Revistas
Revista:
SCIENTIFIC REPORTS
ISSN 2045-2322
Vol. 12
N° 1
Año 2022
Págs.1777
Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy-hypertrophy complex after SIRT. Three groups of 5-8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of Y-90 resin microspheres in rabbits is a reliable animal model to analyse the atrophy-hypertrophy complex and liver damage without toxicity.
Revista:
DIGESTIVE DISEASES
ISSN 0257-2753
Vol. 40
N° 3
Año 2022
Págs.322 - 334
Introduction: Selective internal radiation therapy (SIRT) is a local treatment option for patients with hepatocellular carcinoma (HCC). Its exact role next to other HCC therapies has yet to be defined. In order to identify patients most suitable for SIRT, a SIRT-specific prognostic score should be developed. Methods: A cohort of 72 SIRT patients treated at the University Hospital of Munich was retrospectively analyzed. The prognostic performance of 12 HCC staging systems and prognostic scores was assessed. Cox-regression analysis was used to identify independent prognostic factors, which formed the basis of the Munich-SIRT score (M-SIRT). All scores were ranked by calculating the c-Index and Akaike information criterion (AIC). External validation was performed in a cohort of 128 SIRT patients treated at the University Hospital of Pamplona, Spain. Results: median overall survival was 13 months (95% confidence interval 9.9-21.9). AFP (p = 0.005; hazard ratio [HR] 2.38), albumin (p < 0.001; HR 5.87), and alkaline phosphatase (p < 0.001; HR 8.38) were identified as independent prognostic factors. M-SIRT comprises 3 prognostic groups with a median survival of 38.9, 14.6, and 7.7 months, respectively (I vs. II: p = 0.003, II vs. III: p < 0.001). AIC (318) and concordance index (0.711) ranked M-SIRT superior to the established HCC staging systems, and the score successfully passed external validation in an independent SIRT cohort (I vs. II: p = 0.03; II vs. III: p = 0.007). Conclusion: Therapy-specific prognostic scores can facilitate treatment decisions and prognostication for HCC patients. Considering its performance in 200 SIRT patients, M-SIRT is a promising prognostic tool for HCC patients evaluated for SIRT.
Autores:
Reig, M. (Autor de correspondencia); Forner, A.; Rimola, J.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 76
N° 3
Año 2022
Págs.681 - 693
There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management.
Autores:
Oecal, O.; Schuette, K.; Kupcinskas, J.; et al.
Revista:
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
ISSN 0171-5216
Vol. 148
N° 2
Año 2022
Págs.475 - 485
Purpose To explore the potential correlation between baseline interleukin (IL) values and overall survival or objective response in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Methods A subset of patients with HCC undergoing sorafenib monotherapy within a prospective multicenter phase II trial (SORAMIC, sorafenib treatment alone vs. combined with Y90 radioembolization) underwent baseline IL-6 and IL-8 assessment before treatment initiation. In this exploratory post hoc analysis, the best cut-off points for baseline IL-6 and IL-8 values predicting overall survival (OS) were evaluated, as well as correlation with the objective response. Results Forty-seven patients (43 male) with a median OS of 13.8 months were analyzed. Cut-off values of 8.58 and 57.9 pg/mL most effectively predicted overall survival for IL-6 and IL-8, respectively. Patients with high IL-6 (HR, 4.1 [1.9-8.9], p < 0.001) and IL-8 (HR, 2.4 [1.2-4.7], p = 0.009) had significantly shorter overall survival than patients with low IL values. Multivariate analysis confirmed IL-6 (HR, 2.99 [1.22-7.3], p = 0.017) and IL-8 (HR, 2.19 [1.02-4.7], p = 0.044) as independent predictors of OS. Baseline IL-6 and IL-8 with respective cut-off values predicted objective response rates according to mRECIST in a subset of 42 patients with follow-up imaging available (IL-6, 46.6% vs. 19.2%, p = 0.007; IL-8, 50.0% vs. 17.4%, p = 0.011). Conclusion IL-6 and IL-8 baseline values predicted outcomes of sorafenib-treated patients in this well-characterized prospective cohort of the SORAMIC trial. We suggest that the respective cut-off values might serve for validation in larger cohorts, potentially offering guidance for improved patient selection.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 45
Año 2022
Págs.12 - 20
Yttrium-90 radioembolization (RE) is a widely used transcatheter intraarterial therapy for patients with unresectable liver cancer. In the last decade, computer simulations of hepatic artery hemodynamics during RE have been performed with the aim of better understanding and improving the therapy. In this review, we introduce the concept of computational fluid dynamics (CFD) modeling with a clinical perspective and we review the CFD models used to study RE from the fluid mechanics point of view. Finally, we show what CFD simulations have taught us about the hemodynamics during RE, the current capabilities of CFD simulations of RE, and we suggest some future perspectives.
Revista:
INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939
Vol. 38
N° 4
Año 2022
Págs.e3577
Radioembolization (RE) is a medical treatment for primary and secondary liver cancer that involves the transcatheter intraarterial delivery of micron-sized and radiation-emitting microspheres, with the goal of improving microsphere deposition in the tumoral bed while sparing healthy tissue. An increasing number of in vitro and in silico studies on RE in the literature suggest that the particle injection velocity, spatial location of the catheter tip and catheter type are important parameters in particle distribution. The present in silico study assesses the performance of a novel catheter design that promotes particle dispersion near the injection point, with the goal of generating a particle distribution that mimics the flow split to facilitate tumour targeting. The design is based on two factors: the direction and the velocity at which particles are released from the catheter. A series of simulations was performed with the catheter inserted at an idealised hepatic artery tree with physiologically realistic boundary conditions. Two longitudinal microcatheter positions in the first generation of the tree were studied by analysing the performance of the catheter in terms of the outlet-to-outlet particle distribution and split flow matching. The results show that the catheter with the best performance is one with side holes on the catheter wall and a closed frontal tip. This catheter promotes a flow-split-matching particle distribution, which improves as the injection crossflow increases.
Autores:
Vogel, A.; Cervantes, A.; Chau, I.; et al.
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 33
N° 6
Año 2022
Págs.666
Revista:
CANCERS
ISSN 2072-6694
Vol. 14
N° 9
Año 2022
Págs.2048
Simple Summary Hepatocarcinogenesis is a long process which implies the loss of hepatic functions. Our effort is to understand the mechanisms implicated in this pathological process in order to contribute to the development of new diagnostic markers and therapeutic targets. In this study we have identified a set of lncRNAs significantly downregulated in hepatocellular carcinoma (HCC) in correlation with the grade of tumor dedifferentiation and patients' worse prognosis. Mechanistically, our results show that they are related with hepatic differentiation and at least a subset of those lncRNAs are essential to ensure the expression of other hepato-specific genes required for liver function. Moreover, we demonstrate that the expression of these lncRNAs in HCC is silenced by DNA methylation. All in all, we uncover connected epigenetic alterations involved in the progression of liver cancer and identify potential new biomarkers. Background: Long noncoding RNAs (lncRNAs) are emerging as key players in cancer, including hepatocellular carcinoma (HCC). Here we identify the mechanism implicated in the HCC inhibition of a set of lncRNAs, and their contribution to the process of hepatocarcinogenesis. Methods and Results: The top-ranked 35 lncRNAs downregulated in HCC (Top35 LNDH) were validated in several human HCC cohorts. We demonstrate that their inhibition is associated with promoter hypermethylation in HCC compared to control tissue, and in HCC human cell lines compared to primary hepatocytes. Moreover, demethylating treatment of HCC human cell lines induced the expression of these lncRNAs. The Top35 LNDH were preferentially expressed in the adult healthy liver compared to other tissues and fetal liver and were induced in well-differentiated HepaRG cells. Remarkably, their knockdown compromised the expression of other hepato-specific genes. Finally, the expression of the Top35 LNDH positively correlates with the grade of tumor differentiation and, more importantly, with a better patient prognosis. Conclusions: Our results demonstrate that the selected Top35 LNDH are not only part of the genes that compose the hepatic differentiated signature but participate in its establishment. Moreover, their downregulation through DNA methylation occurs during the process of hepatocarcinogenesis compromising hepatocellular differentiation and HCC patients' prognosis.
Autores:
Ocal, O.; Schinner, R.; Schutte, K.; et al.
Revista:
CANCER IMAGING
ISSN 1740-5025
Vol. 22
N° 1
Año 2022
Págs.1
Background The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. Methods Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; >= 20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. Results The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22-0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS >= 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. Conclusion OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC.
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 76
N° 3
Año 2022
Págs.491 - 494
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 76
N° 2
Año 2022
Págs.257 - 260
Autores:
Ocal, O.; Rossler, D.; Gasbarrini, A.; et al.
Revista:
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
ISSN 0171-5216
Vol. 148
N° 9
Año 2022
Págs.2487 - 2496
Purpose Gadoxetic acid uptake on hepatobiliary phase MRI has been shown to correlate with ss-catenin mutation in patients with HCC, which is associated with resistance to certain therapies. This study aimed to evaluate the prognostic value of gadoxetic acid uptake on hepatobiliary phase MRI in patients with advanced HCC receiving sorafenib. Methods 312 patients with available baseline hepatobiliary phase MRI images received sorafenib alone or following selective internal radiation therapy (SIRT) within SORAMIC trial. The signal intensity of index tumor and normal liver parenchyma were measured on the native and hepatobiliary phase MRI images, and relative tumor enhancement higher than relative liver enhancement were accepted as high gadoxetic acid uptake, and its prognostic value was assessed using univariate and multivariate Cox proportional hazard models. Results The median OS of the study population was 13.4 (11.8-14.5) months. High gadoxetic acid uptake was seen in 51 (16.3%) patients, and none of the baseline characteristics was associated with high uptake. In univariate analysis, high gadoxetic acid uptake was significantly associated with shorter overall survival (10.7 vs. 14.0 months, p = 0.005). Multivariate analysis confirmed independent prognostic value of high gadoxetic acid uptake (HR, 1.7 [1.21-2.3], p = 0.002), as well as Child-Pugh class (p = 0.033), tumor diameter (p = 0.002), and ALBI grade (p = 0.015). Conclusion In advanced HCC patients receiving sorafenib (alone or combined with SIRT), high gadoxetic acid uptake of the tumor on pretreatment MRI, a surrogate of ss-catenin mutation, correlates with shorter survival. Gadoxetic acid uptake status might serve in treatment decision-making process.
Revista:
EKAIA
ISSN 0214-9001
Vol. 42
Año 2022
Págs.339 - 348
Erradioenbolizazioa (RE) gibeleko minbizia tratatzeko metodoetako bat da. Bertan, mikrokateter bidez gibeleko arterian mikroesfera erradioaktiboak injektatzen dira, hauek tumoreak enbolizazio eta erradiazio bidez erasotzeko. Mikroesferen ibilbidea ordenagailu bidezko fluido dinamika simulazioekin (CFD) aztertu daiteke. Kalkulu hauen iraupen luzea arazo bat da medikuntzaren egunerokotasunean simulazioak erabili ahal izateko. Kalkuluak azkartzeko asmoz, odolaren biskositatearen izaera ez¿newtondarra izaera newtondarrera sinplifikatu da. Emaitzek erakutsi dute mikroesferen banaketan eta odolaren hemodinamikan biskositate aldakorraren eragina mespretxagarria dela, odola fluido newtondar bezala aztertzearen sinplifikazioa ontzat emanez.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 45
N° 7
Año 2022
Págs.970 - 971
Revista:
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548
Vol. 78
N° 1
Año 2022
Págs.229 - 243
Precision medicine promises to overcome the constraints of the traditional one-for-all healthcare approach through a clear understanding of the molecular features of a disease, allowing for innovative and tailored treatments. State-of-the-art proteomics has the potential to accurately explore the human proteome to identify, quantify, and characterize proteins associated with disease progression. There is a pressing need for informative biomarkers to diagnose liver disease early in its course to prevent severe disease for which no efficient treatment is yet available. Here, we propose the concept of a cellular pathway as a functional biomarker, whose monitorization may inform normal and pathological status. We have developed a standardized targeted selected-reaction monitoring assay to detect and quantify 13 enzymes of one-carbon metabolism (1CM). The assay is compliant with Clinical Proteomics Tumor Analysis Consortium (CPTAC) guidelines and has been included in the protein quantification assays that can be accessed through the assay portal at the CPTAC web page. To test the feasibility of the assay, we conducted a retrospective, proof-of-concept study on a collection of liver samples from healthy controls and from patients with cirrhosis or hepatocellular carcinoma (HCC). Our results indicate a significant reconfiguration of 1CM upon HCC development resulting from a process that can already be identified in cirrhosis. Our findings indicate that the systematic and integrated quantification of 1CM enzymes is a promising cell function-based biomarker for patient stratification, although further experiments with larger cohorts are needed to confirm these findings.
Revista:
JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN 2051-1426
Vol. 10
N° 2
Año 2022
Págs.e003978
Background Neoantigens, new immunogenic sequences arising from tumor mutations, have been associated with response to immunotherapy and are considered potential targets for vaccination. Hepatocellular carcinoma (HCC) is a moderately mutated tumor, where the neoantigen repertoire has not been investigated. Our aim was to analyze whether tumors in HCC patients contain immunogenic neoantigens suitable for future use in therapeutic vaccination. Methods Whole-exome sequencing and RNAseq were performed in a cohort of fourteen HCC patients submitted to surgery or liver transplant. To identify mutations, single-nucleotide variants (SNV) originating non-synonymous changes that were confirmed at the RNA level were analyzed. Immunogenicity of putative neoAgs predicted by HLA binding algorithms was confirmed by using in vitro HLA binding assays and T-cell stimulation experiments, the latter in vivo, by immunizing HLA-A*02.01/HLA-DRB1*01 (HHD-DR1) transgenic mice, and in in vitro, using human lymphocytes. Results Sequencing led to the identification of a median of 1217 missense somatic SNV per patient, narrowed to 30 when filtering by using RNAseq data. A median of 13 and 5 peptides per patient were predicted as potential binders to HLA class I and class II molecules, respectively. Considering only HLA-A*02.01- and HLA-DRB1*01-predicted binders, 70% demonstrated HLA-binding capacity and about 50% were immunogenic when tested in HHD-DR1 mice. These peptides induced polyfunctional T cells that specifically recognized the mutated but not the wild-type sequence as well as neoantigen-expressing cells. Moreover, coimmunization experiments combining CD8 and CD4 neoantigen epitopes resulted in stronger CD8 T cell responses. Finally, responses against neoantigens were also induced in vitro using human cells. Conclusion These results show that mutations in HCC tumors may generate immunogenic neoantigens with potential applicability for future combinatorial therapeutic strategies.
Revista:
GUT
ISSN 0017-5749
Vol. 71
N° 6
Año 2022
Págs.1141 - 1151
Objective Despite significant progresses in imaging and pathological evaluation, early differentiation between benign and malignant biliary strictures remains challenging. Endoscopic retrograde cholangiopancreatography (ERCP) is used to investigate biliary strictures, enabling the collection of bile. We tested the diagnostic potential of next-generation sequencing (NGS) mutational analysis of bile cell-free DNA (cfDNA). Design A prospective cohort of patients with suspicious biliary strictures (n=68) was studied. The performance of initial pathological diagnosis was compared with that of the mutational analysis of bile cfDNA collected at the time of first ERCP using an NGS panel open to clinical laboratory implementation, the Oncomine Pan-Cancer Cell-Free assay. Results An initial pathological diagnosis classified these strictures as of benign (n=26), indeterminate (n=9) or malignant (n=33) origin. Sensitivity and specificity of this diagnosis were 60% and 100%, respectively, as on follow-up 14 of the 26 and eight of the nine initially benign or indeterminate strictures resulted malignant. Sensitivity and specificity for malignancy of our NGS assay, herein named Bilemut, were 96.4% and 69.2%, respectively. Importantly, one of the four Bilemut false positives developed pancreatic cancer after extended follow-up. Remarkably, the sensitivity for malignancy of Bilemut was 100% in patients with an initial diagnosis of benign or indeterminate strictures. Analysis of 30 paired bile and tissue samples also demonstrated the superior performance of Bilemut. Conclusion Implementation of Bilemut at the initial diagnostic stage for biliary strictures can significantly improve detection of malignancy, reduce delays in the clinical management of patients and assist in selecting patients for targeted therapies.
Autores:
Yau, T. (Autor de correspondencia); Park, J. W.; Finn, R. S.; et al.
Revista:
LANCET ONCOLOGY
ISSN 1470-2045
Vol. 23
N° 1
Año 2022
Págs.77 - 90
Background Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.
Methods In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.
Findings Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15.2 months (IQR 5.7-28.0) for the nivolumab group and 13.4 months (5.7-25.9) in the sorafenib group. Median overall survival was 16.4 months (95% CI 13.9-18.4) with nivolumab and 14.7 months (11.9-17.2) with sorafenib (hazard ratio 0.85 [95% CI 0.72-1.02]; p=0.075; minimum follow-up 22.8 months); the protocol-defined significance level of p=0.0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.
Interpretation First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.
Autores:
Abou-Alfa, G. K.; Chan, S. L.; Kudo, M.; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 40
N° 4
Año 2022
Autores:
Loffler, M. W.; Gori, S.; Izzo, F.; et al.
Revista:
CLINICAL CANCER RESEARCH
ISSN 1078-0432
Vol. 28
N° 12
Año 2022
Págs.2555 - 2566
Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. Patients and Methods: A total of 82 patients with very early-to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints. Results: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against >= 1 vaccinated HLA class I tumor-associated peptide (TAA) and >= 1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. Conclusions: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I- and class II-restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.
Revista:
LANGENBECKS ARCHIVES OF SURGERY
ISSN 1435-2443
Vol. 407
N° 3
Año 2022
Págs.1099 - 1111
Background Liver surgery after radioembolization (RE) entails highly demanding and challenging procedures due to the frequent combination of large tumors, severe RE-related adhesions, and the necessity of conducting major hepatectomies. Laparoscopic liver resection (LLR) and its associated advantages could provide benefits, as yet unreported, to these patients. The current study evaluated feasibility, morbidity, mortality, and survival outcomes for major laparoscopic liver resection after radioembolization. Material and methods In this retrospective, single-center study patients diagnosed with hepatocellular carcinoma, intrahepatic cholangiocarcinoma or metastases from colorectal cancer undergoing major laparoscopic hepatectomy after RE were identified from institutional databases. They were matched (1:2) on several pre-operative characteristics to a group of patients that underwent major LLR for the same malignancies during the same period but without previous RE. Results From March 2011 to November 2020, 9 patients underwent a major LLR after RE. No differences were observed in intraoperative blood loss (50 vs. 150 ml; p = 0.621), operative time (478 vs. 407 min; p = 0.135) or pedicle clamping time (90.5 vs 74 min; p = 0.133) between the post-RE LLR and the matched group. Similarly, no differences were observed on hospital stay ( median 3 vs. 4 days; p = 0.300), Clavien-Dindo = III complications (2 vs. 1 cases; p = 0.250), specific liver morbidity (1 vs. 1 case p = 1.000), or 90 day mortality (0 vs. 0; p = 1.000). Conclusion The laparoscopic approach for post radioembolization patients may be a feasible and safe procedure with excellent surgical and oncological outcomes and meets the current standards for laparoscopic liver resections. Further studies with larger series are needed to confirm the results herein presented.
Autores:
Karlsen, T. H. (Autor de correspondencia); Sheron, N.; Zelber-Sagi, S.; et al.
Revista:
LANCET
ISSN 0140-6736
Vol. 399
N° 10319
Año 2022
Págs.61 - 116
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070
Vol. 48
N° 10
Año 2021
Págs.3048 - 3057
Introduction: Volume changes induced by selective internal radiation therapy (SIRT) may increase the possibility of tumor resection in patients with insufficient future liver remnant (FLR). The aim was to identify dosimetric and clinical parameters associated with contralateral hepatic hypertrophy after lobar/extended lobar SIRT with 90Y-resin microspheres.
Materials and methods: Patients underwent 90Y PET/CT after lobar or extended lobar (right + segment IV) SIRT. 90Y voxel dosimetry was retrospectively performed (PLANET Dose; DOSIsoft SA). Mean absorbed doses to tumoral/non-tumoral-treated volumes (NTL) and dose-volume histograms were extracted. Clinical variables were collected. Patients were stratified by FLR at baseline (T0-FLR): < 30% (would require hypertrophy) and ¿ 30%. Changes in volume of the treated, non-treated liver, and FLR were calculated at < 2 (T1), 2-5 (T2), and 6-12 months (T3) post-SIRT. Univariable and multivariable regression analyses were performed to identify predictors of atrophy, hypertrophy, and increase in FLR. The best cut-off value to predict an increase of FLR to ¿ 40% was defined using ROC analysis.
Results: Fifty-six patients were studied; most had primary liver tumors (71.4%), 40.4% had cirrhosis, and 39.3% had been previously treated with chemotherapy. FLR in patients with T0-FLR < 30% increased progressively (T0: 25.2%; T1: 32.7%; T2: 38.1%; T3: 44.7%). No dosimetric parameter predicted atrophy. Both NTL-Dmean and NTL-V30 (fraction of NTL exposed to ¿ 30 Gy) were predictive of increase in FLR in patients with T0 FLR < 30%, the latter also in the total cohort of patients. Hypertrophy was not significantly associated with tumor dose or tumor size. When ¿ 49% of NTL received ¿ 30 Gy, FLR increased to ¿ 40% (accuracy: 76.4% in all patients and 80.95% in T0-FLR < 30% patients).
Conclusion: NTL-Dmean and NTL exposed to ¿ 30 Gy (NTL-V30) were most significantly associated with increase in FLR (particularly among patients with T0-FLR < 30%). When half of NTL received ¿ 30 Gy, FLR increased to ¿ 40%, with higher accuracy among patients with T0-FLR < 30%.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 39
N° 3 Supl.
Año 2021
Págs.TPS349 - TPS349
Revista:
SCIENTIFIC REPORTS
ISSN 2045-2322
Vol. 11
N° 1
Año 2021
Págs.3895
Radioembolization (RE) with yttrium-90 (Y-90) microspheres, a transcatheter intraarterial therapy for patients with liver cancer, can be modeled computationally. The purpose of this work was to correlate the results obtained with this methodology using in vivo data, so that this computational tool could be used for the optimization of the RE procedure. The hepatic artery three-dimensional (3D) hemodynamics and microsphere distribution during RE were modeled for six Y-90-loaded microsphere infusions in three patients with hepatocellular carcinoma using a commercially available computational fluid dynamics (CFD) software package. The model was built based on in vivo data acquired during the pretreatment stage. The results of the simulations were compared with the in vivo distribution assessed by Y-90 PET/CT. Specifically, the microsphere distribution predicted was compared with the actual Y-90 activity per liver segment with a commercially available 3D-voxel dosimetry software (PLANET Dose, DOSIsoft). The average difference between the CFD-based and the PET/CT-based activity distribution was 2.36 percentage points for Patient 1, 3.51 percentage points for Patient 2 and 2.02 percentage points for Patient 3. These results suggest that CFD simulations may help to predict Y-90-microsphere distribution after RE and could be used to optimize the RE procedure on a patient-specific basis.
Revista:
NATURE REVIEWS GASTROENTEROLOGY AND HEPATOLOGY
ISSN 1759-5053
Vol. 18
N° 8
Año 2021
Págs.525 - 543
Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.
Autores:
Muñoz-Martínez, S.; Sapena, V.; Forner, A.; et al.
Revista:
JHEP REPORTS
ISSN 2589-5559
Vol. 3
N° 3
Año 2021
Págs.100260
Background & Aims: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems and it may have heavily impacted patients with liver cancer (LC). Herein, we evaluated whether the schedule of LC screening or procedures has been interrupted or delayed because of the COVID-19 pandemic. Methods: An international survey evaluated the impact of the COVID-19 pandemic on clinical practice and clinical trials from March 2020 to June 2020, as the first phase of a multicentre, international, and observational project. The focus was on patients with hepatocellular carcinoma or intrahepatic cholangiocarcinoma, cared for around the world during the first COVID-19 pandemic wave. Results: Ninety-one centres expressed interest to participate and 76 were included in the analysis, from Europe, South America, North America, Asia, and Africa (73.7%,17.1%, 5.3%, 2.6%, and 1.3% per continent, respectively). Eighty-seven percent of the centres modified their clinical practice: 40.8% the diagnostic procedures, 80.9% the screening programme, 50% cancelled curative and/or palliative treatments for LC, and 41.7% modified the liver transplantation programme. Forty-five out of 69 (65.2%) centres in which clinical trials were running modified their treatments in that setting, but 58.1% were able to recruit new patients. The phone call service was modified in 51.4% of centres which had this service before the COVID-19 pandemic (n = 19/37). Conclusions: The first wave of the COVID-19 pandemic had a tremendous impact on the routine care of patients with liver cancer. Modifications in screening, diagnostic, and treatment algorithms may have significantly impaired the outcome of patients. Ongoing data collection and future analyses will report the benefits and disadvantages of the strategies implemented, aiding future decision-making. Lay summary: The coronavirus disease 2019 (COVID-19) pandemic has posed unprecedented challenges to healthcare systems globally. Herein, we assessed the impact of the first wave pandemic on patients with liver cancer and found that routine care for these patients has been majorly disrupted, which could have a significant impact on outcomes. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).
Revista:
MATHEMATICS
ISSN 2227-7390
Vol. 9
N° 8
Año 2021
Págs.839
Radioembolization (RE) is a treatment for patients with liver cancer, one of the leading cause of cancer-related deaths worldwide. RE consists of the transcatheter intraarterial infusion of radioactive microspheres, which are injected at the hepatic artery level and are transported in the bloodstream, aiming to target tumors and spare healthy liver parenchyma. In paving the way towards a computer platform that allows for a treatment planning based on computational fluid dynamics (CFD) simulations, the current simulation (model preprocess, model solving, model postprocess) times (of the order of days) make the CFD-based assessment non-viable. One of the approaches to reduce the simulation time includes the reduction in size of the simulated truncated hepatic artery. In this study, we analyze for three patient-specific hepatic arteries the impact of reducing the geometry of the hepatic artery on the simulation time. Results show that geometries can be efficiently shortened without impacting greatly on the microsphere distribution.
Autores:
Kudo, M. (Autor de correspondencia); Matilla, A.; Santoro, A.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 3
Año 2021
Págs.600 - 609
Background & Aims: Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was similar to 3-5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. Methods: This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Results: Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Conclusions: Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. Lay summary: In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° Supl. 2
Año 2021
Págs.S243 - S244
Autores:
Helmberger, T.; Golfieri, R.; Pech, M.; et al.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
Purpose To address the lack of prospective data on the real-life clinical application of trans-arterial radioembolization (TARE) in Europe, the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) initiated the prospective observational studyCIRSE Registry for SIR-Spheres (R) Therapy (CIRT). Materials and Methods Patients were enrolled from 1 January 2015 till 31 December 2017. Eligible patients were adult patients treated with TARE with Y90 resin microspheres for primary or metastatic liver tumours. Patients were followed up for 24 months after treatment, whereas data on the clinical context of TARE, overall survival (OS) and safety were collected. Results Totally, 1027 patients were analysed. 68.2% of the intention of treatment was palliative. Up to half of the patients received systemic therapy and/or locoregional treatments prior to TARE (53.1%; 38.3%). Median overall survival (OS) was reported per cohort and was 16.5 months (95% confidence interval (CI) 14.2-19.3) for hepatocellular carcinoma, 14.6 months (95% CI 10.9-17.9) for intrahepatic cholangiocarcinoma. For liver metastases, median OS for colorectal cancer was 9.8 months (95% CI 8.3-12.9), 5.6 months for pancreatic cancer (95% CI 4.1-6.6), 10.6 months (95% CI 7.3-14.4) for breast cancer, 14.6 months (95% CI 7.3-21.4) for melanoma and 33.1 months (95% CI 22.1-nr) for neuroendocrine tumours. Statistically significant prognostic factors in terms of OS include the presence of ascites, cirrhosis, extra-hepatic disease, patient performance status (Eastern Cooperative Oncology Group), number of chemotherapy lines prior to TARE and tumour burden. Thirty-day mortality rate was 1.0%. 2.5% experienced adverse events grade 3 or 4 within 30 days after TARE. Conclusion In the real-life clinical setting, TARE is largely considered to be a part of a palliative treatment strategy across indications and provides an excellent safety profile.
Autores:
Marino, Z.; Darnell, A.; Lens, S.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 74
N° 2
Año 2021
Págs.491
Revista:
MEDICINA CLINICA
ISSN 0025-7753
Vol. 156
N° 9
Año 2021
Págs.463.e1 - 463.e30
El carcinoma hepatocelular (CHC) es la neoplasia primaria de hígado más frecuente y una de las causas de muerte más común en los pacientes afectos de cirrosis hepática. Simultáneamente al reconocimiento de la relevancia clínica de esta neoplasia, en los últimos años han aparecido novedades importantes en el diagnóstico, evaluación pronóstica y, especialmente, en el tratamiento del CHC. Por tal motivo, desde la Asociación Española para el Estudio del Hígado (AEEH) se ha impulsado la necesidad de actualizar las guías de práctica clínica, invitando de nuevo a todas las sociedades involucradas en el diagnóstico y tratamiento de esta enfermedad a participar en la redacción y aprobación del documento: Sociedad Española de Trasplante Hepático (SETH), Sociedad Española de Radiología Médica (SERAM), Sociedad Española de Radiología Vascular e Intervencionista (SERVEI), Asociación Española de Cirujanos (AEC) y Sociedad Española de Oncología Médica (SEOM). Se han tomado como documentos de referencia las guías de práctica clínica publicadas en 2016, aceptadas como Guía de Práctica Clínica del Sistema Nacional de Salud, incorporando los avances más importantes que se han obtenido en los últimos años. La evidencia científica y la fuerza de la recomendación se basa en el sistema GRADE.
© 2020 Publicado por Elsevier España, S.L.U. Este es un artículo Open Access bajo la licencia CC
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070
Vol. 48
N° Supl. 1
Año 2021
Págs.S287
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 73
N° 6
Año 2021
Págs.2380 - 2396
Background and Aims Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitors. Approach and Results Expression of G9a, DNMT1, and their molecular adaptor, ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient-derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c-Jun-N-terminal-kinase (Jnk)-1/2 and diethyl-nitrosamine (DEN) plus CCl4 treatment (Jnk(Delta hepa) + DEN + CCl4 mice). We found an increased and correlative expression of G9a, DNMT1, and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB-targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in Jnk(Delta hepa) + DEN + CCl4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status. Conclusions Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.
Revista:
TRANSPLANTATION
ISSN 0041-1337
Vol. 105
N° 12
Año 2021
Págs.e398 - e400
Revista:
GUT
ISSN 0017-5749
Vol. 70
N° 2
Año 2021
Págs.388 - 400
Objective Hepatic stellate cells (HSC) transdifferentiation into myofibroblasts is central to fibrogenesis. Epigenetic mechanisms, including histone and DNA methylation, play a key role in this process. Concerted action between histone and DNA-mehyltransferases like G9a and DNMT1 is a common theme in gene expression regulation. We aimed to study the efficacy of CM272, a first-in-class dual and reversible G9a/DNMT1 inhibitor, in halting fibrogenesis. Design G9a and DNMT1 were analysed in cirrhotic human livers, mouse models of liver fibrosis and cultured mouse HSC. G9a and DNMT1 expression was knocked down or inhibited with CM272 in human HSC (hHSC), and transcriptomic responses to transforming growth factor-beta 1 (TGF beta 1) were examined. Glycolytic metabolism and mitochondrial function were analysed with Seahorse-XF technology. Gene expression regulation was analysed by chromatin immunoprecipitation and methylation-specific PCR. Antifibrogenic activity and safety of CM272 were studied in mouse chronic CCl4 administration and bile duct ligation (BDL), and in human precision-cut liver slices (PCLSs) in a new bioreactor technology. Results G9a and DNMT1 were detected in stromal cells in areas of active fibrosis in human and mouse livers. G9a and DNMT1 expression was induced during mouse HSC activation, and TGF beta 1 triggered their chromatin recruitment in hHSC. G9a/DNMT1 knockdown and CM272 inhibited TGF beta 1 fibrogenic responses in hHSC. TGF beta 1-mediated profibrogenic metabolic reprogramming was abrogated by CM272, which restored gluconeogenic gene expression and mitochondrial function through on-target epigenetic effects. CM272 inhibited fibrogenesis in mice and PCLSs without toxicity. Conclusions Dual G9a/DNMT1 inhibition by compounds like CM272 may be a novel therapeutic strategy for treating liver fibrosis.
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 6
Año 2021
Págs.1261 - 1264
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 4
Año 2021
Págs.757 - 760
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 74
N° 2
Año 2021
Págs.265 - 268
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 74
N° 3
Año 2021
Págs.493 - 496
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 74
N° 4
Año 2021
Págs.765 - 768
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 1
Año 2021
Págs.1 - 4
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 2
Año 2021
Págs.257 - 260
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 2
Año 2021
Págs.257 - 260
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 74
N° 2
Año 2021
Págs.265 - 268
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 5
Año 2021
Págs.1013 - 1016
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 74
N° 3
Año 2021
Págs.493 -496
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 74
N° 1
Año 2021
Págs.1 - 4
Autores:
Burra, P. (Autor de correspondencia); Tacke, F.; Ratziu, V.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 6
Año 2021
Págs.1261 -1264
Revista:
BIOLOGY
ISSN 2079-7737
Vol. 10
N° 12
Año 2021
Págs.1341
Simple Summary Liver cancer is one of the leading causes of cancer-related deaths worldwide and balloon-occluded transarterial chemoembolization (B-TACE) has emerged as a safe and effective treatment for liver cancer. However, the hemodynamic alterations that are responsible for the successfulness of the treatment and are produced by the microballoon catheter used during the treatment are not yet well understood. In this study, we developed an in vitro model (IVM) that can simulate B-TACE. We designed clinically relevant experiments, and we obtained clinically realistic results. We conclude that the IVM allows for a visual understanding of a complex phenomenon (i.e., the blood flow redistribution after balloon occlusion) and it could be used as a base for future sophisticated and even patient-specific IVMs; in addition, it could be used to conduct IVM-based research on B-TACE. Background: Balloon-occluded transarterial chemoembolization (B-TACE) has emerged as a safe and effective procedure for patients with liver cancer, which is one of the deadliest types of cancer worldwide. B-TACE consist of the transcatheter intraarterial infusion of chemotherapeutic agents, followed by embolizing particles, and it is performed with a microballoon catheter that temporarily occludes a hepatic artery. B-TACE relies on the blood flow redistribution promoted by the balloon-occlusion. However, flow redistribution phenomenon is not yet well understood. Methods: This study aims to present a simple in vitro model (IVM) where B-TACE can be simulated. Results: By visually analyzing the results of various clinically-realistic experiments, the IVM allows for the understanding of balloon-occlusion-related hemodynamic changes and the importance of the occlusion site. Conclusion: The IVM can be used as an educational tool to help clinicians better understand B-TACE treatments. This IVM could also serve as a base for a more sophisticated IVM to be used as a research tool.
Autores:
Ricke, J. (Autor de correspondencia); Schinner, R.; Seidensticker, M.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 6
Año 2021
Págs.1387 - 1396
Background & Aims: SORAMIC is a previously published randomised controlled trial assessing survival in patients with advanced hepatocellular carcinoma who received sorafenib with or without selective internal radiation therapy (SIRT). Based on the per-protocol (PP) population, we assessed whether the outcome of patients receiving SIRT+sorafenib vs. sorafenib alone was affected by adverse effects of SIRT on liver function. Methods: The PP population consisted of 109 (SIRT+sorafenib) vs. 173 patients (sorafenib alone). Comparisons were made between subgroups who achieved a significant survival benefit or trend towards improved survival with SIRT and the inverse group without a survival benefit: <65 years-old vs. >= 65 years-old, Child Pugh 5 vs. 6, no transarterial chemoembolisation (TACE) vs. prior TACE, no cirrhosis vs. cirrhosis, non-alcohol-vs. alcohol-related aetiology. The albumin-bilirubin (ALBI) score was used to monitor liver function over time during follow-up. Results: ALBI scores increased in all patient groups during follow-up. In the PP population, ALBI score increases were higher in the SIRT+sorafenib than the sorafenib arm (p = 0.0021 month 4, p <0.0001 from month 6). SIRT+sorafenib conferred a survival benefit compared to sorafenib alone in patients aged <65 years old, those without cirrhosis, those with Child-Pugh 5, and those who had not received TACE. A higher increase in ALBI score was observed in the inverse subgroups in whom survival was not improved by adding SIRT (age >= 65 years-old, p <0.05; cirrhosis, p = 0.07; Child-Pugh 6, p <0.05; prior TACE, p = 0.08). Conclusion: SIRT frequently has a negative, often subclinical, effect on liver function in patients with hepatocellular carcinoma, which may impair prognosis after treatment. Careful patient selection for SIRT as well as prevention of clinical and subclinical liver damage by selective treatments, high tumour uptake ratio, and medical prophylaxis could translate into better efficacy. Clinical trial number: EudraCT 2009-012576-27, NCT01126645 Lay summary: This study of treatments in patients with hepatocellular carcinoma found that selective internal radiation therapy (SIRT) has an adverse effect on liver function that may affect patient outcomes. Patients should be carefully selected before they undergo SIRT and the treatment technique should be optimised for maximum protection of non-target liver parenchyma.(C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Revista:
JOURNAL OF IMMUNOLOGY
ISSN 0022-1767
Vol. 206
N° 8
Año 2021
Págs.1932 - 1942
The cell has several mechanisms to sense and neutralize stress. Stress-related stimuli activate pathways that counteract danger, support cell survival, and activate the inflammatory response. We use human cells to show that these processes are modulated by EGOT, a long noncoding RNA highly induced by viral infection, whose inhibition results in increased levels of antiviral IFNstimulated genes (ISGs) and decreased viral replication. We now show that EGOT is induced in response to cell stress, viral replication, or the presence of pathogen-associated molecular patterns via the PI3K/AKT, MAPKs, and NF-kappa B pathways, which lead to cell survival and inflammation. Transcriptome analysis and validation experiments show that EGOT modulates PI3K/AKT and NF-kappa B responses. On the one hand, EGOT inhibition decreases expression of PI3K/AKT-induced cellular receptors and cell proliferation. In fact, EGOT levels are increased in several tumors. On the other hand, EGOT inhibition results in decreased levels of key NF-kappa B target genes, including those required for inflammation and ISGs in those cells that build an antiviral response. Mechanistically, EGOT depletion decreases the levels of the key coactivator TBLR1, essential for transcription by NF-kappa B. In summary, EGOT is induced in response to stress and may function as a switch that represses ISG transcription until a proper antiviral or stress response is initiated. EGOT then helps PI3K/AKT, MAPKs, and NF-kappa B pathways to activate the antiviral response, cell inflammation, and growth. We believe that modulation of EGOT levels could be used as a therapy for the treatment of certain viral infections, immune diseases, and cancer.
Revista:
CANCER RESEARCH
ISSN 0008-5472
Vol. 81
N° 19
Año 2021
Págs.4910 - 4925
Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of bluntended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability. Significance: This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.
Autores:
Kim, T. Y.; Santoro, A.; Kang, Y. K.; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 39
N° 3 Supl.
Año 2021
Págs.269 - 269
Autores:
Ocal, O.; Kupcinskas, J.; Morkunas, E.; et al.
Revista:
EJNMMI RESEARCH
ISSN 2191-219X
Vol. 11
N° 1
Año 2021
Págs.51
Background To confirm the prognostic value of previously published baseline interleukin 6 (IL6) and IL8 cutoff values in survival and liver dysfunction in patients with advanced HCC undergoing Y-90 radioembolization. Methods A total of 83 patients (77 male) represented a subset of HCC patients undergoing Y-90 radioembolization combined with sorafenib as part of the prospective multicenter phase II trial SORAMIC. IL6 and IL8 levels were determined in serum samples collected at baseline. In this post hoc analysis, we sought to confirm the prognostic value of baseline cutoff values of 6.53 pg/mL and 60.8 pg/mL for IL6 and IL8, respectively, in overall survival (OS) or liver dysfunction (grade 2 bilirubin increase) after treatment. Results Median OS was 12.0 months. While low baseline albumin and high bilirubin values were associated with high IL6, liver cirrhosis, alcoholic liver disease, and portal vein infiltration were associated with high IL8. In univariate analysis, high baseline IL6 and IL8 were associated with significantly shorter overall survival (7.8 vs. 19.0 months for IL6 and 8.4 vs. 16.0 months for IL8). In addition to IL values, liver cirrhosis, Child-Pugh grade, baseline albumin (< 36 g/dL), and total bilirubin (>= 17 mu mol/L), and higher mALBI grade (2b &3) values were associated with OS. At multivariate analysis, high baseline IL6 was the only independent prognostic factor for OS (HR 2.35 [1.35-4.1], p = 0.002). Risk factors for liver dysfunction were high baseline IL6, albumin, and total bilirubin, and mALBI grade as found in univariate analysis. High baseline IL6 (HR 2.67 [1.21-5.94], p = 0.016) and total bilirubin >= 17 mu mol/L (HR 3.73 [1.72-8.06], p < 0.001) were independently associated with liver dysfunction. Conclusion In advanced HCC patients receiving Y-90 radioembolization combined with sorafenib, baseline IL6 values proved to be prognostic, confirming previous findings in patients undergoing (90)Yradioembolization. IL6 might be useful for patient selection or stratification in future trials.
Autores:
Rimola, J.; Fonseca, L. G. ; Sapena, V.; et al.
Revista:
EUROPEAN JOURNAL OF RADIOLOGY
ISSN 0720-048X
Vol. 135
Año 2021
Págs.109484
Background and aims: Immune-checkpoint inhibitors are effective in many advanced tumors. However, there is scarce information regarding the radiological response to these agents in hepatocellular carcinoma outside clinical trials. We aimed to describe the radiological response in a retrospective cohort of hepatocellular carcinoma patients treated with nivolumab and to analyze the radiological evolution according to tumor response at first post-treatment radiological assessment. Methods: We reviewed pre-treatment and post-treatment images (CT or MRI) obtained at different time-points in patients with hepatocellular carcinoma treated with nivolumab outside clinical trials at seven Spanish centers, assessing the response according to RECIST 1.1 and iRECIST and registering atypical responses. We also analyzed the imaging findings on subsequent assessments according to tumor status on the first posttreatment imaging assessment. Results: From the 118 patients with hepatocellular carcinoma treated with nivolumab, we finally analyzed data from 31 patients (71 % Child-Pugh A; 74 % BCLC-C). Median follow-up was 8.39 months [IQR 5.00-10.92]; median overall survival was 12.82 months (95 %CI 10.92-34.79). According to RECIST 1.1, the objective response rate was 16 % and according to iRECIST, the objective response rate was 22.6 %. Findings at the first post-treatment assessment varied, showing stable disease in 44.8 % of patients; findings during follow-up also varied widely, including 4 hyperprogressions and 3 pseudoprogressions. Conclusion: Imaging findings during nivolumab treatment are heterogeneous between and within patients. Progression of disease does not always signify treatment failure, and surrogate end-points may not reflect survival outcomes, making the management of hepatocellular carcinoma patients under immunotherapy challenging.
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 32
N° Supl. 3
Año 2021
Págs.S143
Autores:
Kolligs, F.; Arnold, D.; Helmberger, T.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° Supl. 2
Año 2021
Págs.S244 - S245
Autores:
Helmberger, T.; Arnold, D.; Balli, T.; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 39
N° 3
Año 2021
Págs.308 - 308
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 32
N° Supl. 3
Año 2021
Págs.S117
Autores:
Loeffler, M.; Izzo, F.; Gori, S.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° Supl. 2
Año 2021
Págs.S246 - S246
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 39
N° 27
Año 2021
Págs.2991 - 3001
PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade >= 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 74
N° 5
Año 2021
Págs.2333 - 2335
Autores:
Loffroy, R.; Ronot, M. ; Greget, M.; et al.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 44
N° 1
Año 2021
Págs.36 - 49
Purpose Radioembolization has emerged as a treatment modality for patients with primary and secondary liver tumours. This observational study CIRT-FR (CIRSE Registry for SIR-Spheres Therapy in France) aims to evaluate real-life clinical practice on all patients treated with transarterial radioembolization (TARE) using SIR-Spheres yttrium-90 resin microspheres in France. In this interim analysis, safety and quality of life data are presented. Final results of the study, including secondary effectiveness outcomes, will be published later. Overall, CIRT-FR is aiming to support French authorities in the decision making on reimbursement considerations for this treatment. Methods Data on patients enrolled in CIRT-FR from August 2017 to October 2019 were analysed. The interim analysis describes clinical practice, baseline characteristics, safety (adverse events according to CTCTAE 4.03) and quality of life (according to EORTC QLQ C30 and HCC module) aspects after TARE. Results This cohort included 200 patients with hepatocellular carcinoma (114), metastatic colorectal cancer (mCRC; 38) and intrahepatic cholangiocarcinoma (33) amongst others (15). TARE was predominantly assigned as a palliative treatment (79%). 12% of patients experienced at least one adverse event in the 30 days following treatment; 30-day mortality was 1%. Overall, global health score remained stable between baseline (66.7%), treatment (62.5%) and the first follow-up (66.7%). Conclusion This interim analysis demonstrates that data regarding safety and quality of life generated by randomised-controlled trials is reflected when assessing the real-world application of TARE.
Autores:
Greten, T. F. (Autor de correspondencia); Abou-Alfa, G. K.; Cheng, A. L.; et al.
Revista:
JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN 2051-1426
Vol. 9
N° 9
Año 2021
Págs.e002794
Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 74
N° 5
Año 2021
Págs.2791 - 2807
Background and Aims Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4 alpha (HNF4 alpha) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and Results Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4 alpha, driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild-type and Slu7-haploinsufficient/heterozygous (Slu7(+/-)) mice undergoing chronic (CCl4) and acute (acetaminophen) injury. SLU7 expression was restored in CCl4-injured mice using SLU7-expressing adeno-associated viruses (AAV-SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4 alpha P1 to P2 usage. This response was reproduced in Slu7(+/-) mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV-SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4 alpha 1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell's antioxidant machinery. Conclusions Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress-protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
Autores:
Bruix, J.; Chan, S. L.; Galle, P. R.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 75
N° 4
Año 2021
Págs.960 - 974
The last 5 years have witnessed relevant advances in the systemic treatment of hepatocellular carcinoma. New data have emerged since the development of the EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma in 2018. Drugs licensed in some countries now include 4 oral multityrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib), 1 anti-angiogenic antibody (ramucirumab) and 4 immune checkpoint inhibitors, alone or in combination (atezolizumab in combination with bevacizumab, ipilimumab in combination with nivolumab, nivolumab and pembrolizumab in monotherapy). Prolonged survival in excess of 2 years can be expected in most patients with sensitive tumours and well-preserved liver function that renders them fit for sequential therapies. With different choices available in any given setting, the robustness of the evidence of efficacy and a correct matching of the safety profile of a given agent with patient characteristics and preferences are key in making sound therapeutic decisions. The recommendations in this document amend the previous EASL Clinical Practice Guidelines and aim to help clinicians provide the best possible care for patients today. In view of several ongoing and promising trials, further advances in systemic therapy of hepatocellular carcinoma are foreseen in the near future and these recommendations will have to be updated regularly. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Autores:
Pereira, P. L. ; Iezzi, R.; Manfredi, R.; et al.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 44
N° 1
Año 2021
Págs.50 - 62
Purpose Transarterial chemoembolisation (TACE) using irinotecan-eluting beads is an additional treatment option for colorectal cancer liver metastases (CRLM) patients that are not eligible for curative treatment approaches. This interim analysis focuses on feasibility of the planned statistical analysis regarding data distribution and completeness, treatment intention, safety and health-related quality of life (HRQOL) of the first 50 patients prospectively enrolled in the CIrse REgistry for LifePearl (TM) microspheres (CIREL), an observational multicentre study conducted across Europe. Methods In total, 50 patients >= 18 years diagnosed with CRLM and decided to be treated with irinotecan-eluting LifePearl (TM) microspheres TACE (LP-irinotecan TACE) by a multidisciplinary tumour board. There were no further inclusion or exclusion criteria. The primary endpoint is the categorisation of treatment intention, and secondary endpoints presented in this interim analysis are safety, treatment considerations and HRQOL. Results LP-irinotecan TACE was conducted in 42% of patients as salvage therapy, 20% as an intensification treatment, 16% as a first-line treatment, 14% a consolidation treatment and 8% combination treatment with ablation with curative intent. Grade 3 and 4 adverse events were reported by 4% of patients during procedure and by 10% within 30 days. While 38% reported a worse, 62% reported a stable or better global health score, and 54% of patients with worse global health score were treated as salvage therapy patients. Conclusion This interim analysis confirms in a prospective analysis the feasibility of the study, with an acceptable toxicity profile. More patients reported a stable or improved HRQOL than deterioration. Deterioration of HRQOL was seen especially in salvage therapy patients.
Autores:
Lewinska, M.; Santos-Laso, A.; Arretxe, E.; et al.
Revista:
EBIOMEDICINE
ISSN 2352-3964
Vol. 73
Año 2021
Background: Non-alcoholic fatty liver disease (NAFLD) is affecting more people globally. Indeed, NAFLD is a spectrum of metabolic dysfunctions that can progress to hepatocellular carcinoma (NAFLD-HCC). This development can occur in a non-cirrhotic liver and thus, often lack clinical surveillance. The aim of this study was to develop non-invasive surveillance method for NAFLD-HCC. Methods: Using comprehensive ultra-high-performance liquid chromatography mass-spectrometry, we investigated 1,295 metabolites in serum from 249 patients. Area under the receiver operating characteristic curve was calculated for all detected metabolites and used to establish their diagnostic potential. Logistic regression analysis was used to establish the diagnostic score. Findings: We show that NAFLD-HCC is characterised by a complete rearrangement of the serum lipidome, which distinguishes NAFLD-HCC from non-cancerous individuals and other HCC patients. We used machine learning to build a diagnostic model for NAFLD-HCC. We quantified predictive metabolites and developed the NAFLD-HCC Diagnostic Score (NHDS), presenting superior diagnostic potential compared to alpha-fetoprotein (AFP). Patients' metabolic landscapes show a progressive depletion in unsaturated fatty acids and acylcarnitines during transformation. Upregulation of fatty acid transporters in NAFLD-HCC tumours contribute to fatty acid depletion in the serum. Interpretation: NAFLD-HCC patients can be efficiently distinguished by serum metabolic alterations from the healthy population and from HCC patients related to other aetiologies (alcohol and viral hepatitis). Our model can be used for non-invasive surveillance of individuals with metabolic syndrome(s), allowing for early detection of NAFLD-HCC. Therefore, serum metabolomics may provide valuable insight to monitor patients at risk, including morbidly obese, diabetics, and NAFLD patients. (C) 2021 The Author(s). Published by Elsevier B.V.
Revista:
EJNMMI RESEARCH
ISSN 2191-219X
Vol. 11
N° 1
Año 2021
Págs.23
Purpose: To determine which imaging method used during radioembolization (RE) work-up: contrast-enhanced computed tomography (CECT), 99mTc-MAA-SPECT/CT or cone beam-CT (CBCT), more accurately predicts the final target volume (TgV) as well as the influence that each modality has in the dosimetric calculation.
Methods: TgVs from 99mTc-MAA-SPECT/CT, CECT and CBCT were consecutively obtained in 24 patients treated with RE and compared with 90Y PET/CT TgV. Using the TgVs estimated by each imaging modality and a fictitious activity of 1 GBq, the corresponding absorbed doses by tumor and non-tumoral parenchyma were calculated for each patient. The absorbed doses for each modality were compared with the ones obtained using 90Y PET/CT TgV.
Results: 99mTc-MAA-SPECT/CT predicted 90Y PET/CT TgV better than CBCT or CECT, even for selective or superselective administrations. Likewise, 99mTc-MAA-SPECT/CT showed dosimetric values more similar to those obtained with 90Y PET/CT. Nevertheless, CBCT provided essential information for RE planning, such as ensuring the total coverage of the tumor and, in cases with more than one feeding artery, splitting the activity according to the volume of tumor perfused by each artery.
Conclusion: The joint use of 99mTc-MAA-SPECT/CT and CBCT optimizes dosimetric planning for RE procedures, enabling a more accurate personalized approach.
Revista:
CANCERS
ISSN 2072-6694
Vol. 13
N° 11
Año 2021
Págs.2651
Simple Summary
Hepatocellular carcinoma is the major form of liver cancer; it has a high incidence in the global population, and it is a leading cause of the world's cancer burden. Despite great efforts to understand the disease at the molecular level and develop effective treatments for hepatocellular carcinoma patients, current therapies for advanced cases are only effective in a small percentage of patients. Therefore, it is paramount to discover new tumor targets that can be used to develop alternative therapeutic strategies. Promising novel targets could be long non-coding RNAs. These RNA molecules are frequently found to be involved in the development and progression of cancer. More importantly, they can be safely targeted with several strategies. However, our knowledge about long non-coding RNA biology and their clinical relevance remains underdeveloped. In this review, we summarize current efforts to validate the importance of long non-coding RNAs in hepatocellular carcinoma and to evaluate their potential to impact the clinical setting. To do that we highlight lncRNA implication in key events leading to cancer and we describe how affecting lncRNAs could broaden the repertoire of potentially useful targets to help meet the challenge of hepatocellular carcinoma treatment.
LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high prevalence of causative factors, usual cirrhotic status of the tumor-harboring livers and the suboptimal benefit of locoregional and systemic therapies. Despite huge progress in the molecular characterization of HCC, no oncogenic loop addiction has been identified and most genetic alterations remain non-druggable, underscoring the importance of advancing research in novel approaches for HCC treatment. In this context, long non-coding RNAs (lncRNAs) appear as potentially useful targets as they often exhibit high tumor- and tissue-specific expression and many studies have reported an outstanding dysregulation of lncRNAs in HCC. However, there is a limited perspective of the potential role that deregulated lncRNAs may play in HCC progression and aggressiveness or the mechanisms and therapeutic implications behind such effects. In this review, we offer a clarifying landscape of current efforts to evaluate lncRNA potential as therapeutic targets in HCC using evidence from preclinical models as well as from recent studies on novel oncogenic pathways that show lncRNA-dependency.
Revista:
NUCLEIC ACIDS RESEARCH
ISSN 0305-1048
Vol. 49
N° 15
Año 2021
Págs.8592 - 8609
Gene expression is finely and dynamically controlled through the tightly coordinated and interconnected activity of epigenetic modulators, transcription and splicing factors and post-translational modifiers. We have recently identified the splicing factor SLU7 as essential for maintaining liver cell identity and genome integrity and for securing cell division both trough transcriptional and splicing mechanisms. Now we uncover a new function of SLU7 controlling gene expression at the epigenetic level. We show that SLU7 is required to secure DNMT1 protein stability and a correct DNA methylation. We demonstrate that SLU7 is part in the chromatome of the protein complex implicated in DNA methylation maintenance interacting with and controlling the integrity of DNMT1, its adaptor protein UHRF1 and the histone methyl-transferase G9a at the chromatin level. Mechanistically, we found that SLU7 assures DNMT1 stability preventing its acetylation and degradation by facilitating its interaction with HDAC1 and the desubiquitinase USP7. Importantly, we demonstrate that this DNMT1 dependency on SLU7 occurs in a large panel of proliferating cell lines of different origins and in in vivo models of liver proliferation. Overall, our results uncover a novel and non-redundant role of SLU7 in DNA methylation and present SLU7 as a holistic regulator of gene expression.
Autores:
Pereira, P. L.; Arnold, D.; de Baere, T.; et al.
Revista:
DIGESTIVE AND LIVER DISEASE
ISSN 1878-3562
Vol. 52
N° 8
Año 2020
Págs.857 - 861
Background: About 70-80% of patients with colorectal liver metastases appear as ineligible for a curative treatment approach. Transarterial chemoembolisation (TACE) using irinotecan-eluting beads has emerged as a promising treatment option in cases with irresectable liver metastases. Despite being in clinical practice for years, little is known about the treatment characteristics and outcomes when used as per routine hospital practice.
Methods: Patients with hepatic metastases from colorectal cancer origin, admitted to contributing centres to receive TACE with drug-eluting LifePearl® Microspheres loaded with irinotecan, as part of their standard care, will be consecutively added to the registry. Data will be collected until the end of study, loss to follow-up or death. Primary endpoint is the characterisation of the treatment usage at the selected sites in Europe. Secondary endpoints include outcome parameters, safety and toxicity, as well as quality of life.
Conclusion and aims: This multicentre, international, prospective observational study conducted in European centres plans to collect real-life data. This data will form an evidence-base from which conclusions can be drawn on how to improve patient selection and optimise treatment protocols when treating with TACE using irinotecan-eluting microspheres. Trial registration NCT03086096.
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 31
N° Supl. 3
Año 2020
Págs.S202 - S203
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 73
N° 6
Año 2020
Págs.1460 - 1469
Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Results: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 >= 1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Lay summary: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.
Autores:
Edeline, J.; Yau, T. ; Park, J. W.; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 38
N° 4
Año 2020
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 31
N° Supl. 3
Año 2020
Págs.S241 - S242
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070
Vol. 47
N° Suppl. 1
Año 2020
Págs.S58 - S58
Revista:
JMIR RESEARCH PROTOCOLS
ISSN 1929-0748
Vol. 9
N° 4
Año 2020
Págs.e16296
Background: Radioembolization, also known as transarterial radioembolization or selective internal radiation therapy with yttrium-90 (90Y) resin microspheres, is an established treatment modality for patients with primary and secondary liver tumors. However, large-scale prospective observational data on the application of this treatment in a real-life clinical setting is lacking. Objective: The main objective is to collect data on the clinical application of radioembolization with 90Y resin microspheres to improve the understanding of the impact of this treatment modality in its routine practice setting. Methods: Eligible patients are 18 years or older and receiving radioembolization for primary and secondary liver tumors as part of routine practice, as well as have signed informed consent. Data is collected at baseline, directly after treatment, and at every 3-month follow-up until 24 months or study exit. The primary objective of the Cardiovascular and Interventional Radiological Society of Europe Registry for SIR-Spheres Therapy (CIRT) is to observe the clinical application of radioembolization. Secondary objectives include safety, effectiveness in terms of overall survival, progression-free survival (PFS), liver-specific PFS, imaging response, and change in quality of life. Results: Between January 2015 and December 2017, 1047 patients were included in the study. The 24-month follow-up period ended in December 2019. The first results are expected in the third quarter of 2020. Conclusions: The CIRT is the largest observational study on radioembolization to date and will provide valuable insights to the clinical application of this treatment modality and its real-life outcomes.
Revista:
CANCERS
ISSN 2072-6694
Vol. 12
N° 11
Año 2020
Págs.3397
Current immunotherapies based on blockade of immunosuppressive elements provide limited results in liver cancer patients. Here we tested whether combination of this therapy with a vaccine based on the Cold-Inducible RNA Binding Protein (CIRP) would improve its efficacy. Combination of immunotherapy with a CIRP-based vaccine increased vaccine immunogenicity and, when tested in several mouse models of liver cancer, resulted in better therapeutic effects. Despite good immune responses observed in peripheral organs, lymphocytes infiltrating the tumor appeared exhausted, with a weak functional capacity. Finally, by using the same strategy, we prepared a new CIRP-based vaccine containing glypican-3, human antigen commonly found in patients with liver cancer. An equivalent combination enclosing this new vaccine was also highly immunogenic. This suggests that CIRP-based vaccines may enhance the beneficial effects provided by current immunotherapies. However, they should also consider incorporating new elements to overcome limitations observed in tumor lymphocytes.
Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linke
Revista:
JOURNAL OF HEPATOLOGY
ISSN 1600-0641
Vol. 72
N° 2
Año 2020
Págs.320 - 341
Revista:
CANCERS
ISSN 2072-6694
Vol. 12
N° 12
Año 2020
Págs.3748
Simple Summary Chronic liver injury and inflammation leads to excessive deposition of extracellular matrix, known as liver fibrosis, and the distortion of the hepatic parenchyma. Liver fibrosis may progress to cirrhosis, a condition in which hepatic function is impaired and most cases of liver tumors occur. Currently, there are no effective therapies to inhibit and reverse the progression of liver fibrosis, and therefore, chronic liver disease remains a global health problem. In this study we have tested the efficacy of a new class of molecules that simultaneously target two molecular pathways known to be involved in the pathogenesis of hepatic fibrosis. In a clinically relevant mouse model of liver injury and inflammation we show that the combined inhibition of histones deacetylases and the cyclic guanosine monophosphate (cGMP) phosphodiesterase phosphodiesterase 5 (PDE5) results in potent anti-inflammatory and anti-fibrotic effects. Our findings open new avenues for the treatment of liver fibrosis and therefore, the prevention of hepatic carcinogenesis. Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor beta (TGF beta). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.
Autores:
Yau, T. (Autor de correspondencia); Kang, Y. K.; Kim, T. Y.; et al.
Revista:
JAMA ONCOLOGY
ISSN 2374-2437
Vol. 6
N° 11
Año 2020
Págs.e204564
IMPORTANCE Most patients with hepatocellular carcinoma (HCC) are diagnosed with advanced disease not eligible for potentially curative therapies; therefore, new treatment options are needed. Combining nivolumab with ipilimumab may improve clinical outcomes compared with nivolumab monotherapy. OBJECTIVE To assess efficacy and safety of nivolumab plus ipilimumab in patients with advanced HCC who were previously treated with sorafenib. DESIGN, SETTING, AND PARTICIPANTS CheckMate 040 is a multicenter, open-label, multicohort, phase 1/2 study. In the nivolumab plus ipilimumab cohort, patients were randomized between January 4 and September 26, 2016. Treatment group information was blinded after randomization. Median follow-up was 30.7 months. Data cutoff for this analysis was January 2019. Patients were recruited at 31 centers in 10 countries/territories in Asia, Europe, and North America. Eligible patients had advanced HCC (with/without hepatitis B or C) previously treated with sorafenib. A total of 148 patients were randomized (50 to arm A and 49 each to arms B and C). INTERVENTIONS Patients were randomized 1:1:1 to either nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks (arm B); or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C). MAIN OUTCOMES AND MEASURES Coprimary end points were safety, tolerability, and objective response rate. Duration of response was also measured (investigator assessed with the Response Evaluation Criteria in Solid Tumors v1.1). RESULTS Of 148 total participants, 120 were male (81%). Median (IQR) age was 60 (52.5-66.5). At data cutoff (January 2019), the median follow-up was 30.7 months (IQR, 29.9-34.7). Investigator-assessed objective response rate was 32% (95% CI, 20%-47%) in arm A, 27% (95% CI, 15%-41%) in arm B, and 29% (95% CI, 17%-43%) in arm C. Median (range) duration of response was not reached (8.3-33.7+) in arm A and was 15.2 months (4.2-29.9+) in arm B and 21.7 months (2.8-32.7+) in arm C. Any-grade treatment-related adverse events were reported in 46 of 49 patients (94%) in arm A, 35 of 49 patients (71%) in arm B, and 38 of 48 patients (79%) in arm C; there was 1 treatment-related death (arm A; grade 5 pneumonitis). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, nivolumab plus ipilimumab had manageable safety, promising objective response rate, and durable responses. The arm A regimen (4 doses nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks then nivolumab 240 mg every 2 weeks) received accelerated approval in the US based on the results of this study.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 38
N° 15
Año 2020
Autores:
Burra, P. (Autor de correspondencia); Tacke, F. ; Ratziu, V. ; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 73
N° Supl. 1
Año 2020
Págs.745 - 748
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 43
N° 7
Año 2020
Págs.987 - 995
Purpose To assess the feasibility of performing same-day vascular flow redistribution and Yttrium-90 radioembolization (90Y-RE) for hepatic malignancies. Materials and Methods From November 2015 to February 2019, patients undergoing same-day hepatic flow redistribution during work-up angiography,(99m)Technetium-labeled macroaggregated albumin (Tc-99m-MAA) SPECT/CT and 90Y microsphere-RE, were recruited. Within 18 h following the delivery of 90Y resin microspheres, an 90Y-PET/CT study was performed. According to patients' vascular anatomy, flow redistribution was performed by microcoil embolization of extrahepatic branches (group A), intrahepatic non-tumoral vessels (group B) and intrahepatic tumoral arteries (group C). The accumulation of(99m)Tc-MAA particles and microspheres in the redistributed areas was qualitatively evaluated using a 5-point visual scale (grade 1 = < 25% accumulation; grade 5 = 100% accumulation). Differences in the distribution of microspheres among groups were assessed with Mann-WhitneyUtest. Results Twenty-two patients were treated for primary (n = 17) and secondary (n = 5) hepatic malignancies. The MAA-SPECT/CT showed uptake in all the redistributed areas. Regarding the accumulation of microspheres within the redistributed segments in all the groups, perfusion patterns were classified as 2 in 1 case, 4 in 6 cases and 5 in 15 cases. No statistically significant differences were observed between groups A and B-C (Uvalue = 34,p = 0.32) and between groups B and C (Uvalue = 26,p = 0.7). Mean predicted absorbed doses by the tumoral and normal hepatic tissues were 163.5 +/- 131.2 Gy and 60.4 +/- 69.3 Gy, respectively. Mean total procedure time (from work-up angiography to 90Y delivery) was 401 +/- 0.055 min. Conclusion Performing same-day redistribution of the arterial hepatic flow to the target and 90Y-microsphere delivery is feasible in the treatment of liver tumors. Clinical Trials RegistryNCT03380130.
Autores:
Buonaguro, L. ; Mayer, A. ; Loeffler, M. ; et al.
Revista:
CANCER RESEARCH
ISSN 0008-5472
Vol. 80
N° 16
Año 2020
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 73
N° Supl. 1
Año 2020
Págs.S39 - S40
Autores:
Diaz-Gonzalez, A.; Sanduzzi-Zamparelli, M.; Fonseca, L. G.; et al.
Revista:
LIVER INTERNATIONAL
ISSN 1478-3231
Vol. 40
N° 6
Año 2020
Págs.1467 - 1476
Background & Aims Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population.
Methods We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded.
Results As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5 years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4 months (interquartile ranges [IQR], 0.8-3.8), 10.8 months (IQR, 4.5-16.9), and 17.5 months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE.
Conclusions The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.
Autores:
Levillain, H.; Bagni, O. ; Deroose, C. M. ; et al.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070
Vol. 47
N° Supl. 1
Año 2020
Págs.S107 - S108
Revista:
CURRENT MEDICINAL CHEMISTRY
ISSN 0929-8673
Vol. 27
N° 10
Año 2020
Págs.1600 - 1615
Radioembolization (RE) is a valuable treatment for liver cancer. It consists of administering radioactive microspheres via an intra-arterially placed catheter with the aim of lodging these microspheres, which are driven by the bloodstream, in the tumoral bed. Even though it is a safe treatment, some radiation-induced complications may arise. In trying to detect or solve the possible incidences that cause nontarget irradiation, simulating the particle-hemodynamics in hepatic arteries during RE via computational fluid dynamics (CFD) tools has become a valuable approach. This paper reviews the parameters that influence the outcome of RE that have been studied via numerical simulations. In this numerical approach, the outcome of RE is regarded as successful if particles reach the artery branches that feed tumor-bearing liver segments. Up to 10 parameters have been reviewed. The variation of each parameter actually alters the hemodynamics pattern in the vicinities of the catheter tip, and locally alters the incorporation of the particles into the bloodstream. Therefore, in general, the local influences of these parameters should result in global differences in terms of particle distribution in the hepatic artery branches. However, it has been observed that under some (qualitatively described) appropriate conditions where particles align with blood streamlines, the local influence resulting from a variation of a given parameter vanishes and no global differences are observed. Furth
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 43
N° 8
Año 2020
Págs.1182 - 1183
Autores:
He, A. R. ; Yau, T.; Hsu, C. ; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 38
N° 4
Año 2020
Autores:
Yau, T.; Zagonel, V. ; Santoro, A. ; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 38
N° 4
Año 2020
Revista:
INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939
Vol. 36
N° 6
Año 2020
Págs.e3337
In the last decades, the numerical studies on hemodynamics have become a valuable explorative scientific tool. The very first studies were done over idealized geometries, but as numerical methods and the power of computers have become more affordable, the studies tend to be patient specific. We apply the study to the numerical analysis of tumor-targeting during liver radioembolization (RE). RE is a treatment for liver cancer, and is performed by injecting radiolabeled microspheres via a catheter placed in the hepatic artery. The objective of the procedure is to maximize the release of radiolabeled microspheres into the tumor and avoid a healthy tissue damage. Idealized virtual arteries can serve as a generalist approach that permits to separately analyze the effect of a variable in the microsphere distribution with respect to others. However, it is important to use proper physiological boundary conditions (BCs). It is not obvious, the need to account for the effect of tortuosity when using an idealized virtual artery. We study the use of idealized geometry of a hepatic artery as a valid research tool, exploring the importance of using realistic spiral-flow inflow BC. By using a literature-based cancer scenario, we vary two parameters to analyze the microsphere distribution through the outlets of the geometry. The parameters varied are the type of microspheres injected and the microsphere injection velocity. The results with realistic inlet velocity profile showed that the par
Revista:
CANCERS
ISSN 2072-6694
Vol. 12
N° 6
Año 2020
Págs.1644
Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n= 36) and malignant conditions, CCA (n= 36) or PDAC (n= 57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (H-1-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n= 10) and proteins (n= 5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.
Autores:
Berenguer, M. (Autor de correspondencia); Burra, P.; Ghobrial, M.; et al.
Revista:
TRANSPLANTATION
ISSN 0041-1337
Vol. 104
N° 6
Año 2020
Págs.1143 - 1149
Although liver transplantation (LT) is the best treatment for patients with localized hepatocellular carcinoma (HCC), recurrence occurs in 6%-18% of patients. Several factors, particularly morphological criteria combined with dynamic parameters, known before LT modify this risk and combined in prediction models may be used to stratify patients at need of variable surveillance strategies. Additional variables though likely explain differences in recurrence rates in patients with the same pre-LT HCC status. One of these variables is possibly immunosuppression (IS). Once recurrence takes place, management is highly heterogenous. Within the International Liver Transplantation Society Consensus Conference on Liver Transplant Oncology, working group 4 aim was to analyze the data regarding posttransplant management of recipients undergoing LT for HCC. Three areas of research were considered: (1) cancer prediction models and surveillance strategies; (2) tailored IS for cancer recipients; and (3) new adjuvant therapies for HCC recurrence. Following formulation of several questions, a literature search was undertaken with abstract review followed by article retrieval and full-data extraction. The grading of recommendations assessment, development and evaluation (GRADE) system was used for evidence rating incorporating strength of recommendation and quality of evidence.
Autores:
Han, G. H.; Berhane, S.; Toyoda, H.; et al.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 72
N° 1
Año 2020
Págs.198 - 212
Background and Aims The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Approach and Results Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological responses (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) were also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. The median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, cause, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared with existing models (the hepatoma arterial embolization prognostic score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. Conclusions A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 73
N° 3
Año 2020
Págs.735 - 736
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 43
N° 8
Año 2020
Págs.1165 - 1172
Purpose In patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib, post-progression survival (PPS) is marked by the pattern of progression. Our aim was to assess the influence of the pattern of progression to selective internal radiotherapy (SIRT) in PPS among patients with HCC. Methods A retrospective analysis of patients treated with SIRT between 2003 and 2015 was conducted, excluding those with a single nodule < 5 cm or with metastases. Four patterns of progression to SIRT were defined: target tumour growth, non-target tumour growth, new intrahepatic disease, and new extrahepatic disease. PPS was calculated from the time of progression based on RECIST 1.1 criteria. Results Out of the 102 patients who met the selection criteria, 76 progressed after a median follow-up of 15 months. Median PPS was 6.5 months (95% CI 3.8-9.3 months). Patients who progressed at pre-existing lesions had a better PPS (median 12.5 months) than those who progressed with new lesions inside or outside the liver (median 4.2 months) (p = 0.02). In a Cox model adjusted by liver function and systemic inflammation, the pattern of progression had a hazard ratio of 1.64 (95% CI 0.92-2.93;p = 0.093). Conclusion In a cohort of HCC patients treated with SIRT, the pattern of progression associated with worst survival was the development of new intrahepatic lesions or extrahepatic metastases.
Autores:
Kelley, R. ; Kudo, M. ; Harris, W.; et al.
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 31
N° Supl. 3
Año 2020
Págs.S233 - S234
Revista:
COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING
ISSN 1025-5842
Vol. 22
N° 5
Año 2019
Págs.518 - 532
Balloon-occluded transarterial chemoembolisation (B-TACE) is an intraarterial transcatheter treatment for liver cancer. In B-TACE, an artery-occluding microballoon catheter occludes an artery and promotes collateral circulation for drug delivery to tumours. This paper presents a methodology for analysing the haemodynamics during B-TACE, by combining zero-dimensional and three-dimensional modelling tools. As a proof of concept, we apply the methodology to a patient-specific hepatic artery geometry and analyse two catheter locations. Results show that the blood flow redistribution can be predicted in this proof-of-concept study, suggesting that this approach could potentially be used to optimise catheter location.
Autores:
Diaz-Gonzalez, A.; Sanduzzi-Zamparelli, M.; da Fonseca, L.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° Supl. 1
Año 2019
Págs.E599 - E600
Autores:
da Fonseca, L. G. ; Minguez, B.; Perello, C. ; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° Supl. 1
Año 2019
Págs.E88
Autores:
Mercade, T. M.; Moreno, V.; John, B.; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 37
N° 15
Año 2019
Revista:
CANCER RESEARCH
ISSN 0008-5472
Vol. 79
N° 13
Año 2019
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 30
Año 2019
Autores:
Yau, T.; Park, J. W.; Finn, R. S.; et al.
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 30
N° Supl. 5
Año 2019
Págs.v874 - v875
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 70
Año 2019
Págs.131A - 132A
Autores:
Kudo, M.; Matilla, A.; Santoro, A.; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 37
N° 4
Año 2019
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° Supl. 1
Año 2019
Págs.E27 - E28
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° 1
Año 2019
Págs.E619
Autores:
Llopiz, Diana; Ruiz, Marta; Villanueva, Lorea; et al.
Revista:
CANCER IMMUNOLOGY IMMUNOTHERAPY
ISSN 0340-7004
Vol. 68
N° 3
Año 2019
Págs.379 - 393
Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-gamma production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 0174-1551
Vol. 42
N° 9
Año 2019
Págs.1262 - 1270
Revista:
CANCER RESEARCH
ISSN 0008-5472
Vol. 79
N° 20
Año 2019
Págs.5167 - 5180
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.
Autores:
Ricke, J. (Autor de correspondencia); Klumpen, H. J.; Amthauer, H.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 71
N° 6
Año 2019
Págs.1164 - 1174
Background & Aims: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 ( Y-90) resin microspheres - to sorafenib alone in patients with advanced HCC. Methods: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. Results: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients 65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. Conclusion: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. Lay summary: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with m yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Autores:
Goyal, L. ; Frigault, M. ; Meyer, T. ; et al.
Revista:
CANCER RESEARCH
ISSN 0008-5472
Vol. 79
N° Supl. 13
Año 2019
Autores:
Cabrera, R. ; Singal, A. ; Parikh, N. D.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° 1
Año 2019
Págs.E832
Revista:
LIVER INTERNATIONAL
ISSN 1478-3223
Vol. 39
N° Supl. 1
Año 2019
Págs.123 - 142
Most of the patients with cholangiocarcinoma (CCA) present with advanced (inoperable or metastatic) disease, and relapse rates are high in those undergoing potentially curative resection. Previous treatment nihilism of patients with advanced disease has been replaced by active clinical research with the advent of randomized clinical trials (RCTs) and a much greater effort at understanding molecular mechanisms underpinning CCA. Three RCTs have recently been reported evaluating adjuvant chemotherapy following curative resection; only one of these has the potential to change practice. The BILCAP study failed to meet its primary endpoint by intention-to-treat analysis; however, a survival benefit was seen in a preplanned sensitivity analysis (predominantly adjusting for lymph nodes status). This, along with the numerical difference in median overall survival has led to the uptake of adjuvant capecitabine by many clinicians. In patients with advanced disease, the only level 1 data available supports the use of cisplatin and gemcitabine for the first-line treatment of patients with advanced disease; there is no established second-line chemotherapy. Previous forays into targeted therapy have proven unfruitful (namely targeting the epithelial growth factor receptor and vascular endothelial growth factor pathways). An increasing number of genomic subtypes are being defined; for some of these on-target therapeutic options are under active investigation. The most developed are studies targeting IDH-1 (isocitrate dehydrogenase) mutations and FGFR-2 (fibroblast growth factor receptor) fusions, with promising early results. Several other pathways are under evaluation, along with early studies targeting the immune environment; these are too premature to change practice to date. These emerging treatments are discussed.
Autores:
Loffler, M. W. (Autor de correspondencia); Mohr, C.; Bichmann, L. ; et al.
Revista:
GENOME MEDICINE
ISSN 1756-994X
Vol. 11
Año 2019
Background: Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in HCCs. Methods: In-depth multi-omics analyses included whole exome and transcriptome sequencing to define individual patient-specific search spaces of neoepitope candidates. Evidence for the natural presentation of mutated HLA ligands was investigated through an in silico pipeline integrating proteome and HLA ligandome profiling data. Results: The approach was successfully validated in a state-of-the-art dataset from malignant melanoma, and despite multi-omics evidence for somaticmutations, mutated naturally presented HLA ligands remained elusive in HCCs. An analysis of extensive cancer datasets confirmed fundamental differences of tumor mutational burden in HCC and malignantmelanoma, challenging the notion that exome-derived mutations contribute relevantly to the expectable neoepitope pool in malignancies with only few mutations. Conclusions: This study suggests that exome-derived mutated HLA ligands appear to be rarely presented in HCCs, inter alia resulting from a low mutational burden as compared to other malignancies such as malignantmelanoma. Our results therefore demand widening the target scope for personalized immunotherapy beyond this limited range of mutated neoepitopes, particularly for malignancies with similar or lower mutational burden.
Autores:
Yau, T.; Kang, Y. K. ; Kim, T. Y.; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X
Vol. 37
N° 15 Supl.
Año 2019
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° 1
Año 2019
Págs.E365 - E366
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° 1
Año 2019
Págs.E821 - E822
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 70
N° 2
Año 2019
Págs.547 - 562
Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low-molecular-weight metabolites by new high-throughput techniques is a strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic profiles of PSC and CCA have also been compared. The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, and PSC and healthy individuals (n = 20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19-9 (CA 19-9) and alpha-fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3), and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy-proven). The proposed model yielded 0.890 AUC, 75% sensitivity, and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity, and 70% specificity. These results were validated in independent cohorts of 14-15 patients per group and compared with profiles found in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Conclusion: Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.
Revista:
NUCLEIC ACIDS RESEARCH
ISSN 0305-1048
Vol. 47
N° 7
Año 2019
Págs.3450 - 3466
Genome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA-DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle arrest and severe mitotic derangements with loss of sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the generation of truncated forms of the splicing factor SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant negative, or by gain-of-function, SRSF3-TR impair the correct splicing and expression of the splicing regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found in cancer cells of different tissue origin and also in the normal mouse liver, demonstrating a conserved and fundamental role of SLU7 in the preservation of genome integrity. Therefore, the dowregulation of SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the process of hepatocarcinogenesis.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 69
N° 4
Año 2019
Págs.1632 - 1647
Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ's function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha-naphthyl-isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up-regulated. Importantly, Areg(-/-) mice showed aggravated liver injury after BDL and ANIT administration compared to Areg(+/+) mice. Recombinant AREG protected from ANIT and BDL-induced liver injury and reduced BA-triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up-regulation in both tissues. Most interestingly, Areg(-/-) mice displayed high hepatic cholesterol 7 alpha-hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg(-/-) mice, and recombinant AREG down-regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr(-/-) mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA-FXR through activation of suppressor of cytokine signaling-3 (SOC3). Conclusion: AREG-EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070
Vol. 46
N° SUPPL 1
Año 2019
Págs.S481 - S482
Revista:
LIVER INTERNATIONAL
ISSN 1478-3223
Vol. 39
N° 12
Año 2019
Págs.2460 - 2461
Autores:
Marino, Z. ; Darne, A.; Lens, S.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 70
N° 5
Año 2019
Págs.874 - 884
Background & aims: Despite direct-acting antivirals being highly effective at eradicating hepatitis C virus infection, their impact on the development of hepatocellular carcinoma (HCC) remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing HCC.
Methods: This was a retrospective multicenter study focusing on cirrhotic patients treated with direct-acting antivirals until December 2016. Clinical and radiologic characteristics were collected before the start of antiviral therapy, at follow-up and at HCC development. Diagnosis of HCC was centrally validated and its incidence was expressed as HCC/100 person-years.
Results: A total of 1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved a sustained virologic response. Median time of follow-up was 19.6 months. Seventy-two patients developed HCC within a median of 10.3 months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 person-years (95% CI 2.96-4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated with a higher risk of HCC. The relative risk was significantly increased in patients with non-characterized nodules at baseline 2.83 (95% CI 1.55-5.16) vs. absence of non-characterized nodules. When excluding these patients, the risk remained increased.
Conclusion: These data expose a clear-cut time association between interferon-free treatm
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070
Vol. 46
N° 3
Año 2019
Págs.661 - 668
PURPOSE:
Patients with hepatocellular carcinoma (HCC) of intermediate stage (BCLC-B according to the Barcelona Clinic Liver Cancer classification) are a heterogeneous group with different degrees of liver function impairment and tumour burden. The recommended treatment is transarterial chemoembolization (TACE). However, patients in this group may be judged as poor candidates for TACE because the risk-benefit ratio is low. Such patients may receive transarterial radioembolization (TARE) only by entering a clinical trial. Experts have proposed that the stage could be further divided into four substages based on available evidence of treatment benefit. We report here, for the first time, the outcome in patients with BCLC-B2 substage HCC treated with TARE.
METHODS:
A retrospective analysis of the survival of 126 patients with BCLC-B2 substage HCC treated with TARE in three European hospitals was performed.
RESULTS:
Overall median survival in patients with BCLC-B2 substage was not significantly different in relation to tumour characteristics; 19.35 months (95% CI 8.27-30.42 months) in patients with a single large (>7 cm) HCC, and 18.43 months (95% CI 15.08-21.77 months) in patients with multinodular HCC (p¿=¿0.27). However, there was a higher proportion of long-term survivors at 36 months among those with a single large tumour (29%) than among those with multiple tumours (16.8%).
CONCLUSION:
Given the poor efficacy of TACE in treating patients with BCLC-B2 substage HCC, TARE
Autores:
Unfried, J. P.; Serrano, G. ; Suarez, B.; et al.
Revista:
CANCER RESEARCH
ISSN 0008-5472
Vol. 78
N° 13
Año 2018
Autores:
Rimola, J.; Diaz-Gonzalez, A.; Darnell, A.; et al.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 67
N° 2
Año 2018
Págs.612 - 622
The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. Conclusion: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2018;67:612-622).
Revista:
ONCOTARGET
ISSN 1949-2553
Vol. 9
N° 16
Año 2018
Págs.12842 - 12852
Long Non-Coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. Several lncRNAs are involved in cell proliferation and are deregulated in several human tumors. Few lncRNAs have been described to play a role in Acute Lymphoblastic Leukemia (ALL). In this study, we carried out a genome wide lncRNA expression profiling in ALL samples and peripheral blood samples obtained from healthy donors. We detected 43 lncRNAs that were aberrantly expressed in ALL. Interestingly, among them, linc-PINT showed a significant downregulation in T and B-ALL. Re-expression of linc-PINT in ALL cells induced inhibition of leukemic cell growth that was associated with apoptosis induction and cell cycle arrest in G2/M phase. linc-PINT induced the transcription of HMOX1 which reduced the viability of ALL cells. Intriguingly, we observed that treatment with anti-tumoral epigenetic drugs like LBH-589 (Panobinostat) and Curcumin induced the expression of linc-PINT and HMOX1 in ALL. These results indicate that the downregulation of linc-PINT plays a relevant role in the pathogenesis of ALL, and linc-PINT re-expression may be one of the mechanisms exerted by epigenetic drugs to reduce cell proliferation in ALL.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 68
N° Supl. 1
Año 2018
Págs.S16 - S16
Autores:
Vogel, A. (Autor de correspondencia); Cervantes, A. ; Chau, I. ; et al.
Revista:
ANNALS OF ONCOLOGY
ISSN 0923-7534
Vol. 29
N° Supl. 4
Año 2018
Págs.238 - 255
Revista:
CLINICAL CANCER RESEARCH
ISSN 1078-0432
Vol. 24
N° 7
Año 2018
Págs.1518 - 1524
Treatment of patients with hepatocellular carcinoma (HCC) in the advanced stage remains a great challenge, with very few drugs approved. After decades of failure of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with HCC in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells and mostly provide immunosuppressive signals. Monoclonal antibodies able to block these molecules have shown antitumor activity against a wide spectrum of human cancers. Clinical experience with checkpoint inhibitors in HCC includes early trials with the anti-CTLA-4 agent tremelimumab and a large phase II trial with the anti-PD-1 agent nivolumab. The latter has shown strong activity particularly as second-line therapy, both in terms of tumor response and patient survival. At least three topics should be the focus of future research: (i) the search for activity in patients at less-advanced stages, including the adjuvant treatment of patients with resectable or ablatable tumors; (ii) the enhanced efficacy of combination therapies, including particularly the combination with those targeted and locoregional therapies that may have a synergistic effect or act upon mechanisms of primary or acquired resistance to checkpoint inhibitors; and (iii) the identification of clinical features and serumor tissue biomarkers that would allow a better patient selection for individual treatments. Hopefully, ongoing trials will help to design better treatments in the future. (C) 2017 AACR.
Autores:
Reig, M.; Marino, Z. ; Darnell, A.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 68
Año 2018
Págs.S118 - S118
Revista:
CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN 1699-048X
Vol. 20
N° 5
Año 2018
Págs.658 - 665
Synchronous liver metastases (LM) from gastric (GC) or esophagogastric junction (EGJ) adenocarcinoma are a rare events. Several trials have evaluated the role of liver surgery in this setting, but the impact of preoperative therapy remains undetermined. Patients with synchronous LM from GC/EGJ adenocarcinoma who achieved disease control after induction chemotherapy (ICT) and were subsequently scheduled to chemoradiotherapy (CRT) to the primary tumor and surgery assessment were retrospectively analyzed. Pathological response, patterns of relapse, progression-free survival (PFS), and overall survival (OS) were calculated. From July 2002 to September 2012, 16 patients fulfilling the inclusion criteria were identified. Primary tumor site was GC (nine patients) or EGJ (seven patients). LM were considered technically unresectable in nine patients. Radiological response to the whole neoadjuvant program was achieved in 13 patients. Eight patients underwent surgical resection of the primary tumor; in five of these LM were resected. A complete pathological response in the primary or in the LM was found in four and three patients, respectively. The most frequent site of relapse/progression was systemic (eight patients). Local and liver-only relapses were observed in two patients each. After a median follow-up of 91 months, the median OS and PFS were 23.0 (95% CI 13.2-32.8) and 17.0 months (95% CI 11.7-22.3). 5-year actuarial PFS is 17.6%. Our results suggest that an intensified approach using ICT followed by CRT in synchronous LM from GC/EGJ adenocarcinoma is feasible and may translate into prolonged survival times in selected patients.
Autores:
Kudo, M.; Matilla, A. M.; Santoro, A.; et al.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 68
N° 6
Año 2018
Págs.1445A - 1446A
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 68
N° Supl. 1
Año 2018
Págs.S74 - S74
Revista:
INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939
Vol. 34
N° e2983
Año 2018
Revista:
ONCOTARGETS AND THERAPY
ISSN 1178-6930
Vol. 11
Año 2018
Págs.7315 - 7321
Purpose: This study aimed to compare clinically relevant outcomes following transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) in patients with unresectable hepatocellular carcinoma (HCC) using only prospective randomized clinical trials as a source of information. Materials and methods: A meta-analysis was performed to compare the efficacy of TARE and TACE in treating patients with unresectable HCC. Only prospective randomized trials were included in the quantitative analysis. Overall and progression-free survival, disease control rate, and transplantation rate were the variables under analysis. Results: Overall survival at 1 year was similar between the two treatment groups (OR =1.31, 95% CI: 0.56-3.04, P=0.53). Progression-free survival at 1 year was also not statistically different between the two treatments (OR =0.23, 95% CI: 0.02-2.45, P=0.22). Although a higher proportion of patients underwent transplantation in the TARE group (30% vs 20.8%), this difference was not statistically significant (OR =0.68, 95% CI: 0.23-2.01; P=0.49). Conclusion: TARE and TACE provide similar outcomes in unresectable HCC. The role of TARE should be explored in selected patient subpopulations in future clinical trials.
Revista:
JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 1051-0443
Vol. 29
N° 9
Año 2018
Págs.1305 - 1306
Revista:
HEPATIC ONCOLOGY
ISSN 2045-0923
Vol. 5
N° 2
Año 2018
Págs.HEP09
The hormone secretion in pancreatic neuroendocrine tumors (pNET) causes an important interference in patients' quality of life. We present two cases of pNET metastatic to the liver (a pancreatic endocrine carcinoma with a severe hormonal syndrome and an insulinoma with severe crisis of hypoglycemia and coma) refractory to conventional treatments, which were finally solved with selective internal radiation therapy (SIRT), a nonstandard level 1 therapy. We show two examples of an excellent control of symptoms together with a long survival after treatment with SIRT. The evidence supporting the use of this therapy is level 2. Our case reports strongly support the use of SIRT for the severe clinical syndrome in pNET metastatic to the liver and refractory to somatostatin analogs.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 68
N° 1
Año 2018
Págs.157 - 166
Drug development in hepatocellular carcinoma (HCC) has been characterised by many failures in the past. Despite good rationales and promising phase II data, many phase III trials failed. Immunotherapy represents an alternative treatment approach that has been successful in many different cancer types. As an inflammation induced cancer, HCC represents a very interesting target for immune based approaches. Indeed, early results from clinical trials testing immune checkpoint inhibitors are not only promising, but have already led to evaluation in a phase III setting. Herein, we summarise our current knowledge on the rationale, mechanism of action and clinical data for immune checkpoint blockade in HCC. In addition, we provide an overview of other novel immune based approaches currently under development for the treatment of HCC, such as adoptive cell based and antibody-based approaches. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 68
N° Supl. 1
Año 2018
Págs.S677 - S677
Revista:
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
ISSN 0925-4439
Vol. 1864
N° 4
Año 2018
Págs.1468 - 1477
The poor prognosis of cholangiocarcinoma (CCA) is in part due to late diagnosis, which is currently achieved by a combination of clinical, radiological and histological approaches. Available biomarkers determined in serum and biopsy samples to assist in CCA diagnosis are not sufficiently sensitive and specific. Therefore, the identification of new biomarkers, preferably those obtained by minimally invasive methods, such as liquid biopsy, is important. The development of innovative technologies has permitted to identify a significant number of genetic, epigenetic, proteomic and metabolomic CCA features with potential clinical usefulness in early diagnosis, prognosis or prediction of treatment response. Potential new candidates must be rigorously evaluated prior to entering routine clinical application. Unfortunately, to date, no such biomarker has achieved validation for these purposes. This review is an up-to-date of currently used biomarkers and the candidates with promising characteristics that could be included in the clinical practice in the next future. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 68
Año 2018
Págs.S72 - S73
Revista:
INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939
Vol. 33
N° 2
Año 2017
Liver radioembolization (RE) is a treatment option for patients with unresectable and chemorefractory primary and metastatic liver tumours. RE consists of intra-arterially administering via catheter radioactive microspheres that locally attack the tumours, sparing healthy tissue. Prior to RE, the standard practice is to conduct a treatment-mimicking pretreatment assessment via the infusion of Tc-99m-labelled macroaggregated albumin microparticles. The usefulness of this pretreatment has been debated in the literature, and thus, the aim of the present study is to shed light on this issue by numerically simulating the liver RE pretreatment and actual treatment particle-haemodynamics in a patient-specific hepatic artery under two different literature-based cancer scenarios and two different placements of a realistic end-hole microcatheter in the proper hepatic artery. The parameters that are analysed are the following: microagent quantity and size (accounting for RE pretreatment and treatment), catheter-tip position (near the proper hepatic artery bifurcation and away from it), and cancer burden (10% and 30% liver involvement). The conclusion that can be reached from the simulations is that when it comes to mimicking RE in terms of delivering particles to tumour-bearing segments, the catheter-tip position is much more important (because of the importance of local haemodynamic pattern alteration) than the infused microagents (i.e. quantity and size). Cancer burden is another important feature because the increase in blood flow rate to tumour-bearing segments increases the power to drag particles. These numerical simulation-based conclusions are in agreement with clinically observed events reported in the literature. Copyright (c) 2016 John Wiley & Sons, Ltd.
Revista:
ANNALS OF TRANSPLANTATION
ISSN 1425-9524
Vol. 22
Año 2017
Págs.141 - 147
Background: Immunosuppression increases the risk of malignancy in liver transplant recipients. The potential impact of mycophenolate mofetil monotherapy on this risk has not been studied. Material/Methods: The incidence and risk factors for de novo malignancies of 392 liver transplant recipients with a survival higher than 3 months and a mean follow-up of 8.5 years were studied. Results: De novo malignancies were diagnosed in 126 patients (32.1%) (64 non-melanoma skin cancer and 81 other malignancies). Sixty-nine patients (18.1%) stopped receiving calcineurin inhibitors and were maintained on mycophenolate mofetil monotherapy. The proportion of time on mycophenolate mofetil monotherapy (obtained after dividing the time on monotherapy by the time until diagnosis of neoplasia/last follow-up) was independently associated with a lower risk of de novo malignancy (HR: 0.16, 95% CI: 0.05-0.48; P=0.001), non-melanoma skin cancer (HR: 0.17, 95% CI: 0.03-0.79; P=0.024), and other malignancies (HR: 0.23, 95% CI: 0.07-0.77; P=0.017). Older age and male sex were also associated with a higher risk of malignancy, and transplantation for hepatocellular carcinoma increased the risk of non-melanoma skin cancer. Conclusions: Mycophenolate mofetil monotherapy is associated with a lower risk of cancer in liver transplant recipients compared with maintenance immunosuppression with calcineurin inhibitors.
Autores:
Mayer, A. ; Accolla, R.; Ma, Y. T. ; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 66
N° Supl. 1
Año 2017
Págs.S445 - S446
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 66
N° Supl 1
Año 2017
Págs.984A
Revista:
JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 1051-0443
Vol. 28
N° 11
Año 2017
Págs.1536 - 1542
Purpose:To determine if baseline patient, tumor, and pretreatment evaluation characteristics could help identify patients who require technetium-99m (Tc-99m) macroaggregated albumin Tc-(99m MAA) imaging before selective internal radiation therapy (SIRT). Materials and Methods: In this retrospective analysis, 532 consecutive patients with primary (n = 248) or metastatic (n = 284) liver tumors were evaluated between 2006 and 2015. Variables were compared between patients in whom Tc-99m MAA imaging results contraindicated/modified SIRT administration with yttrium-90 (Y-90) resin microspheres and those who were treated as initially planned. The Tc-99m MAA findings that contraindicated/modified SIRT were a lung shunt fraction (LSF) > 20%, gastrointestinal Tc-99m MAA uptake, or a mismatch between Tc-99m MAA uptake and intrahepatic tumor distribution. Results: LSF > 20% and gastrointestinal MAA uptake were observed in 7.5% and 3.9% of patients, respectively, and 11% presented a mismatch. Presence of a single lesion (odds ratio [OR] = 2.4) and vascular invasion (OR = 5.5) predicted LSF > 20%, and GI MAA uptake was predicted by the presence of liver metastases (OR = 3.7) and Tc-99m MAA injection through the common/proper hepatic artery (OR = 4.7). Vascular invasion (OR = 4.1) was the only predictor of LSF > 20% and/or GI MAA uptake (sensitivity = 49.2%, specificity = 80.3%, negative predictive value = 92.4%). Previous antiangiogenic treatment (OR = 2.4) and presence of a single lesion (OR = 2.6) predicted mismatch. Conclusions: Imaging with Tc-99m MAA is essential in SIRT workup because baseline characteristics may not adequately predict Tc-99m MAA results. Nevertheless, the absence of vascular invasion potentially identifies a group of patients at low risk of SIRT contraindication/modification in whom performing SIRT in a single session (ie, pretreatment evaluation and SIRT on the same day) should be explored.
Revista:
ONCOTARGET
ISSN 1949-2553
Vol. 8
N° 25
Año 2017
Págs.40967 - 40981
The identification of new targets for systemic therapy of hepatocellular carcinoma (HCC) is an urgent medical need. Recently, we showed that hNatB catalyzes the N-alpha-terminal acetylation of 15% of the human proteome and that this action is necessary for proper actin cytoskeleton structure and function. In tumors, cytoskeletal changes influence motility, invasion, survival, cell growth and tumor progression, making the cytoskeleton a very attractive antitumor target. Here, we show that hNatB subunits are upregulated in in over 59% HCC tumors compared to non-tumor tissue and that this upregulation is associated with microscopic vascular invasion. We found that hNatB silencing blocks proliferation and tumor formation in HCC cell lines in association with hampered DNA synthesis and impaired progression through the S and the G2/M phases. Growth inhibition is mediated by the degradation of two hNatB substrates, tropomyosin and CDK2, which occurs when these proteins lack N-alpha-terminal acetylation. In addition, hNatB inhibition disrupts the actin cytoskeleton, focal adhesions and tight/adherens junctions, abrogating two proliferative signaling pathways, Hippo/YAP and ERK1/2. Therefore, inhibition of NatB activity represents an interesting new approach to treating HCC by blocking cell proliferation and disrupting actin cytoskeleton function.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 66
N° Supl. 1
Año 2017
Págs.82A
Revista:
LANCET
ISSN 0140-6736
Vol. 389
N° 10088
Año 2017
Págs.2492 - 2502
BACKGROUND:
For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis.
METHODS:
We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (¿18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878.
FINDINGS:
Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase.
INTERPRETATION:
Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma.
FUNDING:
Bristol-Myers Squibb.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 66
N° 1
Año 2017
Págs.S34 - S35
Revista:
TRANSLATIONAL RESEARCH
ISSN 1931-5244
Vol. 188
Año 2017
Págs.80 - 91.e2
The aim of this nonrandomized, open label, phase 1 clinical trial was to evaluate the safety and the feasibility of the treatment with autologous bone marrow-derived endothelial progenitor cells (EPC) in decompensated liver cirrhosis. In addition, the changes in liver function and hepatic venous pressure gradient (HVPG) and their relation with the characteristics of the cellular product were analyzed. Twelve patients with Child-Pugh ¿8 liver cirrhosis underwent bone marrow harvest for ex vivo differentiation of EPC. The final product was administered through the hepatic artery in a single administration. Patients underwent clinical and radiologic follow-up for 12 months. The phenotype and the ability to produce cytokines and growth factors of the final cellular suspension were analyzed. Eleven patients were treated (feasibility 91%). No treatment-related severe adverse events were observed as consequence of any study procedure or treatment. Model for end-stage liver disease score improved significantly (P 0.042) in the first 90 days after cells administration and 5 of the 9 patients alive at 90 days showed a decreased of HVPG. There was a direct correlation between the expression of acetylated-low density lipoprotein and von Willebrand factor in the cellular product and the improvement in liver function and HVPG. The treatment with EPCs in patients with decompensated liver cirrhosis is safe and feasible and might have therapeutic potential. Patients receiving a higher amount
Revista:
TRANSLATIONAL RESEARCH
ISSN 1931-5244
Vol. 188
Año 2017
Págs.80 - 91
The aim of this nonrandomized, open label, phase 1 clinical trial was to evaluate the safety and the feasibility of the treatment with autologous bone marrow-derived endothelial progenitor cells (EPC) in decompensated liver cirrhosis. In addition, the changes in liver function and hepatic venous pressure gradient (HVPG) and their relation with the characteristics of the cellular product were analyzed. Twelve patients with Child-Pugh ¿8 liver cirrhosis underwent bone marrow harvest for ex vivo differentiation of EPC. The final product was administered through the hepatic artery in a single administration. Patients underwent clinical and radiologic follow-up for 12 months. The phenotype and the ability to produce cytokines and growth factors of the final cellular suspension were analyzed. Eleven patients were treated (feasibility 91%). No treatment-related severe adverse events were observed as consequence of any study procedure or treatment. Model for end-stage liver disease score improved significantly (P 0.042) in the first 90 days after cells administration and 5 of the 9 patients alive at 90 days showed a decreased of HVPG. There was a direct correlation between the expression of acetylated-low density lipoprotein and von Willebrand factor in the cellular product and the improvement in liver function and HVPG. The treatment with EPCs in patients with decompensated liver cirrhosis is safe and feasible and might have therapeutic potential. Patients receiving a higher amount
Revista:
ONCOTARGET
ISSN 1949-2553
Vol. 9
N° 5
Año 2017
Págs.6652 - 6656
Sorafenib is a multi-kinase inhibitor and a vascular endothelial growth factor (VEGF) inhibitor approved to treat patients with advanced hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma. Its most common side effects are asthenia/fatigue, skin toxicity, diarrhea and arterial hypertension. Reported respiratory adverse reactions include dyspnea, cough, pleural effusion and hoarseness. The aim of this report is to describe for the first time the occurrence of pneumatocele in two patients treated with Sorafenib. Patients had no respiratory symptoms and alternative diagnoses were ruled out. Primary tumors were different (liver metastases from a pancreatic neuroendocrine tumor and hepatocellular carcinoma) but both patients had been treated with yttrium 90 radioembolization 9 and 17 months before starting on Sorafenib, respectively. No complications occurred and Sorafenib withdrawal was followed by radiologic improvement.
Revista:
HEPATOLOGY
ISSN 0270-9139
Vol. 66
N° 3
Año 2017
Págs.969 - 982
Selective internal radiation therapy (or radioembolization) by intra-arterial injection of radioactive yttrium-90-loaded microspheres is increasingly used for the treatment of patients with liver metastases or primary liver cancer. The high-dose beta-radiation penetrates an average of only 2.5 mm from the source, thus limiting its effects to the site of delivery. However, the off-target diversion of yttrium-90 microspheres to tissues other than the tumor may lead to complications. The most prominent of these complications include radiation gastritis and gastrointestinal ulcers, cholecystitis, radiation pneumonitis, and radioembolization-induced liver disease, which may occur despite careful pretreatment planning. Thus, selective internal radiation therapy demands an expert multidisciplinary team approach in order to provide comprehensive care for patients. This review provides recommendations to multidisciplinary teams on the optimal medical processes in order to ensure the safe delivery of selective internal radiation therapy. Based on the best available published evidence and expert opinion, we recommend the most appropriate strategies for the prevention, early diagnosis, and management of potential radiation injury to the liver and to other organs.
Revista:
LIVER INTERNATIONAL
ISSN 1478-3223
Vol. 37
N° 1
Año 2017
Págs.32 - 34
Revista:
LIVER INTERNATIONAL
ISSN 1478-3223
Vol. 37
N° 1
Año 2017
Págs.32-34
Revista:
ANNALS OF SURGICAL ONCOLOGY
ISSN 1068-9265
Vol. 24
N° 9
Año 2017
Págs.2465 - 2473
Background. Reports show that selective internal radiation therapy (SIRT) may downsize inoperable liver tumors to resection or transplantation, or enable a bridge-to-transplant. A small-cohort study found that long-term survival in patients undergoing resection following SIRT appears possible but no robust studies on postsurgical safety outcomes exist. The Post-SIR-Spheres Surgery Study was an international, multicenter, retrospective study to assess safety outcomes of liver resection or transplantation following SIRT with yttrium-90 (Y-90) resin microspheres (SIR-Spheres (R); Sirtex). Methods. Data were captured retrospectively at participating SIRT centers, with Y-90 resin microspheres, surgery (resection or transplantation), and follow-up for all eligible patients. Primary endpoints were perioperative and 90-day postoperative morbidity and mortality. Standard statistical methods were used. Results. The study included 100 patients [hepatocellular carcinoma: 49; metastatic colorectal cancer (mCRC): 30; cholangiocarcinoma, metastatic neuroendocrine tumor, other: 7 each]; 36% of patients had one or more lines of chemotherapy pre-SIRT. Sixty-three percent of patients had comorbidities, including hypertension (44%), diabetes (26%), and cardiopathy (16%). Post-SIRT, 71 patients were resected and 29 received a liver transplant. Grade 3+ peri/postoperative complications and any grade of liver failure were experienced by 24 and 7% of patients, respectively. Four patients died < 90 days postsurgery; all were trisectionectomies (mCRC: 3; cholangiocarcinoma: 1) and typically had one or more previous chemotherapy lines and presurgical comorbidities. Conclusions. In 100 patients undergoing liver surgery after receiving SIRT, mortality and complication rates appeared acceptable given the risk profile of the recruited patients.
Revista:
INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939
Año 2017
Págs.e02895
Liver radioembolization is a promising treatment option for combating liver tumors. It is performed by placing a microcatheter in the hepatic artery and administering radiation-emitting microspheres through the arterial bloodstream so that they get lodged in the tumoral bed. In avoiding nontarget radiation, the standard practice is to conduct a pretreatment, in which the microcatheter location and injection velocity are decided. However, between pretreatment and actual treatment some of the parameters that influence the particle distribution in the liver can vary, resulting in radiation-induced complications. The present study aims to analyze the influence of a commercially available microcatheter with an angled tip and particle injection velocity in terms of segment-to-segment particle distribution. Specifically, four tip orientations and two injection velocities are combined to yield a set of eight numerical simulations of the particle-hemodynamics in a patient-specific truncated hepatic artery. For each simulation, four cardiac pulses are simulated. Particles are injected during the first cycle, and the remaining pulses enable the majority of the injected particles to exit the computational domain. Results indicate that, in terms of injection velocity, particles are more spread out in the cross-sectional lumen areas as the injection velocity increases. The tip's orientation also plays a role because it influences the near-tip hemodynamics, therefore altering the particle travel through the hepatic artery. However, results suggest that particle distribution tries to match the blood flow split, therefore particle injection velocity and microcatheter tip orientation playing a minor role in segment-to-segment particle distribution.
Revista:
TRANSPLANTATION
ISSN 0041-1337
Vol. 101
N° 3
Año 2017
Págs.548 - 554
Background. The pure laparoscopic approach in right hepatectomy (LRH) for living donor liver transplantation (LDLT) is a controversial issue. Some authors have reported the procedure to be feasible but surgical outcomes and impact on short and longterm morbidity rates are yet to be determined. The aim of this study is to present the results of a preliminary 5 consecutive cases series of LRH for LDLT and to compare it with a successive cohort of open right hepatectomies (ORH) for LDLT. Methods. From May 2013 to October 2015, 5 consecutive donors underwent LRH for LDLT in our center. The previous last 10 ORH for LDLT were selected for comparison. Special care was taken to include all adverse events. Each patient's complications were graded with the Clavien-Dindo Classification and scored with the Comprehensive Complication Index. Results. All 5 consecutive donors completed a pure laparoscopic procedure. All allografts (open and laparoscopically procured) were successfully transplanted with no primary graft failures. Only 2 Clavien-Dindo Grade-I complications occurred in the LRH donors, while ORH donors had 10 Grade I, 2 Grade II and 1 Grade IIIa complications in the short term (< 3 months). In the long term (6-12 months follow-up), LRH donors had a significant lower incidence of complications (Comprehensive Complication Index: 1.74; SD, 3891 vs 15.2 SD; 8.618; P = 0.006). Conclusions. In our experience, LRH for LDLT is a feasible procedure. Further comparative series may support our preliminary findings of reduced incidence and severity of complications as compared with the open approach.
Autores:
Waked, I. ; Berhane, S. ; Toyoda, H. ; et al.
Revista:
BRITISH JOURNAL OF CANCER
ISSN 0007-0920
Vol. 116
N° 4
Año 2017
Págs.448 - 454
Background: Transarterial chemo-embolisation (TACE) is recommended for patients with BCLC intermediate stage hepatocellular carcinoma (stage B), particularly in patients with good underlying liver function and minimal symptoms. The hepatoma arterial embolisation prognostic (HAP) score combines measures of liver function and tumour-related factors to offer a simple prognostic scoring system. The Albumin-Bilirubin (ALBI) grade permits assessment of the impact of liver function on survival. We aimed to investigate these two models and vascular invasion (VI). Methods: In an international cohort of 3030 patients undergoing TACE, we examined the impact of liver function as assessed by the ALBI score, the HAP score and VI on survival. Results: Classification according to ALBI grade resulted in non-overlapping survival curves in the overall data set and all regional cohorts. The HAP score was also validated. Tumour number, aetiology and VI were identified as additional independent prognostic risk factors not currently included in the HAP score. Survival was particularly poor for patients with VI. Conclusions: The ALBI grade categorised patients receiving TACE into three clear prognostic groups, thereby emphasising the importance of underlying liver function in the outcome of TACE. The HAP score has been validated internationally and the serious adverse impact of VI is clearly shown.
Autores:
Reig, M. ; Marino, Z. ; Perello, C. ; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 66
N° Supl. 1
Año 2017
Págs.S20
Revista:
LIVER INTERNATIONAL
ISSN 1478-3223
Vol. 36
N° 8
Año 2016
Págs.1206-1212
After a median follow-up of 6 months, 60 deaths had occurred: 38 and 22 in SOR and RE groups respectively. Median survival was 6.7 months (95%CI 5.2-8.1 months) for the entire cohort, and 8.8 months (95%CI 1.8-15.8) in the RE group and 5.4 months (95%CI 2.7-8.1) in the SOR group (P = 0.047). The difference in survival was still statistically significant when 13 patients in the RE group who started SOR after a median time of 8 months were censored from the analysis.
CONCLUSIONS:
In a cohort of patients with HCC and PVI treatment with RE was associated with a more prolonged survival compared with SOR.
Revista:
REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
ISSN 1130-0108
Vol. 108
N° 8
Año 2016
Págs.479 - 484
Background: Agenesis of the dorsal pancreas is a rare malformation. Since 1911 and until 2008, 53 cases have been reported. Several authors have recently described the association of this anomaly with neoplasia of the ventral pancreas, thus we performed a systematic review of the literature from 2008 to 2015.
Methods: A systematic review of the MedLine and ISI Web of Science Databases from 2008 until 2015 was carried out, and 30 articles which met the inclusion criteria were identified that included a total of 53 patients: 7 children and 46 adults.
Conclusions: Although dorsal pancreatic agenesis is a rare malformation, given its association with non-alcoholic pancreatitis and neoplasia of the residual pancreas, physicians should maintain an expectant attitude.
Autores:
Diaz Gonzalez, A.; Rimola, J.; Maria, R.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278
Vol. 64
N° Supl. 2
Año 2016
Págs.S319
Revista:
JOURNAL OF BIOMECHANICS
ISSN 0021-9290
Vol. 49
N° 15
Año 2016
Págs.3705 - 3713
Radioembolization, which consist of the implantation of radioactive microspheres via intra-arterially placed microcatheter, is a safe and effective treatment for liver cancer. Nevertheless, radioembolization-related complications and side effects may arise, which are an active area of ongoing research. The catheter design has been claimed as an option in reducing these complications. In this paper, the influence of catheter type and location are investigated. The study was undertaken by numerically simulating the particle¿hemodynamics in a patient-specific hepatic artery during liver radioembolization. The parameters modified were cancer scenario (30% liver involvement in the right lobe, `scenario A¿, and in both lobes, `scenario B¿), catheter type (standard end-hole microcatheter, SMC, and antireflux catheter, ARC), and the location of the tip in the proper hepatic artery (in the straight part, `inlet¿, and near the bifurcation, `bifurcation¿). Comparing ARC with SMC, the maximum and average (over segments) absolute difference in the percentage of particles that reached each segment were 19.62% and 9.06% when injecting near the inlet for scenario A; 3.54% and 1.07% injecting near the bifurcation for scenario A; and 18.31% and 11.85% injecting near the inlet for scenario B. It seems, therefore, that the location of the catheter tip in the artery is crucial in terms of particle distribution. Moreover, even though the near-tip blood flow was altered due to the presence of a catheter, the particle distribution matched the flow split if the distance between the injection point and the first bifurcation encountered enabled the alignment of particles with blood flow.
Revista:
EUROPEAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
ISSN 0954-691X
Vol. 28
N° 2
Año 2016
Págs.139 - 145
Objective Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver. Patients and methods We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded. Results REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, â-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P< 0.05), nonprotein respiratory quotient (P< 0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P< 0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism. Conclusion Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice.
