Revistas
Revista:
CANCERS
ISSN:
2072-6694
Año:
2023
Vol.:
15
N°:
3
Págs.:
733
Simple Summary Radioembolization is a locoregional therapy used in primary liver malignancies with different applications depending on the treatment goal. The aim of this retrospective study was to evaluate postoperative and long-term survival outcomes of patients with unresectable or high biological risk HCC and ICC treated with RE that were finally rescued to liver surgery with curative intent. In a cohort of 34 patients, we assessed that liver resection and transplantation after RE seem safe and feasible with adequate short-term outcomes. Moreover, long-term outcomes after RE and LR were optimal, with a 10-year OS rate greater than 50% for HCC and ICC patients. On the other hand, the 10-year OS rates from RE were also greater than 50% for patients with HCC downstaged or bridged to LT. Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. Methods: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005-2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. Results: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien-Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. Conclusion: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2022
Vol.:
12
N°:
1
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.
Autores:
Caballero-Marcos, A.; Citores, M. J.; Alonso-Fernández, R.; et al.
Revista:
LIVER TRANSPLANTATION
ISSN:
1527-6465
Año:
2022
Vol.:
28
N°:
6
Págs.:
1039 - 1050
Long-term humoral immunity and its protective role in liver transplantation (LT) patients have not been elucidated. We performed a prospective multicenter study to assess the persistence of immunoglobulin G (IgG) antibodies in LT recipients 12 months after coronavirus disease 2019 (COVID-19). A total of 65 LT recipients were matched with 65 nontransplanted patients by a propensity score including variables with recognized impact on COVID-19. LT recipients showed a lower prevalence of anti-nucleocapsid (27.7% versus 49.2%; P = 0.02) and anti-spike IgG antibodies (88.2% versus 100.0%; P = 0.02) at 12 months. Lower index values of anti-nucleocapsid IgG antibodies were also observed in transplantation patients 1 year after COVID-19 (median, 0.49 [interquartile range, 0.15-1.40] versus 1.36 [interquartile range, 0.53-2.91]; P < 0.001). Vaccinated LT recipients showed higher antibody levels compared with unvaccinated patients (P < 0.001); antibody levels reached after vaccination were comparable to those observed in nontransplanted individuals (P = 0.70). In LT patients, a longer interval since transplantation (odds ratio, 1.10; 95% confidence interval, 1.01-1.20) was independently associated with persistence of anti-nucleocapsid IgG antibodies 1 year after infection. In conclusion, compared with nontransplanted patients, LT recipients show a lower long-term persistence of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies. However, SARS-CoV-2 vaccination after COVID-19 in LT patients achieves a significant increase in antibody levels, comparable to that of nontransplanted patients.
Revista:
BMC MEDICAL EDUCATION
ISSN:
1472-6920
Año:
2022
Vol.:
22
N°:
1
Págs.:
779
Background One of the most important challenges in medical education is the preparation of multiple-choice questions able to discriminate between students with different academic level. Average questions may be very easy for students with good performance, reducing their discriminant power in this group of students. The aim of this study was to analyze if the discriminative power of multiple-choice questions is different according to the students' academic performance. Methods We retrospectively analyzed the difficulty and discrimination indices of 257 multiple-choice questions used for the end of course examination of pathophysiology and analyzed whether the discrimination indices were lower in students with good academic performance (group 1) than in students with moderate/poor academic performance (group 2). We also evaluated whether case-based questions maintained their discriminant power better than factual questions in both groups of students or not. Comparison of the difficulty and discrimination indices between both groups was based on the Wilcoxon test. Results Difficulty index was significantly higher in group 1 (median: 0.78 versus 0.56; P < 0.001) and discrimination index was significantly higher in group 2 (median: 0.21 versus 0.28; P < 0.001). Factual questions had higher discriminative indices in group 2 than in group 1 (median: 0.28 versus 0.20; P < 0.001), but discriminative indices of case-based questions did not differ significantly between groups (median: 0.30 versus 0.24; P = 0.296). Conclusions Multiple-choice question exams have lower discriminative power in the group of students with high scores. The use of clinical vignettes may allow to maintain the discriminative power of multiple-choice questions.
Revista:
MEDICINA CLINICA
ISSN:
0025-7753
Año:
2022
Vol.:
158
N°:
12
Págs.:
E17 - E18
Revista:
JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN:
2051-1426
Año:
2022
Vol.:
10
N°:
2
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:
JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN:
2051-1426
Año:
2022
Vol.:
10
N°:
11
Págs.:
e005457 -*
Purpose To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization.Patients and methods NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naive to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS).Results 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1).Conclusions The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT.
Autores:
Loffler, M. W.; Gori, S.; Izzo, F.; et al.
Revista:
CLINICAL CANCER RESEARCH
ISSN:
1078-0432
Año:
2022
Vol.:
28
N°:
12
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
Año:
2022
Vol.:
407
N°:
3
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.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN:
1619-7070
Año:
2021
Vol.:
48
N°:
10
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%.
Autores:
Caballero-Marcos, A.; Salcedo, M. (Autor de correspondencia); Alonso-Fernández, R.; et al.
Revista:
AMERICAN JOURNAL OF TRANSPLANTATION
ISSN:
1600-6135
Año:
2021
Vol.:
21
N°:
8
Págs.:
2876 - 2884
The protective capacity and duration of humoral immunity after SARS-CoV-2 infection are not yet understood in solid organ transplant recipients. A prospective multicenter study was performed to evaluate the persistence of anti-nucleocapsid IgG antibodies in liver transplant recipients 6 months after coronavirus disease 2019 (COVID-19) resolution. A total of 71 liver transplant recipients were matched with 71 immunocompetent controls by a propensity score including variables with a well-known prognostic impact in COVID-19. Paired case-control serological data were also available in 62 liver transplant patients and 62 controls at month 3 after COVID-19. Liver transplant recipients showed a lower incidence of anti-nucleocapsid IgG antibodies at 3 months (77.4% vs. 100%, p < .001) and at 6 months (63.4% vs. 90.1%, p < .001). Lower levels of antibodies were also observed in liver transplant patients at 3 (p = .001) and 6 months (p < .001) after COVID-19. In transplant patients, female gender (OR = 13.49, 95% CI: 2.17-83.8), a longer interval since transplantation (OR = 1.19, 95% CI: 1.03-1.36), and therapy with renin-angiotensin-aldosterone system inhibitors (OR = 7.11, 95% CI: 1.47-34.50) were independently associated with persistence of antibodies beyond 6 months after COVID-19. Therefore, as compared with immunocompetent patients, liver transplant recipients show a lower prevalence of anti-SARS-CoV-2 antibodies and more pronounced antibody levels decline.
Autores:
Marino, Z.; Darnell, A.; Lens, S.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN:
0168-8278
Año:
2021
Vol.:
74
N°:
2
Págs.:
491
Autores:
Colmenero, J.; Rodríguez Perálvarez, M. (Autor de correspondencia); Salcedo, M.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN:
0168-8278
Año:
2021
Vol.:
74
N°:
1
Págs.:
148 - 155
Background & Aims: The incidence and outcomes of coronavirus disease 2019 (COVID-19) in immunocompromised patients are a matter of debate. Methods: We performed a prospective nationwide study including a consecutive cohort of liver transplant patients with COVID-19 recruited during the Spanish outbreak from 28 February to 7 April, 2020. The primary outcome was severe COVID-19, defined as the need for mechanical ventilation, intensive care, and/or death. Age- and gender-standardised incidence and mortality ratios (SIR and SMR) were calculated using data from the Ministry of Health and the Spanish liver transplant registry. Independent predictors of severe COVID-19 among hospitalised patients were analysed using multivariate Cox regression. Results: A total of 111 liver transplant patients were diagnosed with COVID-19 (SIR = 191.2 [95% CI 190.3-192.2]). The epidemiological curve and geographic distribution overlapped widely between the liver transplant and general populations. After a median follow-up of 23 days, 96 patients (86.5%) were admitted to hospital and 22 patients (19.8%) required respiratory support. A total of 12 patients were admitted to the ICU (10.8%). The mortality rate was 18%, which was lower than in the matched general population (SMR = 95.5 [95% CI 94.2-96.8]). Overall, 35 patients (31.5%) met criteria of severe COVID-19. Baseline immunosuppression containing mycophenolate was an independent predictor of severe COVID-19 (relative risk = 3.94; 95% CI 1.59-9.74; p = 0.003), particularly at doses higher than 1,000 mg/day (p = 0.003). This deleterious effect was not observed with calcineurin inhibitors or everolimus and complete immunosuppression withdrawal showed no benefit. Conclusions: Being chronically immunosuppressed, liver transplant patients have an increased risk of acquiring COVID-19 but their mortality rates are lower than the matched general population. Upon hospital admission, mycophenolate dose reduction or withdrawal could help in preventing severe COVID-19. However, complete immunosuppression withdrawal should be discouraged. Lay summary: In liver transplant patients, chronic immunosuppression increases the risk of acquiring COVID-19 but it could reduce disease severity. Complete immunosuppression withdrawal may not be justified. However, mycophenolate withdrawal or temporary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hospitalised patients. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Revista:
HEPATOLOGY
ISSN:
0270-9139
Año:
2021
Vol.:
74
N°:
5
Págs.:
2333 - 2335
Revista:
EJNMMI RESEARCH
ISSN:
2191-219X
Año:
2021
Vol.:
11
N°:
1
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:
BMC MEDICAL EDUCATION
ISSN:
1472-6920
Año:
2021
Vol.:
21
N°:
1
Págs.:
249
Background: Active learning strategies such as formative assessment through clinical cases may help to get a deeper learning. We have studied the effect of this kind of online formative assessment in pathophysiology teaching.
Methods: Seven brief clinical cases were used to give formative assessment in the first semester of a pathophysiology course. To evaluate its effect on learning, we analyzed the proportion of students that passed the end of semester exam with a score above 60 over 100. We also analyzed the effect of the intervention according to the students' previous academic performance.
Results: Ninety-six students participated in the study and sat the exam. Sixty-five of them passed it. Students that passed the exam had a higher previous academic performance and had done a higher number of exercises of formative assessment, both in univariate and multivariate analysis. The participants were divided in three groups, according to their previous academic performance. In the intermediate group, the number of cases done by the students who passed the exam was significantly higher than in those who did not pass it (median: 4 versus 0; P = 0.009).
Conclusion: Formative assessment through web-based clinical cases was followed by an improvement of the academic results in pathophysiology, mainly in students with intermediate performance.
Revista:
CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN:
0174-1551
Año:
2020
Vol.:
43
N°:
8
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:
Llaneras, J.; Riveiro-Barciela, M. ; Lens, S. ; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN:
0168-8278
Año:
2019
Vol.:
71
N°:
4
Págs.:
666 - 672
Background & Aims: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. Methods: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. Results: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevirtr +dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. Conclusion: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. Lay summary: Treatment with sofosbuvirtvelpatasvir/voxilapre vir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile. (C) 2019 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
Autores:
Loffler, M. W. (Autor de correspondencia); Mohr, C.; Bichmann, L. ; et al.
Revista:
GENOME MEDICINE
ISSN:
1756-994X
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.
Revista:
HEPATOLOGY
ISSN:
0270-9139
Año:
2019
Vol.:
70
N°:
2
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.
Autores:
Marino, Z. ; Darne, A.; Lens, S.; et al.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN:
0168-8278
Año:
2019
Vol.:
70
N°:
5
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:
ONCOTARGETS AND THERAPY
ISSN:
1178-6930
Año:
2018
Vol.:
11
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
Año:
2018
Vol.:
29
N°:
9
Págs.:
1305 - 1306
Revista:
ANNALS OF TRANSPLANTATION
ISSN:
1425-9524
Año:
2017
Vol.:
22
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.
Revista:
JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN:
1051-0443
Año:
2017
Vol.:
28
N°:
11
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
Año:
2017
Vol.:
8
N°:
25
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:
TRANSLATIONAL RESEARCH
ISSN:
1931-5244
Año:
2017
Vol.:
188
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
Año:
2017
Vol.:
188
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
Año:
2017
Vol.:
9
N°:
5
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:
TRANSPLANTATION
ISSN:
0041-1337
Año:
2017
Vol.:
101
N°:
3
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
Año:
2017
Vol.:
116
N°:
4
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.
Revista:
LIVER INTERNATIONAL
ISSN:
1478-3223
Año:
2016
Vol.:
36
N°:
8
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:
EUROPEAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
ISSN:
0954-691X
Año:
2016
Vol.:
28
N°:
2
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.
Autores:
Philip J. Johnson ; Sarah Berhane; Chiaki Kagebayashi ; et al.
Revista:
JOURNAL OF CLINICAL ONCOLOGY
ISSN:
0732-183X
Año:
2015
Vol.:
33
N°:
6
Págs.:
550-58
The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C-P grade.
Revista:
MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT
ISSN:
2329-0501
Año:
2015
Vol.:
2
Págs.:
15006
The lack of antiviral cellular immune responses in patients with chronic hepatitis C virus (HCV) infection suggests that T-cell vaccines may provide therapeutic benefit. Due to the central role that dendritic cells (DC) play in the activation of T-cell responses, our aim was to carry out a therapeutic vaccination clinical trial in HCV patients using DC. Five patients with chronic HCV infection were vaccinated with three doses of 5¿×¿10(6) or 10(7) autologous DC transduced with a recombinant adenovirus encoding NS3 using the adapter protein CFh40L, which facilitates DC transduction and maturation. No significant adverse effects were recorded after vaccination. Treatment caused no changes in serum liver enzymes nor in viral load. Vaccination induced weak but consistent expansion of T-cell responses against NS3 and adenoviral antigens. Patients' DC, as opposed to murine DC or DC from healthy subjects, secreted high IL-10 levels after transduction, inducing the activation of IL-10-producing T cells. IL-10 blockade during vaccine preparation restored its ability to stimulate anti-NS3 Th1 responses. Thus, vaccination with adenovirus-transduced DC is safe and induces weak antiviral immune responses. IL-10 associated with vaccine preparation may be partly responsible for these effects, suggesting that future vaccines should consider concomitant inhibition of this cytokine
Revista:
TRANSPLANT IMMUNOLOGY
ISSN:
0966-3274
Año:
2015
Vol.:
33
N°:
2
Págs.:
110 - 116
Several studies have shown that some liver transplant recipients may tolerate immunosuppression withdrawal. Mechanisms and biomarkers of tolerance are not well known. Methods: Twenty-four LT patients with immunosuppression side-effects underwent progressive immunosuppression withdrawal. Peripheral lymphocyte populations and secretion of cytokines were analyzed at baseline and during withdrawal until tolerance (n = 15) or rejection (n = 9), as well as 3. months after tolerance achievement or rejection resolution (as follow-up). Immunological markers were compared among groups. Results: The percentages of CD3 + CD4 + cells progressively decreased in both groups. CD3 + CD8 + cells gradually increased in tolerant patients. B lymphocytes gradually decreased in tolerant and initially in non-tolerant patients, reverting at rejection. Regulatory T cells progressively increased until rejection in non-tolerants, decreasing to basal levels after renewing immunosuppression; no significant changes were found in tolerant patients. The percentages and absolute counts of natural killer cells significantly increased in both groups, being more evident in tolerant patients. The secretion of several cytokines was higher in non-tolerant patients when rejection was diagnosed. Conclusions: The greater increase of natural killer cells in tolerant patients suggests their potential role in the tolerance phenomenon
Revista:
LIVER INTERNATIONAL
ISSN:
1478-3223
Año:
2015
Vol.:
35
N°:
6
Págs.:
1715-21
Single-session SIRT appeared to be as safe and had a similar impact on HRQoL as multiple sessions of TACE, suggesting that SIRT might be an alternative option for patients eligible for TACE.
Revista:
REVISTA ESPAÑOLA DE MEDICINA NUCLEAR E IMAGEN MOLECULAR
ISSN:
2253-654X
Año:
2015
Vol.:
34
N°:
4
Págs.:
244 - 257
Revista:
LIVER INTERNATIONAL
ISSN:
1478-3223
Año:
2015
Vol.:
35
N°:
5
Págs.:
1590 - 96
BACKGROUND & AIMS:
Radioembolization may rarely induce liver disease resulting in a syndrome that is similar to veno-occlusive disease complicating bone marrow transplantation where inflammation, endothelial cell activation and thrombosis are likely involved. We hypothesized that similar mechanisms could be implicated in radioembolization-induced liver disease (REILD). Moreover, lobar radioembolization may induce hypertrophy of the non-treated hemiliver most probably by inducing liver regeneration.
METHODS:
In patients with hepatocellular carcinoma, we prospectively studied serum levels of markers of liver regeneration, oxidative stress, pro-inflammatory pathways, endothelial activation and coagulation parameters over 2 months after radioembolization.
RESULTS:
Although REILD did not occur among 14 treated patients, a decrease in effective liver blood flow was observed. Radioembolization was followed by a persistent increase in pro-inflammatory (interleukin 6 and 8) and oxidative stress (malondyaldehide) markers, an induction of endothelial injury markers (vW factor and PAI-1) and an activation of the coagulation cascade (factor VIII, PAI-1, D-Dimer) as well as a significant increase in factors related to liver regeneration (FGF-19 and HGF).
CONCLUSION:
Radioembolization activates liver regeneration, produces oxidative stress, activates inflammatory cytokines and induces endothelial injury with partial activation of the coagulation cascade. These findings may have implicati
Revista:
JAMA DERMATOLOGY
ISSN:
2168-6068
Año:
2014
Vol.:
150
N°:
6
Págs.:
664 - 666
Revista:
GASTROENTEROLOGIA Y HEPATOLOGIA
ISSN:
0210-5705
Año:
2014
Vol.:
37
N°:
4
Págs.:
233-239
The FibroScan(®) XL probe has been specifically designed for obese patients to measure liver stiffness by transient elastography, but it has not been well tested in non-obese patients. The aim of this study was to compare the M and XL FibroScan(®) probes in a series of unselected obese (body mass index above 30 kg/m(2)) and non-obese patients with chronic liver disease. Two hundred and fifty-four patients underwent a transient elastography examination with both the M and XL probes. The results obtained with the two probes were compared in the whole series and in obese (n=82) and non-obese (n=167) patients separately. The reliability of the examinations was assessed using the criteria defined by Castéra et al. The proportion of reliable exams was significantly higher when the XL probe was used (83% versus 73%; P=.001). This significance was maintained in the group of obese patients (82% versus 55%; P<.001), but not in the non-obese patients (84% versus 83%). Despite a high correlation between the stiffness values obtained with the two probes (R=.897; P<.001), and a high concordance in the estimation of fibrosis obtained with the two probes (Cronbach's alpha value: 0.932), the liver stiffness values obtained with the XL probe were significantly lower than those obtained with the M probe, both in the whole series (9.5 ± 9.1 kPa versus 11.3 ± 12.6 kPa; P<0.001) and in the obese and non-obese groups. In conclusion, transient elastography with the XL probe allows a higher proportio
Revista:
TRANSPLANTATION PROCEEDINGS
ISSN:
0041-1345
Año:
2014
Vol.:
46
N°:
9
Págs.:
3082 - 3083
Background. The role of liver biopsy in the evaluation of a candidate for living liver donation is controversial. Some authors suggest doing it routinely, but others do it only in selected cases. The aim of this work was to evaluate the usefulness of protocol liver biopsy in the evaluation of candidates for living liver donation.
Methods. Ninety potential candidates for living liver donation were evaluated. In 46 cases donation was contraindicated without the need of liver biopsy. In the remaining 44 candidates, liver biopsy was done on a protocol basis. The usefulness of protocol biopsy was compared with the use of biopsy according to the recommendations of the Vancouver Forum.
Results. Fifteen of the 44 biopsies were indicated according to the recommendations of the Vancouver Forum. Twelve of them were normal, and 3 had liver steatosis or steatohepatitis. Of the 29 biopsies done per protocol, 28 were normal and 1 showed liver steatosis. Donation was contraindicated according to liver biopsy findings in 3 of the 15 patients with liver biopsy done according to the Vancouver Forum recommendations and in none of the 29 patients with biopsy done per protocol (P=.034).
Conclusions. Protocol liver biopsy has a limited utility in the evaluation of the candidates for living liver donation.
Revista:
HPB
ISSN:
1365-182X
Año:
2014
Vol.:
16
N°:
3
Págs.:
243-49
The present results warrant further studies to better elucidate the mechanism underlying this phenomenon of spared hemiliver hypertrophy and to investigate its role as an alternative to portal vein embolization in the management of patients with potentially resectable liver tumours.
Revista:
JOURNAL OF HEPATOLOGY
ISSN:
0168-8278
Año:
2013
Vol.:
59
N°:
1
Págs.:
81-88
Background & Aims: Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients.
Methods: Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B).
Results: A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy, particularly in those patients with a more prominent drop in viral load. This antiviral effect was associated with an enhanced specific anti-HCV immune response.
Conclusions: Tremelimumab safety profile and antitumor and antiviral activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis, support further investigation. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Revista:
ACTA GASTRO-ENTEROLOGICA BELGICA
ISSN:
1784-3227
Año:
2013
Vol.:
76
N°:
2
Págs.:
246-50
Patients with heart failure have increased liver stiffness, that appears to be related with the severity of heart failure
Revista:
VISZERALMEDIZIN
ISSN:
1662-6664
Año:
2013
Vol.:
29
N°:
2
Págs.:
92-102
Revista:
ANNALS OF TRANSPLANTATION
ISSN:
1425-9524
Año:
2013
Vol.:
18
Págs.:
587 - 592
Background: The prognosis of non-cutaneous malignancies after liver transplantation is dismal, mainly because most cases are diagnosed at advanced stages. In the last decade, studies have shown the potential role of screening for lung cancer with low-radiation dose computed tomography.
Material/Methods: Fifty-nine liver transplant recipients with a cumulative dose of smoking greater than 10 pack-years were enrolled in a lung cancer screening program using yearly low-radiation dose computed tomography.
Results: Lung cancer was diagnosed in 7 patients (11.8%), 5 of which were in stage Ia at diagnosis. Patients with lung cancer were significantly older (median age 66 vs. 58 years), had a higher cumulative history of smoking, and had emphysema more frequently than patients without cancer.
Conclusions: Screening for lung cancer with low-radiation dose computed tomography in liver transplant recipients results in the diagnosis of lung cancer in early stages.
Revista:
Hepatology
ISSN:
0270-9139
Año:
2013
Vol.:
57
N°:
3
Págs.:
1078 - 1087
Radioembolization (RE)-induced liver disease (REILD) has been defined as jaundice and ascites appearing 1 to 2 months after RE in the absence of tumor progression or bile duct occlusion. Our aims were to study the incidence of REILD in a large cohort of patients and the impact of a series of changes introduced in the processes of treatment design, activity calculation, and the routine use of ursodeoxycholic acid and low-dose steroids (modified protocol). Between 2003 and 2011, 260 patients with liver tumors treated by RE were studied (standard protocol: 75, modified protocol: 185). REILD appeared only in patients with cirrhosis or in noncirrhosis patients exposed to systemic chemotherapy prior to RE. Globally, the incidence of REILD was reduced in the modified protocol group from 22.7% to 5.4% and the incidence of severe REILD from 13.3% to 2.2% (P < 0.0001). Treatment efficacy was not jeopardized since 3-month disease control rates were virtually identical in both groups (66.7% and 67.2%, P = 0.93). Exposure to chemotherapy in the 2-month period following RE and being treated by the standard protocol were independent predictors of REILD among noncirrhosis patients. In cirrhosis, the presence of a small liver (total volume <1.5 L), an abnormal bilirubin (>1.2 mg/dL), and treatment in a selective fashion were independently associated with REILD. Conclusion: REILD is an uncommon but relevant complication that appears when liver tissue primed by cirrhosis or prior and subsequent chemotherapy is exposed to the radiation delivered by radioactive microspheres. We designed a comprehensive treatment protocol that reduces the frequency and the severity of REILD. (HEPATOLOGY 2013)
Revista:
EJSO
ISSN:
0748-7983
Año:
2013
Vol.:
39
N°:
8
Págs.:
920-921
Revista:
JOURNAL OF HEPATOLOGY
ISSN:
0168-8278
Año:
2013
Vol.:
58
N°:
5
Págs.:
1056-1057
Revista:
LIVER TRANSPLANTATION
ISSN:
1527-6465
Año:
2013
Vol.:
19
N°:
9
Págs.:
937 - 944
Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty-four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4+, CD8+, and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range¿=¿8.5-22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P¿=¿0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P¿=¿0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n¿=¿7 for an interval¿>¿10 years and an SI¿<¿20), 100% reached tolerance; in the second group (n¿=¿10 for an interval¿>¿10 years and an SI¿>¿20 or an interval¿<¿10 years and an SI¿<¿20), 60% reached tolerance; and in the third group (n¿=¿7 for an interval¿<¿10 years and an SI¿>¿20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables¿the time from transplantation and the SI¿may help to identify these patients.
Revista:
Transplantation Proceedings
ISSN:
0041-1345
Año:
2012
Vol.:
44
N°:
9
Págs.:
2603 - 26058
Revista:
RARE TUMORS
ISSN:
2036-3605
Año:
2012
Vol.:
4
N°:
2
Págs.:
106-109
Hepatic epithelioid hemangioendothelioma (HEH) is a rare disease of unknown etiology for which a standard systemic treatment has not been established. The common expression of vascular endothelial growth factor (VEGF) and its receptor in HEH provide a rationale for the reported use of antiangiogenic drugs, including bevacizumab, lenalidomide and thalidomide. We report a case of a young male patient with HEH who was treated with sorafenib for almost 2 years. Sorafenib was used instead of other VEGF inhibitors due to its convenient oral route, its dual antiangiogenic and antiproliferative activity, and its favorable safety profile. Sorafenib therapy resulted in durable stabilization with progressive calcification of liver tumors and minor but stable response of lung lesions
Revista:
Journal of Hepatology
ISSN:
0168-8278
Año:
2012
Vol.:
56
N°:
2
Págs.:
464 - 473
Revista:
European Journal of surgical Oncology
ISSN:
0748-7983
Año:
2012
Vol.:
38
N°:
7
Págs.:
594 - 601
Revista:
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY RESEARCH
ISSN:
2224-3992
Año:
2012
Vol.:
1
N°:
6
Págs.:
111 - 113
Revista:
Transplantation Proceedings
ISSN:
0041-1345
Año:
2012
Vol.:
44
N°:
6
Págs.:
1568 - 1570
Revista:
ANNALS OF SURGICAL ONCOLOGY
ISSN:
1068-9265
Año:
2011
Vol.:
18
N°:
7
Págs.:
1964 - 1971
Revista:
Nuclear Medicine & Radiation Therapy
ISSN:
2155-9619
Año:
2011
Vol.:
2
N°:
1
Págs.:
1 - 6
Revista:
Liver Transplantation
ISSN:
1527-6465
Año:
2011
Vol.:
17
N°:
4
Págs.:
402 - 408
Liver transplant recipients have an increased risk of malignancy. Smoking is related to some of the most frequent causes of posttransplant malignancy. The incidence and risk factors for the development of neoplasia related to smoking (head and neck, lung, esophageal, and kidney and urinary tract carcinomas) were studied in 339 liver transplant recipients. Risk factors for the development of smoking-related neoplasia were also studied in 135 patients who had a history of smoking so that it could be determined whether smoking withdrawal was associated with a lower risk of malignancy. After a mean follow-up of 7.5 years, 26 patients were diagnosed with 29 smoking-related malignancies. The 5- and 10-year actuarial rates were 5% and 13%, respectively. In multivariate analysis, smoking and older age were independently associated with a higher risk of malignancy. In the smoker subgroup, the variables related to a higher risk of malignancy were active smoking and older age. In conclusion, smoking withdrawal after liver transplantation may have a protective effect against the development of neoplasia
Autores:
Sangro, Bruno; Carpanese, Livio; Cianni, Roberto; et al.
Revista:
Hepatology
ISSN:
0270-9139
Año:
2011
Vol.:
54
N°:
3
Págs.:
868 - 878
Revista:
Expert Opinion on Pharmacotherapy
ISSN:
1465-6566
Año:
2011
Vol.:
12
N°:
7
Págs.:
1057 - 1073
Revista:
Journal of Hepatology
ISSN:
0168-8278
Año:
2011
Vol.:
55
N°:
4
Págs.:
828 - 837
Revista:
International Journal of Radiation Oncology, Biology, Physics
ISSN:
0360-3016
Año:
2010
Vol.:
77
N°:
5
Págs.:
1441 - 1448
Revista:
HOSPITAL PRACTICE
ISSN:
2154-8331
Año:
2010
Vol.:
38
N°:
3
Págs.:
103 - 109
Revista:
Journal of vascular and interventional radiology (Print)
ISSN:
1051-0443
Año:
2010
Vol.:
21
N°:
8
Págs.:
1205 - 1212
Revista:
Cardiovascular and Interventional Radiology
ISSN:
0174-1551
Año:
2010
Vol.:
33
N°:
3
Págs.:
523 - 531