; hazard ratio: 0.48,
< 0.01). In patients with large or multinodular intermediate-stage HCC exceeding the up-to-seven criteria with Child-Pugh A liver function, who usually do not benefit from TACE, lenvatinib provides a more favorable outcome than TACE.
Abstract
It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present ...study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child–Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.
Thermal ablation therapy, including radiofrequency ablation (RFA) and microwave ablation (MWA), is considered the optimal locoregional treatment for unresectable early-stage hepatocellular carcinomas ...(HCCs). Percutaneous image-guided ablation is a minimally invasive treatment that is being increasingly performed because it achieves good clinical outcomes with a lower risk of complications. However, the physics and principles of RFA and MWA markedly differ. Although percutaneous thermal ablation under image guidance may be challenging in HCC cases with limited access or a risk of thermal injury, a number of ablative techniques, each of which may be advantageous and disadvantageous for individual cases, are available. Furthermore, even when a HCC is eligible for ablation based on tumor selection and technical factors, additional patient factors may have an impact on whether it is the appropriate treatment choice. Therefore, a basic understanding of the advantages and limitations of each ablation device and imaging guidance technique, respectively, is important. We herein provide an overview of the basic principles of tissue heating in thermal ablation, clinical and laboratory parameters for ablation therapy, preprocedural management, imaging assessments of responses, and early adverse events. We also discuss associated challenges and how they may be overcome using optimized imaging techniques.
Deterioration surveys of large structures such as furnaces have been mainly conducted by visual inspection, but it is desirable to automatically detect deterioration using point clouds captured by ...the terrestrial laser scanner. In this study, we propose flexible methods for detecting various scales of cracks, delamination, and adhesion on furnace walls by using a machine learning technique. Since small cracks have few geometrical features, they are detected from the reflection intensity images generated by projecting a point cloud onto a two-dimensional plane. For detecting cracks on the image, we use the U-Net fine-tuned by crack images denoised with a median filter. For detecting delamination and adhesion, a wall surface is approximated by a smooth B-spline surface, and deterioration is detected as differences between the point cloud and the approximated surface. However, in this method, the resolution of the B-spline surface has to be carefully determined according to the expected deterioration sizes. To robustly detect deterioration at various scales, we introduce multiscale 3D features, and detect deterioration using both multiscale 3D features and 2D features. In actual walls, it is difficult to distinguish between cracks and delamination because delamination grows from cracks. To detect both types of deterioration in a uniform manner, we combine the two detectors and propose an integrated detector for detecting deterioration at various scales. Our experimental results showed that our methods could stably detect various scales of degradation on furnace walls.
This study investigated the impact of baseline liver function according to the Child-Pugh score and ALBI (albumin-bilirubin) grade on the outcomes of patients with unresectable hepatocellular ...carcinoma treated with lenvatinib.
A total of 82 lenvatinib treated patients were included. The correlations of baseline liver function according to the Child-Pugh score and ALBI grade with treatment outcomes, including objective response rate per mRECIST (modified Response Evaluation Criteria in the Solid Tumor), time to treatment failure, treatment duration, and likelihood of treatment discontinuation due to adverse events, were assessed in patients with hepatocellular carcinoma treated with lenvatinib. Patients were divided into four groups: (1) Child-Pugh score 5 and ALBI grade 1 (group 1), (2) Child-Pugh score 5 and ALBI grade 2 (group 2), (3) Child-Pugh score 6 (group 3), and (4) Child-Pugh score ≥7 (group 4). Univariate and multivariate analyses were performed to identify the factors contributing to the objective response rate and likelihood of discontinuation due to adverse events.
Among the 82 patients analyzed, group 1 had the highest objective response rate (57.1%) and the lowest likelihood of treatment discontinuation because of adverse events (11.1%) among the four groups (
< 0.05 and
< 0.05). Multivariate analysis identified ALBI grade 1 and baseline AFP level <200 ng/mL as the significant predictors of a high objective response rate (
< 0.05 and
< 0.01), and confirmed that patients with ALBI grade 1 had the lowest probability of treatment discontinuation due to adverse events (
< 0.01).
Patients with Child-Pugh score of 5 and ALBI grade 1 predicted a higher response rate and lower treatment discontinuation due to adverse events by lenvatinib treatment.
We investigated the effects of moderate hypoxia (FiO2 = 15%) on different kinetics between pulmonary ventilation (Formula: see text) and heart rate (HR) during treadmill walking. Breath-by-breath ...Formula: see text, oxygen uptake (Formula: see text), carbon dioxide output (Formula: see text), and HR were measured in 13 healthy young adults. The treadmill speed was sinusoidally changed from 3 to 6 km·h-1 with four oscillation periods of 1, 2, 5, and 10 min. The amplitude (Amp), phase shift (PS) and mean values of these kinetics were obtained by harmonic analysis. The mean values of all of these responses during walking at a sinusoidally changing speed became greater under hypoxia compared to normoxia (FiO2 = 21%), indicating that moderate hypoxia could achieve an increased energy expenditure (increased Formula: see text and Formula: see text) and hyperventilation. The Amp values of the Formula: see text, Formula: see text, and Formula: see text kinetics were not significantly different between normoxia and hypoxia at most periods, although a significantly smaller Amp of the HR was observed at faster oscillation periods (1 or 2 min).The PS of the HR was significantly greater under hypoxia than normoxia at the 2, 5, and 10 min periods, whereas the PS of the Formula: see text, Formula: see text, and Formula: see text responses was not significantly different between normoxia and hypoxia at any period. These findings suggest that the lesser changes in Amp and PS in ventilatory and gas exchange kinetics during walking at a sinusoidally changing speed were remarkably different from a deceleration in HR kinetics under moderate hypoxia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 ...or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8
T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4
T cells, CD8
T cells, CD20
B cells, and FOXP3
Tregs. Overall, the activation of CD8
T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
Aim
The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral ...effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration.
Methods
This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated.
Results
Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty‐eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog.
Conclusion
In rare cases, HBsAg‐positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.
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