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Background: Ablation is a first-line treatment for Barcelona Clinic Liver Cancer (BCLC)-0/A hepatocellular carcinoma (HCC). However, there are scarce data about patients’ outcomes after recurrence. The present study evaluates the impact of patient and tumor characteristics at baseline and at recurrence on the Clinical Decision-Making process. Methods: We evaluated BCLC-0/A patients treated with percutaneous ablation from January 2010 to November 2018. Clinical and radiological data such as age, tumor location at ablation, pattern of recurrence/progression, and comorbidities during follow-up were registered. Tumor location was divided into ‘suboptimal’ vs. ‘optimal’ locations for ablation. The Clinical Decision-Making was based on tumor burden, liver dysfunction, or comorbidities. The statistical analysis included the time-to-recurrence/progression, censoring at time of death, date of last follow-up or liver transplantation, and time-to-event was estimated by the Kaplan–Meier method and Cox regression models to evaluate the risk of an event of death and change of treatment strategy. Results: A total of 225 patients [39.1% BCLC-0 and 60.9% BCLC-A] were included, 190 had unifocal HCC and 82.6% were ≤3 cm. The complete response rate and median overall survival were 96% and 60.7 months. The HCC nodules number (Hazard Ratio—HR 3.1), Child-Pugh (HR 2.4), and Albumin-Bilirubin score (HR 3.2) were associated with increased risk of death during follow-up. HCC in ‘suboptimal location’ presented a shorter time to recurrence. When comorbidities prevented further loco-regional or systemic treatment, the risk of death was significantly increased (HR 2.0, p = 0.0369) in comparison to those who received treatment. Conclusions: These results expose the impact of non-liver comorbidities when considering treatment for recurrence after ablation in the real-world setting and in research trials. Ultimately, we identified an orphan population for which effective interventions are needed.

Understanding how reaction conditions affect metal-support interactions in catalytic materials is one of the most challenging tasks in heterogeneous catalysis research. Metal nanoparticles and their supports often undergo changes in structure and oxidation state when exposed to reactants, hindering a straightforward understanding of the structure-activity relations using only ex situ or ultrahigh vacuum techniques. Overcoming these limitations, we explored the metal-support interaction between gold nanoparticles and ceria supports in ultrahigh vacuum and after exposure to CO. A combination of in situ methods (on powder and model Au/CeO2 samples) and theoretical calculations was applied to investigate the gold/ceria interface and its reactivity toward CO exposure. X-ray photoelectron spectroscopy measurements rationalized by first-principles calculations reveal a distinctly inhomogeneous charge distribution, with Au+ atoms in contact with the ceria substrate and neutral Au0 atoms at the surface of the Au nanoparticles. Exposure to CO partially reduces the ceria substrate, leading to electron transfer to the supported Au nanoparticles. Transferred electrons can delocalize among the neutral Au atoms of the particle or contribute to forming inert Auδ− atoms near oxygen vacancies at the ceria surface. This charge redistribution is consistent with the evolution of the vibrational frequencies of CO adsorbed on Au particles obtained using diffuse reflectance infrared Fourier transform spectroscopy.

Background The aim of the study was to analyze the association between the liver uptake of Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) in the hepatobiliary phase (HBP) in cirrhotic patients and the presence of clinically significant portal hypertension (CSPH), and how these features impact on hepatocellular carcinoma (HCC) detection in the HBP. Patients and methods Post-hoc analysis of a prospective cohort of 62 cirrhotic patients with newly US-detected nodule between 1–2 cm (study group). Twenty healthy subjects were used as control group. Qualitative and quantitative analysis of the liver contrast uptake in the HBP assessed by Relative Liver-Enhancement (RLE), Liver-Spleen (LSCR), Liver-Muscle (LMCR), and Liver-Kidney Contrast-Ratio (LKCR), Contrast Enhancement Index (CEI), and Hepatic Uptake (HUI), and biliary excretion, were registered. CSPH was confirmed invasively (HVPG > 10 mmHg) or by indirect parameters. The appearance of HCC at the HBP was analyzed. Results Nineteen patients (30.6%) did not have CSPH. In 41 patients (66.1%) the final diagnosis was HCC. All indices were significantly higher in the control group, indicating a more intense HBP liver signal intensity compared to patients with cirrhosis, even if the comparison was restricted to patients with no CSPH. CSPH was associated to a lower rate of HCC hypointensity in the HBP (51.9% vs. 85.7% without CSPH, p = 0.004). Conclusions Liver uptake of Gd-EOB-DTPA at the HBP is decreased in cirrhosis even if the liver function is minimally impaired and it falls down significantly in patients with CSPH compromising the recognition of hypointense lesions. This fact may represent a limitation for the detection of small HCC in patients with cirrhosis and CSPH.

Dermatologic adverse events (DAEs) are associated with a better outcome in patients with hepatocellular carcinoma (HCC) irrespective of the therapeutic agent received. The exact mechanisms associated with the development of DAEs are unknown although several studies point to direct toxicity of tyrosine kinase inhibitors (TKIs) to the skin or an immune-mediated reaction triggered by the oncologic treatment. As is the case in other conditions, individual genetic variants may partially explain a higher risk of DAEs.To evaluate the contribution of several gene variants to the risk of developing DAEs in HCC patients treated with TKIs.We first analyzed 27 single-nucleotide polymorphisms (SNPs) from 12 genes selected as potential predictors of adverse event (AE) development in HCC patients treated with sorafenib [Barcelona Clinic Liver Cancer 1 (BCLC1) cohort]. Three additional cohorts were analyzed forThe BCLC1 cohort showed that patients with arterial hypertension (AHT) (HR = 1.61;DAE development in HCC patients receiving TKIs could be explained by the

Gastrointestinal adverse events (GIAEs) are common in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. Diarrhea is a prevalent event responsible for treatment interruptions and dosage modifications. Our study evaluates the role of baseline blood L-glutamine (L-Gln) levels in the prediction of gastrointestinal adverse events development early during treatment (eGIAE). Blood L-Gln was measured in 135 patients with advanced HCC prior to starting sorafenib. Any adverse events developed during therapy were registered in a prospective database. We used Mann–Whitney U and Fisher’s exact tests to compare quantitative or categorical variables, respectively, Kaplan–Meier method to analyze time to event variables, log-rank test for the survival functions and Cox regression models to estimate hazard ratios (HR). Fifteen per cent of patients developed eGIAE, with diarrhea as the most frequent one. Patients displaying the lowest L-Gln levels presented a significant higher risk of eGIAE, while those with the highest levels were protected from eGIAE and achieved better survival. Our study shows for the first time the association of baseline blood L-Gln levels with eGIAE development in HCC patients during sorafenib treatment. Low L-Gln concentrations might reflect a potentially compromised intestinal barrier that becomes clinically relevant early after treatment start.

Polyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC).The current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0. Patients in Cohort I were assigned to receive target doxorubicin doses of 75, 100, or 150 mg. Analyses were performed on the basis of the specific dose of doxorubicin that the patients received because some patients received less than the assigned dose. Patients in Cohort II received the maximum safe tested dose. Adverse events were classified according to the Common Terminology Criteria for Adverse Events version 4.03. The tumor response was evaluated every 3 months according to the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors.The maximum tested safe dose of doxorubicin was 150 mg. For the groups that received ≤75, 75-100, and 101-150 mg of doxorubicin, the peak plasma concentrations were 286.7 ng/mL ± 220.1, 157.1 ng/mL ± 94.6, and 245.4 ng/mL ± 142.8, respectively; the areas under the curves calculated from 0 to 24 h were 421.7 (ng × h)/mL ± 221.2, 288.1 (ng × h)/mL ± 100.9, and 608.3 (ng × h)/mL ± 319.3, respectively, with almost complete clearance at 24 h. There was no death within 30 d. The best objective response rate was 81%, and the disease control rate was 91%. The median overall survival was 27.2 months (95% confidence interval [CI], 17.5 months to not evaluated [n.e.]); the median progression-free survival was 9.8 months (95% CI, 5.5 months to n.e.).PEG-DEMs demonstrated a favorable safety profile with low systemic concentration of doxorubicin, and promising efficacy.

PDF file, 10.8MB, Supplementary Table 1: Clinical characteristics of human hepatocellular carcinoma samples. Supplementary Table 2: Clinical Characteristics of 5 public HCC datasets. Supplementary Table 3: Wnt-pathway mRNA list: 210 Wnt-related genes from the literature. Supplementary Table 4: Wnt-pathway miRNA list: 49 Wnt-related miRNAs from the literature. Supplementary Table 5: Significantly differentially expressed Wnt-related genes in CTNNB1- and Wnt-TGF_-class samples of the training set. Supplementary Table 6: Summary of dysregulated CTNNB1- and Wnt-TGF_-Wnt-genes according to their cellular localization and their known or suspected function. Supplementary Table 7: Expression of known liver-related Wnt-target-genes. Supplementary Table 8: Correlation of Wnt-related transcription factors to Wnt-target-genes in the training set. Supplementary Table 9: Frequency _catenin IHC positive samples and CTNNB1 mutations Wnt-related and non-Wnt-related subclasses of HCC in the in training (T) and validation (V) sets. Supplementary Table 10: Differentially expressed Wnt-related-miRNAs in 89 HCC samples of the training set. Supplementary Table 11: Enrichment of samples identified by CTNNB1-, Wnt-TGF__ WntGenes- and CTNNB1-mutation-signature in CTNNB1 and Wnt-TGF_ subclasses in 5 independent datasets (Fisher's Exact Test). Supplementary Table 12: 21 Liver Cancer cell lines analyzed by GSEA for gene expression profiles similar to either CTNNB1 or Wnt-TGF_ class. Supplementary Figure 1: Differential Expression of Wnt-pathway mRNAs in the CTNNB1- and Wnt-TGF Beta-classes in the training set. Supplementary Figure 2: Differential Expression of Wnt-pathway-miRNAs in the CTNNB1- and Wnt-TGF Beta-classes in the training set. Supplementary Figure 3: Validation of CTNNB1- and Wnt-TGF Beta-specific Wnt-related mRNA profiles and mutation-status in 5 public HCC datasets. Supplementary Figure 4: Validation of the mutation signature in an independent cohort of HCC. Supplementary Figure 5: Correlation of gene expression data from 21 different liver cancer cell lines with CTNNB1 and Wnt-TGF Beta class signatures by GSEA. Supplementary Figure 6: Baseline luciferase levels in Wnt reporter liver cancer cells stably transduced with TCF/LEF luciferase reporter. Supplementary Figure 7: Sorafenib decreases beta-catenin protein levels in 4 liver cancer cell lines.

The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets allow unprecedented gene expression analyses. Here, using these datasets, we performed pan-cancer and pan-tissue identification of coding and long noncoding RNA (lncRNA) transcripts differentially expressed in tumors and preferentially expressed in healthy tissues and/or tumors. Pan-cancer comparison of mRNAs and lncRNAs showed that lncRNAs were deregulated in a more tumor-specific manner. Given that lncRNAs are more tissue-specific than mRNAs, we identified healthy tissues that preferentially express lncRNAs upregulated in tumors and found that testis, brain, the digestive tract, and blood/spleen were the most prevalent. In addition, specific tumors also upregulate lncRNAs preferentially expressed in other tissues, generating a unique signature for each tumor type. Most tumors studied downregulated lncRNAs preferentially expressed in their tissue of origin, probably as a result of dedifferentiation. However, the same lncRNAs could be upregulated in other tumors, resulting in "bimorphic" transcripts. In hepatocellular carcinoma (HCC), the upregulated genes identified were expressed at higher levels in patients with worse prognosis. Some lncRNAs upregulated in HCC and preferentially expressed in healthy testis or brain were predicted to function as oncogenes and were significantly associated with higher tumor burden, and poor prognosis, suggesting their relevance in hepatocarcinogenesis and/or tumor evolution. Taken together, therapies targeting oncogenic lncRNAs should take into consideration the healthy tissue, where the lncRNAs are preferentially expressed, to predict and decrease unwanted secondary effects and increase potency.Significance:Comprehensive analysis of coding and noncoding genes expressed in different tumors and normal tissues, which should be taken into account to predict side effects from potential coding and noncoding gene-targeting therapies.

Functional analysis with GSEA. A. Enrichment plots of cell cycle genes for each lncRNA. B. Specific enrichment plots for the indicated lncRNAs. FDR q-value = 0. NES indicates the normalized enrichment score. C. Expression correlation of LINC00665 with ZNF gene clusters of chr 19. Pearson correlation of the expression of the indicated genes with the levels of LINC00665. All genes have been ordered by location at chr19 p12, q13.41 or q13.12, where LINC00665 gene is located.

Coding and lncRNAs specifically or preferentially expressed in different tissues or tumors. Donor tissues. Values (in percentage) used to build the pie chart of Fig. 4B. IPA. Ingenuity analysis of cancer categories enriched for mRNAs donated by the indicated tissues. p values are indicated. Only tumors with a p value higher than 1.0E-03 are indicated. GO. Gene ontology analysis of the functions enriched for mRNAs donated by the indicated tissues. FDR values are indicated.

Purpose: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer.Experimental Design: The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model.Results: Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFβ class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFβ class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt signaling and β-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFβ class), SNU398 (CTNNB1-mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class–specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals.Conclusions: Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature. Clin Cancer Res; 18(18); 4997–5007. ©2012 AACR.

Supplementary Information from Focal Gains of VEGFA and Molecular Classification of Hepatocellular Carcinoma

BACKGROUNDIn women, risk stratification for a major adverse coronary event (MACE) is complex, and moreover women have often been underrepresented in cardiovascular studies. This study aims to establish aCOronaryRiskScore inWOmen (CORSWO) to predict MACE.METHODSFrom a cohort of 25,943 consecutive patients referred for clinical gSPECT-MPI (gated single-photon emission computed tomography myocardial perfusion imaging), 2,226 women (aged 66.7±11.6 years) were included. During the follow-up (mean 4±2.7 years) post gSPECT-MPI, MACE (unstable-angina requiring hospitalization, non-fetal myocardial infarction, coronary revascularization, cardiac death) was assessed. The patients were divided into training (n=1460) and validation (n=766) groups. To obtain the predictor model, LASSO-regression analysis with 10-fold cross-validation was used.RESULTSIn training group, 148 women had MACE (0.026/patient/year). The best model (ROC area:0.8, Brier score:0.0777) to stratify women included: age >69 years (OR:1.6); diabetes mellitus (OR:2); angina-history (OR:1.6); nitrate (OR:1.5); left bundle branch block (OR:1.2); pharmacological test (OR:1.6); ST-segment-depression (≥1mm) (OR:2); stress angina (OR:1.3); myocardial ischemia >5% (OR:2.6); perfusion defect at rest >9% (OR:2.4); perfusion defect at stress >6% (OR:1.7); end-systolic volume index >15 ml (OR:1.6); and left ventricular ejection fraction CONCLUSIONSIn a clinical practice setting we can obtain an excellent coronary risk stratification in women, however at the expense of multiple variables.CLINICAL PERSPECTIVEWhat Is New?The coronary risk stratification of women depends on of the multiple clinical, exercise and imaging variables.This new risk score allows the risk to be calculated for individual women in a simple way with a mean of a 4-year follow-up.What Are the Clinical Implications?CORSWO is an effective tool to stratify the risk for major adverse coronary event in 5 risk levels, very low, low, moderate, high and very high risk with a good accuracy.

Background & Aims Information about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with liver cancer is lacking. This study characterizes the outcomes and mortality risk in this population. Methods Multicentre retrospective, cross-sectional, international study of liver cancer patients with SARS-CoV-2 infection registered between February and December 2020. Clinical data at SARS-CoV-2 diagnosis and outcomes were registered. Results Two hundred fifty patients from 38 centres were included, 218 with hepatocellular carcinoma (HCC) and 32 with intrahepatic cholangiocarcinoma (iCCA). The median age was 66.5 and 64.5 years, and 84.9% and 21.9% had cirrhosis in the HCC and iCCA cohorts respectively. Patients had advanced cancer stage at SARS-CoV-2 diagnosis in 39.0% of the HCC and 71.9% of the iCCA patients. After a median follow-up of 7.20 (IQR: 1.84–11.24) months, 100 (40%) patients have died, 48% of the deaths were SARS-CoV-2-related. Forty (18.4%) HCC patients died within 30-days. The death rate increase was significantly different according to the BCLC stage (6.10% [95% CI 2.24–12.74], 11.76% [95% CI 4.73–22.30], 20.69% [95% CI 11.35–31.96] and 34.52% [95% CI 17.03–52.78] for BCLC 0/A, B, C and D, respectively; p = .0017). The hazard ratio was 1.45 (95% CI 0.49–4.31; p = .5032) in BCLC-B versus 0/A, and 3.13 (95% CI 1.29–7.62; p = .0118) in BCLC-C versus 0/A in the competing risk Cox regression model. Nineteen out of 32 iCCA (59.4%) died, and 12 deaths were related to SARS-CoV-2 infection. Conclusions This is the largest cohort of liver cancer patients infected with SARS-CoV-2. It characterizes the 30-day mortality risk of SARS-CoV-2 infected patients with HCC during this period., Spanish Health Ministry; Ricerca Corrente, Grant/Award Number: RC2019/105-01, RC2018/105-01 and RC2017/105-01; European Association for the Study of the Liver (Andrew Burroughs Fellowship); Cancer Treatment and Research Trust (CTRT); Wellcome Trust Strategic Fund, Grant/Award Number: PS3416; Cancer Research UK (CR UK) centre, Grant/Award Number: C9380/A26813, C18342/A23390 and C9380/A18084; Instituto de Salud Carlos III, Grant/Award Number: PI18/0358, PI15/00145, CD18/00126, PI19/00819, FI19/00222, 16-0026, PI044031, PI18/00768, PI18/00542 and PI13/01229; Bristol Myers Squibb and Celgene; Cancer Research UK, Grant/Award Number: RCCPDB-Nov21/100008