Nuestros investigadores

Bruno Carlos Sangro Gómez-Acebo

Publicaciones científicas más recientes (desde 2010)

Autores: Banales, J. M.; Iñarrairaegui, Mercedes; Arbelaiz, A.; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 70  Nº 2  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.
Autores: Santa María, Eva; Rodríguez, Carlos Manuel; Uriarte, Iker; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 69  Nº 4  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.
Autores: Aramburu, Jorge, (Autor de correspondencia); Antón, R; Rivas, Alejandro; et al.
Revista: COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING
ISSN 1025-5842  Vol. 22  Nº 5  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: Urtasun, R.; Elizalde, M.; et al.
Revista: NUCLEIC ACIDS RESEARCH
ISSN 0305-1048  Vol. 47  Nº 7  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.
Autores: Unfried, Juan Pablo; Serrano, G.; Suarez, Beatriz; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 79  Nº 20  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: Diana Llopiz; Marta Ruiz; Lorea Villanueva; et al.
Revista: CANCER IMMUNOLOGY IMMUNOTHERAPY
ISSN 0340-7004  Vol. 68  Nº 3  2019  págs. 379 - 393
Autores: Melero, Ignacio Javier; Neely, J. ; Sangro, Bruno; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 30  2019 
Autores: Sangro, Bruno; Hsu, C. ; Kang, Y. K. ; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 70  2019  págs. 131A - 132A
Autores: Yau, T.; Kang, Y. K. ; Kim, T. Y.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 37  Nº 15 Supl.  2019 
Autores: Melero, Ignacio Javier; Neely, J.; Sangro, Bruno; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 79  Nº 13  2019 
Autores: Kudo, M.; Matilla, A.; Santoro, A.; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 37  Nº 4  2019 
Autores: Colyn, L.; Alvarez-Sola, G.; Latasa, María Ujué; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 70  Nº Supl. 1  2019  págs. E27 - E28
Autores: Iñarrairaegui, Mercedes; Melero, Ignacio Javier; Sangro, Bruno, (Autor de correspondencia)
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 24  Nº 7  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: Greten, T. F.; Sangro, Bruno, (Autor de correspondencia)
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 68  Nº 1  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.
Autores: Macias, R. I. R., (Autor de correspondencia); Banales, J. M.; Sangro, Bruno; et al.
Revista: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
ISSN 0925-4439  Vol. 1864  Nº 4  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.
Autores: Cappelli, A.; Sangro, Paloma; Mosconi, C.; et al.
Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070  Vol. 46  Nº 3  2018  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: Chopitea, Ana; Pardo, Fernando; et al.
Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN 1699-048X  Vol. 20  Nº 5  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: Gardini, A. C.; Tamburini, E. ; Iñarrairaegui, Mercedes; et al.
Revista: ONCOTARGETS AND THERAPY
ISSN 1178-6930  Vol. 11  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.
Autores: Bilbao, José Ignacio; Rodríguez, Javier; et al.
Revista: HEPATIC ONCOLOGY
ISSN 2045-0923  Vol. 5  Nº 2  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.
Autores: Aramburu, Jorge, (Autor de correspondencia); Antón, R; Rivas, Alejandro; et al.
Revista: INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939  Vol. 34  Nº e2983  2018 
Autores: San José, Edurne; Ezponda, Teresa; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 9  Nº 16  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.
Autores: Vogel, A., (Autor de correspondencia); Cervantes, A. ; Chau, I. ; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 4  2018  págs. 238 - 255
Autores: Bilbao, José Ignacio; Sancho, Lidia; et al.
Revista: JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 1051-0443  Vol. 29  Nº 9  2018  págs. 1305 - 1306
Autores: Santamaria, E. ; Rodríguez, Carlos Manuel; Uriarte, Iker; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 68  Nº Supl. 1  2018  págs. S74 - S74
Autores: Meyer, T.; Melero, Ignacio Javier; Yau, T.; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 68  Nº Supl. 1  2018  págs. S16 - S16
Autores: Kudo, M.; Matilla, A. M.; Santoro, A.; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 68  Nº 6  2018  págs. 1445A - 1446A
Autores: Sangro, Bruno; Martínez, Diego; Bester, L.; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 66  Nº 3  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.
Autores: Sangro, Bruno; Rodríguez-Fraile, M;
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 37  Nº 1  2017  págs. 32 - 34
Autores: Aramburu, Jorge; Antón, R; Rivas, Alejandro; et al.
Revista: INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939  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.
Autores: El-Khoueiry, A. B.; Sangro, Bruno; Yau, T. ; et al.
Revista: LANCET
ISSN 0140-6736  Vol. 389  Nº 10088  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.
Autores: Martínez, Diego; D'Avola, Delia; et al.
Revista: ANNALS OF TRANSPLANTATION
ISSN 1425-9524  Vol. 22  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: Rotellar, Fernando; Pardo, Fernando; Benito, Alberto; et al.
Revista: TRANSPLANTATION
ISSN 0041-1337  Vol. 101  Nº 3  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: Sancho, Lidia; Rodríguez-Fraile, M; Bilbao, José Ignacio; et al.
Revista: JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY
ISSN 1051-0443  Vol. 28  Nº 11  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.
Autores: Aramburu, Jorge; Antón, R; Rivas, Alejandro; et al.
Revista: INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939  Vol. 33  Nº 2  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.
Autores: Elosegui-Artola, A.; D'Avola, Delia; Carte, Beatriz; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 8  Nº 25  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.
Autores: D'Avola, Delia; Carmona, Francisco de Asís; et al.
Revista: TRANSLATIONAL RESEARCH
ISSN 1931-5244  Vol. 188  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
Autores: Sangro, Bruno; Rodríguez-Fraile, M;
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 37  Nº 1  2017  págs. 32-34
Autores: D'Avola, Delia; Fernández-Ruiz, Veronica; Carmona, Francisco de Asís; et al.
Revista: TRANSLATIONAL RESEARCH
ISSN 1931-5244  Vol. 188  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 [greater than or equal to]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 of functionally active EPC showed an improvement of liver function and portal hypertension suggesting that the potential usefulness of these cells for the treatment of liver cirrhosis deserves further evaluation.
Autores: Waked, I. ; Berhane, S. ; Toyoda, H. ; et al.
Revista: BRITISH JOURNAL OF CANCER
ISSN 0007-0920  Vol. 116  Nº 4  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: Pardo, Fernando; Sangro, Bruno; Lee, R. C. ; et al.
Revista: ANNALS OF SURGICAL ONCOLOGY
ISSN 1068-9265  Vol. 24  Nº 9  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.
Autores: Sangro, Paloma; et al.
Revista: ONCOTARGET
ISSN 1949-2553  Vol. 9  Nº 5  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.
Autores: Reig, M. ; Marino, Z. ; Perello, C. ; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 66  Nº Supl. 1  2017  págs. S20
Autores: Unfried, Juan Pablo; Serrano, G.; Sangro, Paloma; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 66  Nº Supl 1  2017  págs. 984A
Autores: Sangro, Bruno; Yau, T. ; Hsu, C.; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 66  Nº 1  2017  págs. S34 - S35
Autores: Mayer, A. ; Accolla, R.; Ma, Y. T. ; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 66  Nº Supl. 1  2017  págs. S445 - S446
Autores: Sangro, Bruno; Melero, Ignacio Javier; Yau, T.; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 66  Nº Supl. 1  2017  págs. 82A
Autores: Álvarez-Cienfuegos, Francisco Javier; Rotellar, Fernando; Salguero, J.; et al.
Revista: REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
ISSN 1130-0108  Vol. 108  Nº 8  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: D'Avola, Delia; Carmona, Francisco de Asís; Miriam Méndez; et al.
Revista: TRANSLATIONAL RESEARCH
ISSN 1931-5244  Vol. 188  Nº S1931-5244(16)00063-3  2016  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
Autores: D'Avola, Delia; Sangro, Bruno; Grossios, N.; et al.
Revista: JOURNAL OF HEPATOLOGY
ISSN 0168-8278  Vol. 65  Nº 4   2016  págs. 776 - 783
BACKGROUND & AIMS: Acute intermittent porphyria (AIP) results from porphobilinogen deaminase (PBGD) haploinsufficiency, which leads to hepatic over-production of the neurotoxic heme precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) and the occurrence of neurovisceral attacks. Severe AIP is a devastating disease that can only be corrected by liver transplantation. Gene therapy represents a promising curative option. The objective of this study was to investigate the safety of a recombinant adeno-associated vector expressing PBGD (rAAV2/5-PBGD) administered for the first time in humans for the treatment of AIP. METHODS: In this phase I, open label, dose-escalation, multicenter clinical trial, four cohorts of 2 patients each received a single intravenous injection of the vector ranging from 5×10(11) to 1.8×10(13) genome copies/kg. Adverse events and changes in urinary PBG and ALA and in the clinical course of the disease were periodically evaluated prior and after treatment. Viral shedding, immune response against the vector and vector persistence in the liver were investigated. RESULTS: Treatment was safe in all cases. All patients developed anti-AAV5 neutralizing antibodies but no cellular responses against AAV5 or PBGD were observed. There was a trend towards a reduction of hospitalizations and heme treatments, although ALA and PBG levels remained unchanged. Vector genomes and transgene expression could be detected in the liver one year after therapy. CONCLUSIONS: rAAV2/5-PBGD administration is safe but AIP metabolic correction was not achieved at the doses tested in this trial. Notwithstanding, the treatment had a positive impact in clinical outcomes in most patients. LAY SUMMARY: Studies in an acute intermittent porphyria (AIP) animal model have shown that gene delivery of PBGD to hepatocytes using an adeno-associated virus vector (rAAV2/5-PBG) prevent mice from suffering porphyria acute attacks. In this phase I, open label, dose-escalation, multicenter clinical trial we show that the administration of rAAV2/5-PBGD to patients with severe AIP is safe but metabolic correction was not achieved at the doses tested; the treatment, however, had a positive but heterogeneous impact on clinical outcomes among treated patients and 2 out of 8 patients have stopped hematin treatment. CLINICAL TRIAL NUMBER: The observational phase was registered at Clinicaltrial.gov as NCT 02076763. The interventional phase study was registered at EudraCT as n° 2011-005590-23 and at Clinicaltrial.gov as NCT02082860.
Autores: Aramburu, J.; Antón, R.; Rivas, A.; et al.
Revista: INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939  Vol. 32  Nº 11  2016  págs. e02764
Some of the latest treatments for unresectable liver malignancies (primary or metastatic tumours), which include bland embolisation, chemoembolisation, and radioembolisation, among others, take advantage of the increased arterial blood supply to the tumours to locally attack them. A better understanding of the factors that influence this transport may help improve the therapeutic procedures by taking advantage of flow patterns or by designing catheters and infusion systems that result in the injected beads having increased access to the tumour vasculature. Computational analyses may help understand the haemodynamic patterns and embolic-microsphere transport through the hepatic arteries. In addition, physiological inflow and outflow boundary conditions are essential in order to reliably represent the blood flow through arteries. This study presents a liver cancer arterial perfusion model based on a literature review and derives boundary conditions for tumour-bearing liver-feeding hepatic arteries based on the arterial perfusion characteristics of normal and tumorous liver segment tissue masses and the hepatic artery branching configuration. Literature-based healthy and tumour-bearing realistic scenarios are created and haemodynamically analysed for the same patient-specific hepatic artery. As a result, this study provides boundary conditions for computational fluid dynamics simulations that will allow researchers to numerically study, for example, various intravascular devices used for liver disease intra-arterial treatments with different cancer scenarios.
Autores: Conchillo, María de los Ángeles; et al.
Revista: EUROPEAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
ISSN 0954-691X  Vol. 28  Nº 2  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.
Autores: de la Torre, Manuel Antonio; De la Rosa, PA; et al.
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 36  Nº 8  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.
Autores: Aramburu, Jorge; Antón, R; Rivas, Alejandro; et al.
Revista: JOURNAL OF BIOMECHANICS
ISSN 0021-9290  Vol. 49   Nº 15   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.
Autores: Aramburu, Jorge; Antón, R; Rivas, Alejandro; et al.
Revista: INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING
ISSN 2040-7939  Vol. 32  Nº 11  2016  págs. e02764
Some of the latest treatments for unresectable liver malignancies (primary or metastatic tumours), which include bland embolisation, chemoembolisation, and radioembolisation, among others, take advantage of the increased arterial blood supply to the tumours to locally attack them. A better understanding of the factors that influence this transport may help improve the therapeutic procedures by taking advantage of flow patterns or by designing catheters and infusion systems that result in the injected beads having increased access to the tumour vasculature. Computational analyses may help understand the haemodynamic patterns and embolic-microsphere transport through the hepatic arteries. In addition, physiological inflow and outflow boundary conditions are essential in order to reliably represent the blood flow through arteries. This study presents a liver cancer arterial perfusion model based on a literature review and derives boundary conditions for tumour-bearing liver-feeding hepatic arteries based on the arterial perfusion characteristics of normal and tumorous liver segment tissue masses and the hepatic artery branching configuration. Literature-based healthy and tumour-bearing realistic scenarios are created and haemodynamically analysed for the same patient-specific hepatic artery. As a result, this study provides boundary conditions for computational fluid dynamics simulations that will allow researchers to numerically study, for example, various intravascular devices
Autores: Aramburu, Jorge; Antón, R; Rivas, Alejandro; et al.
Revista: JOURNAL OF BIOMECHANICS
ISSN 0021-9290  Vol. 49  Nº 15  2016  págs. 3714 - 3721
Liver radioembolization is a treatment option for patients with primary and secondary liver cancer. The procedure consists of injecting radiation-emitting microspheres via an intra-arterially placed microcatheter, enabling the deposition of the microspheres in the tumoral bed. The microcatheter location and the particle injection rate are determined during a pretreatment work-up. The purpose of this study was to numerically study the effects of the injection characteristics during the first stage of microsphere travel through the bloodstream in a patient-specific hepatic artery (i.e., the near-tip particle¿hemodynamics and the segment-to-segment particle distribution). Specifically, the influence of the distal direction of an end-hole microcatheter and particle injection point and velocity were analyzed. Results showed that the procedure targeted the right lobe when injecting from two of the three injection points under study and the remaining injection point primarily targeted the left lobe. Changes in microcatheter direction and injection velocity resulted in an absolute difference in exiting particle percentage for a given liver segment of up to 20% and 30%, respectively. It can be concluded that even though microcatheter placement is presumably reproduced in the treatment session relative to the pretreatment angiography, the treatment may result in undesired segment-to-segment particle distribution and therefore undesired treatment outcomes due to modifications of any of the parameters studied, i.e., microcatheter direction and particle injection point and velocity.
Autores: Diaz Gonzalez, A.; Rimola, J.; Maria, R.; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 64  Nº Supl. 2  2016  págs. S319
Autores: Melero, Ignacio Javier; Sangro, Bruno; Yau, T.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Suppl. 6  2016  págs. 615O
Background Median overall survival (OS) for first-line (1L) treatment of advanced hepatocellular carcinoma (aHCC) with sorafenib (sor) is up to 11¿mo and 7¿8¿mo with best supportive care (BSC) post-sor failure. Nivolumab (nivo), an IgG4 mAb to the programmed death-1 (PD-1) receptor, was evaluated in a phase 1/2 study of patients (pts) with aHCC. After the multiple ascending-dose escalation (ESC) phase, dose expansion (EXP) followed. Interim results are presented. Methods Pts had histologically confirmed aHCC, Child-Pugh (CP) scores ¿ 7 (ESC) or¿¿¿6 (EXP). ESC pts who previously failed, refused, or were intolerant (intol) of sor received nivo 0.1¿10¿mg/kg across 3 cohorts: uninfected HCC, HBV-, and HCV-infected. EXP pts received nivo 3¿mg/kg across 4 cohorts: uninfected sor naïve/intol, uninfected sor progressors, HBV-, and HCV-infected. Primary endpoints were safety (ESC) and overall response rate (ORR) by RECIST 1.1 (EXP). Other endpoints included OS, duration of response (DOR), and programmed death-ligand 1 (PD-L1) assessment. Results 48 (ESC) and 214 (EXP) pts were enrolled and treated with nivo. At baseline, 85% and 70% were CP¿=¿5, 77% and 75% had extrahepatic metastasis, and 73% and 66% had prior sor, for ESC and EXP, respectively. EXP safety profile was similar to that of previously reported ESC. In EXP, treatment-related adverse events (TRAEs) occurred in 65% of pts; 18% of pts had grade 3¿4. Most common TRAEs were fatigue (21%), pruritus (15%), rash (12%), and diarrhea (9%); most common grade 3¿4 TRAEs were increases in AST (4%), lipase and ALT (3% each), and amylase (2%). Efficacy data are presented in the table. Responses occurred regardless of underlying HCC etiology and PD-L1 expression. Conclusions Nivo was well tolerated in pts with aHCC. ORR and OS rate for ESC is favorable to historic BSC data. Tolerability and efficacy profiles are consistent between ESC and EXP phases of this ongoing study.
Autores: Sancho, Lidia; Rodríguez-Fraile, M; Prieto, Elena; et al.
Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070  Vol. 43  Nº Suppl. 1  2016  págs. S12 - S12
Autores: Melero, Ignacio Javier; Sangro, Bruno; Yau, T.; et al.
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 64  Nº 6  2016  págs. 1124A
Autores: Martínez, Diego; de la Torre, Manuel Antonio; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 64  Nº Supl.2  2016  págs. S695
Autores: Samim, M.; Van Veenendaal, L. M. ; Braat, M. N. G. J.; et al.
Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070  Vol. 43  Nº Supl. 1  2016  págs. S299 - S300
Autores: Prieto, Jesús María; Melero, Ignacio Javier; Sangro, Bruno;
Revista: NATURE REVIEWS GASTROENTEROLOGY AND HEPATOLOGY
ISSN 1759-5045  Vol. 12  Nº 12  2015  págs. 681 - 700
Advanced hepatocellular carcinoma (HCC) is a serious therapeutic challenge and targeted therapies only provide a modest benefit in terms of overall survival. Novel approaches are urgently needed for the treatment of this prevalent malignancy. Evidence demonstrating the antigenicity of tumour cells, the discovery that immune checkpoint molecules have an essential role in immune evasion of tumour cells, and the impressive clinical results achieved by blocking these inhibitory receptors, are revolutionizing cancer immunotherapy. Here, we review the data on HCC immunogenicity, the mechanisms for HCC immune subversion and the different immunotherapies that have been tested to treat HCC. Taking into account the multiplicity of hyperadditive immunosuppressive forces acting within the HCC microenvironment, a combinatorial approach is advised. Strategies include combinations of systemic immunomodulation and gene therapy, cell therapy or virotherapy.
Autores: Zabaleta, Aintzane; D'Avola, Delia; Llopiz, Diana Isabel; et al.
Revista: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT
ISSN 2329-0501  Vol. 2  2015  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
Autores: Pennington B.; Akehurst R; ; Wasan H,; et al.
Revista: JOURNAL OF MEDICAL ECONOMICS
ISSN 1369-6998  Vol. 18  Nº 10  2015  págs. 797 - 804
OBJECTIVE: Selective internal radiation therapy (SIRT) using SIR-Spheres(®) (90)Y-labeled resin microspheres has been shown to be a well-tolerated, effective treatment in patients with inoperable liver-dominant chemotherapy-refractory metastatic colorectal cancer (mCRC). This study estimated the cost-effectiveness of (90)Y-resin microspheres compared to best supportive care (BSC) from a UK perspective. METHODS: Survival data from a comparative retrospective cohort study was analyzed and used in a state-transition cost-effectiveness model, using quality-adjusted life years (QALYs) gained as the measure of effectiveness. The model incorporated costs for the SIRT procedure, monitoring, further treatment, adverse events, and death. Utility values, reflecting patient quality-of-life, were taken from a published source. RESULTS: SIRT using (90)Y-resin microspheres compared to BSC improved overall survival by a mean of 1.12 life years and resulted in a cost per QALY gained of £28,216. In sensitivity analysis, this varied between £25,015-£28,817. CONCLUSION: In an area of large unmet need, treatment with (90)Y-resin microspheres offers a clinically effective and cost-effective treatment option.
Autores: Aramburu, Jorge; Antón, R; Bernal, N.; et al.
Revista: PROCEEDINGS OF THE INSTITUTION OF MECHANICAL ENGINEERS PART H-JOURNAL OF ENGINEERING IN MEDICINE
ISSN 0954-4119  Vol. 229  Nº 4  2015  págs. 291 - 306
Physiological outflow boundary conditions are necessary to carry out computational fluid dynamics simulations that reliably represent the blood flow through arteries. When dealing with complex three-dimensional trees of small arteries, and therefore with multiple outlets, the robustness and speed of convergence are also important. This study derives physiological outflow boundary conditions for cases in which the physiological values at those outlets are not known (neither in vivo measurements nor literature-based values are available) and in which the tree exhibits symmetry to some extent. The inputs of the methodology are the three-dimensional domain and the flow rate waveform and the systolic and diastolic pressures at the inlet. The derived physiological outflow boundary conditions, which are a physiological pressure waveform for each outlet, are based on the results of a zero-dimensional model simulation. The methodology assumes symmetrical branching and is able to tackle the flow distribution problem when the domain outlets are at branches with a different number of upstream bifurcations. The methodology is applied to a group of patient-specific arteries in the liver. The methodology is considered to be valid because the pulsatile computational fluid dynamics simulation with the inflow flow rate waveform (input of the methodology) and the derived outflow boundary conditions lead to physiological results, that is, the resulting systolic and diastolic pressures at the inlet match the inputs of the methodology, and the flow split is also physiological.
Autores: Kolligs, Frank T; Bilbao, José Ignacio; Jakobs, Tobias; et al.
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 35  Nº 6  2015  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.
Autores: Sarobe, Pablo; Merino, J; et al.
Revista: TRANSPLANT IMMUNOLOGY
ISSN 0966-3274  Vol. 33  Nº 2  2015  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
Autores: Iñarrairaegui, Mercedes; Páramo, José Antonio; et al.
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 35  Nº 5  2015  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
Autores: Philip J. Johnson ; Sarah Berhane; Chiaki Kagebayashi ; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 33  Nº 6  2015  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.
Autores: Ricke, J.; Bulla, K.; Kolligs, F.; et al.
Revista: LIVER INTERNATIONAL
ISSN 1478-3223  Vol. 35  Nº 2  2015  págs. 620 - 626
Background & Aims: The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 (90Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. Methods: Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ¿B7) and ECOG performance status <2 were screened. Radioembolization was administered using a sequential lobar approach. On day 3 after the last radioembolization procedure, sorafenib 200 mg twice daily was initiated escalating to 400 mg twice daily 1 week later; a matching sorafenib dose schedule was initiated in the control arm. Results: Patients were followed up for a median of 8.3 months. Median total implanted activity of 90Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ¿3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. Conclusions: Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone.
Autores: D'Avola, Delia; Carmona, Francisco de Asís; Mendez, M.; et al.
Revista: JOURNAL OF HEPATOLOGY (ONLINE)
ISSN 0168-8278  Vol. 62  Nº Supl. 2  2015  págs. S344 - S345
Autores: Sangro, Bruno;
Revista: FUTURE ONCOLOGY
ISSN 1479-6694  Vol. 10  Nº 15S  2014  págs. 57 - 59
Autores: Sangro, Bruno; Salem, R.;
Revista: SEMINARS IN LIVER DISEASE
ISSN 0272-8087  Vol. 34  Nº 4  2014  págs. 435 - 443
Transarterial chemoembolization (TACE) and radioembolization (RE) are frequently used to treat patients with hepatocellular carcinoma who cannot receive curative therapies. Transarterial chemoembolization is a heterogeneous group of procedures; based on two positive clinical trials and three meta-analyses, conventional TACE is the standard of care for patients in the intermediate stage. Transarterial chemoembolization with drug-eluting beads has been recently introduced as a more standardized way of performing TACE with similar outcomes and less systemic effects. Radioembolization is a form of brachytherapy in which microspheres are used as a source of internal radiation. Evidence supporting the use of RE derives from consistent, large-cohort series involving patients with more advanced hepatocellular carcinoma, not suitable for TACE or for those who have failed TACE. Transarterial chemoembolization and RE should not be considered competing therapies, but rather complementary tools. The clinical indications for TACE and RE will be further refined as results of ongoing large-scale studies become available.
Autores: Kennedy, A. S.; Sangro, Bruno;
Revista: CURRENT ONCOLOGY REPORTS
ISSN 1523-3790  Vol. 16  Nº 3  2014  págs. 373
The most common non-surgical approaches for the treatment of localized hepatocellular carcinoma remain hepatic artery-delivered particles laden with chemotherapy (TACE), or radioactive microparticles (TARE). External beam radiotherapy has been an effective option in many parts of the world for selected HCC patients, but now has an expanded role with stereotactic and proton beam technologies. This review focuses on existing evidence and current guidance for utilizing these modalities for localized, but unresectable, non-transplantable HCC patients.x
Autores: Sangro, Bruno;
Revista: BEST PRACTICE AND RESEARCH IN CLINICAL GASTROENTEROLOGY
ISSN 1521-6918  Vol. 28  Nº 5  2014  págs. 909 - 914
Chemoembolization and radioembolization are at the core of the treatment of patients with hepatocellular carcinoma who cannot receive potentially curative therapies such as transplantation, resection or percutaneous ablation. They differ in the mechanism of action (ischaemia and increase cytotoxic drug exposure for chemoembolization, internal irradiation for radioembolization) and may target different patient populations. Chemoembolization with cytotoxic drug-eluting beads is a more standardized although not necessarily more effective way of performing chemoembolization. Cytoreduction is achieved in most patients but complete tumor ablation may be achieved and lead to extended survival. Grade 1 level of evidence support the use of chemoembolization for the treatment of patients in the early and intermediate stages while grade 2 evidence supports the use of radioembolization for the treatment of patients in intermediate to advanced stages. Selecting the best candidates for both techniques is still a work in progress that ongoing clinical trials are trying to address
Autores: Sangro, Bruno;
Revista: GASTROENTEROLOGIA Y HEPATOLOGIA
ISSN 0210-5705  Vol. 37  Nº S2  2014  págs. 95 - 101
The two intraarterial techniques used in the treatment of hepatocellular carcinoma (HCC) are the transarterial chemoembolization (TACE) and radioembolization (RE). TACE includes various procedures whose objective is to expose tumor cells to a chemotherapy agent and induce acute ischemia in the tumor. The survival benefit obtained by adding a chemotherapy agent or lipiodol to simple particle embolization has not been demonstrated in 2 meta-analyses, which suggests that the antitumor effect is primarily ischemic. RE is a form of brachytherapy that consists of an intraarterial injection of microspheres loaded with yttrium 90 as the source of radiation, a pure beta emitter with a mean tissue penetration of 2. mm. TACE is performed in several sessions every 4-8 weeks, while RE is generally a single procedure. The guidelines adopted by the main research societies support the use of TACE for the palliative treatment of patients with intermediate stage HCC. This is a level 1 recommendation based on the positive results of 2 randomized clinical trials and 3 meta-analyses and on several uncontrolled studies with thousands of patients with unresectable HCC. Survival in clinical practice studies is heterogeneous due to the heterogeneity of the treated population. The survival rate varies from 8% to 26% at 5 years, and the median is 16-40 months in the early stage and 15-27 months in the intermediate stage. TACE with drug-eluting beads (DEB-TACE) has not shown superiority versus conventional TACE in terms of improved survival or tumor response, but it decreases the severe chemotherapy-related adverse events. One of its advantages is the standardization of the procedure, while its primary disadvantage is the onset of biliary complications when used nonselectively. There is level 2 evidence to support the use of RE in HCC, evidence that comes from patient cohorts with consistent results and case-control studies. The treated population includes mainly patients with unresectable tumors, who are considered suboptimal candidates for TACE or are progressing toward this condition, and those for whom TACE was directly contraindicated by the presence of portal vein thrombosis. Consequently, these patients tend to have large or extensively bilobar tumors and other factors for a poor prognosis. The overall survival reported for patients in the intermediate and advanced stages is 16-18 months and 7-17 months, respectively. A number of retrospective studies have reported comparable survival for patients treated with TACE and RE in the same institution; however, these results should be interpreted as a generator of ideas and not as an equivalent efficacy test. Although the combination of systemic agents such as sorafenib with intraarterial techniques is attractive, the results to date are not encouraging. In the only available randomized trial that compared the combination of a continuous regimen of sorafenib started before the first session of DEB-TACE versus DEB-TACE alone, neither the time to progression nor the overall survival were significantly different between the 2 groups. TACE and RE are contraindicated in cases of decompensated cirrhosis. TACE is also contraindicated for patients with considerable tumor burden in whom the procedure cannot be performed selectively and in patients with portal vein invasion.
Autores: Silva, N.; Bilbao, José Ignacio; et al.
Revista: HPB
ISSN 1365-182X  Vol. 16  Nº 3  2014  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.
Autores: Sangro, Bruno;
Revista: FUTURE ONCOLOGY
ISSN 1479-6694  Vol. 10   Nº 15 S1  2014  págs. 7 - 11
Autores: Alfaro, Carlos; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 20  Nº 22  2014  págs. 5697-5707
IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.
Autores: Seidensticker, M.; Seidensticker, R.; Damm, R.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9   Nº 11  2014  págs. e112731
Background/Aim: Targeted radiotherapy of liver malignancies has found to be effective in selected patients. A key limiting factor of these therapies is the relatively low tolerance of the liver parenchyma to radiation. We sought to assess the preventive effects of a combined regimen of pentoxifylline (PTX), ursodeoxycholic acid (UDCA) and low-dose low molecular weight heparin (LMWH) on focal radiation-induced liver injury (fRILI). Methods and Materials: Patients with liver metastases from colorectal carcinoma who were scheduled for local ablation by radiotherapy (image-guided high-dose-rate interstitial brachytherapy) were prospectively randomized to receive PTX, UDCA and LMWH for 8 weeks (treatment) or no medication (control). Focal RILI at follow-up was assessed using functional hepatobiliary magnetic resonance imaging (MRI). A minimal threshold dose, i.e. the dose to which the outer rim of the fRILI was formerly exposed to, was quantified by merging MRI and dosimetry data. Results: Results from an intended interim-analysis made a premature termination necessary. Twenty-two patients were included in the per-protocol analysis. Minimal mean hepatic threshold dose 6 weeks after radiotherapy (primary endpoint) was significantly higher in the study treatment-group compared with the control (19.1 Gy versus 14.6 Gy, p = 0.011). Qualitative evidence of fRILI by MRI at 6 weeks was observed in 45.5% of patients in the treatment versus 90.9% of the control group. No significant differences between the groups were observed at the 12-week follow-up. Conclusions: The post-therapeutic application of PTX, UDCA and low-dose LMWH significantly reduced the extent and incidence fRILI at 6 weeks after radiotherapy. The development of subsequent fRILI at 12 weeks (4 weeks after cessation of PTX, UDCA and LMWH during weeks 1-8) in the treatment group was comparable to the control group thus supporting the observation that the agents mitigated fRILI.
Autores: Herrero, José Ignacio; Iñarrairaegui, Mercedes; D'Avola, Delia; et al.
Revista: GASTROENTEROLOGIA Y HEPATOLOGIA
ISSN 0210-5705  Vol. 37  Nº 4  2014  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
Autores: D'Avola, Delia; Carmona, Francisco de Asís; Mendez, M.; et al.
Revista: MOLECULAR THERAPY
ISSN 1525-0016  Vol. 22  Nº Supl.1  2014  págs. S273 - S274
Autores: D'Avola, Delia; Carmona, Francisco de Asís; Mendez, M.; et al.
Revista: HUMAN GENE THERAPY
ISSN 1043-0342  Vol. 25  Nº 11  2014  págs. A45 - A46
Autores: Salem, R.; Mazzaferro, V.; Sangro, Bruno;
Revista: HEPATOLOGY
ISSN 0270-9139  Vol. 58  Nº 6  2013  págs. 2188 - 2197
Autores: Lau, W. Y.; Sangro, Bruno; Chen, P. J.; et al.
Revista: ONCOLOGY
ISSN 0030-2414  Vol. 84  Nº 5  2013  págs. 311 - 318
Background/Purpose: Patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) have an extremely poor prognosis and relatively few treatment options. Method: During a consensus meeting, experts met to examine the published data for HCC treatment strategies in patients with PVTT. Results: Many treatment guidelines consider the presence of PVTT a contraindication to partial hepatectomy or liver transplantation. Transarterial chemoembolization (TACE) is associated with an increased risk of ischemic necrosis of liver and of treatment-related death in patients with PVTT, and is, therefore, limited to a select group of patients with good hepatic function and adequate collateral circulation around the occluded portal vein. Systemic sorafenib results in survival benefit in patients regardless of the presence of PVTT. However, side effects are common, and there are no effects on time-to-symptom progression or quality of life. Transarterial radioembolization (TARE) with yttrium-90 microspheres is emerging as a valuable strategy. A wider range of patients with PVTT are suitable for this procedure compared to TACE. TARE is as effective as TACE in HCC and has quality-of-life advantages. Conclusion: In patients with HCC with PVTT, medical evidence suggests that TARE is a good choice of treatment.
Autores: Iñarrairaegui, Mercedes; D'Avola, Delia; Sangro, Bruno;
Revista: VISZERALMEDIZIN
ISSN 1662-6664  Vol. 29  Nº 2  2013  págs. 92-102
Autores: Hernández, Rubén; Sangro, Bruno; Berraondo, Pedro; et al.
Revista: EXPERT OPINION ON INVESTIGATIONAL DRUGS
ISSN 1354-3784  Vol. 22  Nº 7  2013  págs. 827 - 841
INTRODUCTION: Cytokines are key mediators of the immune system and have been proposed as therapeutic agents against cancer, either as recombinant proteins, or as transgenes in gene therapy approaches. Stimulation of immune responses against cancer cells is an appealing method to treat tumors with high risk of relapse and systemic dissemination. AREAS COVERED: We provide a critical overview of clinical trials involving the use of cytokines for the treatment of liver, colon and pancreatic cancers. Special attention has been paid to advances in the field of gene therapy and oncolytic viruses. The potential of new developments still in a pre-clinical stage is also discussed. We have revised public sources of information (PubMed, US National Institutes of Health clinical trials database) up to January 2013. EXPERT OPINION: The complexity of the immune system and the unfavorable pharmacokinetic properties of cytokines limit the efficacy of these molecules as single agents for the treatment of cancer. Expression from gene therapy vectors, together with new methods of targeting and stabilization, may overcome these hurdles. We believe cytokines will play a crucial role as part of combined approaches, enhancing the action of adoptive cell immunotherapy, oncolytic viruses or biological therapies.
Autores: Alegre, Félix; Herrero, José Ignacio; Iñarrairaegui, Mercedes; et al.
Revista: ACTA GASTRO-ENTEROLOGICA BELGICA
ISSN 1784-3227  Vol. 76  Nº 2  2013  págs. 246-50
Patients with heart failure have increased liver stiffness, that appears to be related with the severity of heart failure
Autores: Iñarrairaegui, Mercedes; D'Avola, Delia; Sangro, Bruno;
Revista: VISZERALMEDIZIN
ISSN 1662-6664  Vol. 29  Nº 2  2013  págs. 92-102
Autores: Barbero, R.; Rodríguez, Carlos Manuel; Pérez-Vizcaíno, F.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 8  Nº 1  2013  págs. e52683
Zolmitriptan reduces portal hypertension and non-selective beta-blockers can improve this effect. Combination therapy deserves consideration for patients with portal hypertension failing to respond to non-selective beta-blockers.
Autores: Bolondi, L; Burroughs, Andrew; Dufour, Jen-Francois; et al.
Revista: Seminars in Liver Disease
ISSN 0272-8087  Vol. 32  Nº 4  2013  págs. 348 - 359
Autores: Joy, S. M.; Blauvelt, B. M.; Tuncer, M. A.; et al.
Revista: EUROPEAN JOURNAL OF PUBLIC HEALTH
ISSN 1101-1262  Vol. 23  Nº 6  2013  págs. 951 - 957
As liver cancer incidence and mortality remain high in many parts of Europe, a more comprehensive response is required to reduce the burden. Expert stakeholders should be involved in the design of responses because they have important insights about potentially effective responses and will be affected by policy changes. We aimed to prioritize liver cancer control strategies based on European liver cancer stakeholders' views of which strategies would have the greatest impact in a comprehensive liver cancer control plan. METHODS: One hundred liver cancer clinical, policy and advocacy stakeholders from France, Germany, Italy, Spain and Turkey were surveyed. Respondents completed 12 conjoint choice tasks in which they chose which of two subsets of 11 strategies would have the greatest impact in their country. RESULTS: All strategies were considered likely to have a positive impact (P < 0.01). The highest priority strategy was monitoring of at-risk populations, followed by centres of excellence, clinical education, multidisciplinary management, national guidelines, measuring social burden, public awareness, risk assessment and referral, research infrastructure and access to treatments. CONCLUSIONS: Canvassing stakeholder views through a conjoint analysis survey provided a robust quantitative prioritization that can complement traditional qualitative consultation processes. The prioritized strategies provide a logical starting point for decision makers considering developing national plans or collaborative efforts to achieve comprehensive liver cancer control in Europe.
Autores: Sangro, Bruno; Gomez-Martin C; de la Mata M; et al.
Revista: JOURNAL OF HEPATOLOGY
ISSN 0168-8278  Vol. 59  Nº 1  2013  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.
Autores: Rita Golfieri; Bilbao, José Ignacio; Livio Carpanese; et al.
Revista: JOURNAL OF HEPATOLOGY
ISSN 0168-8278  Vol. 59  Nº 4  2013  págs. 753-61
Radioembolization appears to be as well-tolerated and effective for the elderly as it is for younger patients with unresectable HCC. Age alone should not be a discriminating factor for the management of HCC patients.
Autores: Rodríguez, I.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 19  Nº 22  2013  págs. 6151 - 6162
Purpose: Immunostimulatory monoclonal antibodies (ISmAb) that unleash antitumor immune responses are showing efficacy in cancer clinical trials. Anti-B7-H1 (PD-L1) monoclonal antibodies (mAb) block a critical inhibitory pathway in T cells, whereas anti-CD137 and OX40 mAbs provide T-cell costimulation. A combination of these ISmAbs (anti-CD137 + anti-OX40 + anti-B7-H1) was tested using a transgenic mouse model of multifocal and rapidly progressing hepatocellular carcinoma, in which c-myc drives transformation and cytosolic ovalbumin (OVA) is expressed in tumor cells as a model antigen. Experimental Design: Flow-cytometry and immunohistochemistry were used to quantify tumor-infiltrating lymphocytes (TIL) elicited by treatment and assess their activation status and cytolytic potential. Tolerance induction and its prevention/reversal by treatment with the combination of ISmAbs were revealed by in vivo killing assays. Results: The triple combination of ISmAbs extended survival of mice bearing hepatocellular carcinomas in a CD8-dependent fashion and synergized with adoptive T-cell therapy using activated OVA-specific TCR-transgenic OT-1 and OT-2 lymphocytes. Mice undergoing therapy showed clear increases in tumor infiltration by activated and blastic CD8(+) and CD4(+) T lymphocytes containing perforin/granzyme B and expressing the ISmAb-targeted receptors on their surface. The triple combination of ISmAbs did not result in enhanced OVA-specific cytotoxic T lymphocyte (CTL) activity but other antigens expressed by cell lines derived from such hepatocellular carcinomas were recognized by endogenous TILs. Adoptively transferred OVA-specific OT-1 lymphocytes into tumor-bearing mice were rendered tolerant, unless given the triple mAb therapy. Conclusion: Extension of survival and dense T-cell infiltrates emphasize the translational potential of combinational immunotherapy strategies for hepatocellular carcinoma.
Autores: Carretero, Cristina; Herráiz, María Teresa; et al.
Revista: WORLD JOURNAL OF GASTROENTEROLOGY
ISSN 1007-9327  Vol. 19  Nº 19  2013  págs. 2935 - 2940
IM: To evaluate the long-term natural history of the gastroduodenal lesions secondary to extrahepatic embolization with Ytrium 90(Y-90) spheres. METHODS: From September 2003 to January 2012, 379 procedures of liver radioembolization(RE) using resin microspheres loaded with Y-90 were performed in our center. We have retrospectively compiled the data from 379 RE procedures performed in our center. We report a comprehensive clinical, analytical, endoscopic and histologic long-term follow-up of a series of patients who developed gastroduodenal lesions after the treatment. RESULTS: Six patients(1.5%) developed gastrointestinal symptoms and had gastrointestinal lesions as shown by upper endoscopy in the next 12 wk after RE. The mean time between RE and the appearance of symptoms was 5 wk. Only one patient required endoscopic and surgical treatment. The incidence of gastrointestinal ulcerations was 3.75%(3/80) when only planar images were used for the pre-treatment evaluation. It was reduced to 1%(3/299) when single-photon emission computed tomography(SPECT) images were also performed. The symptoms that lasted for a longer time were nausea and vomiting, until 25 mo after the treatment. CONCLUSION: All patients were free from severe symptoms at the end of follow-up. The routine use of SPECT has decreased the incidence of gastrointestinal lesions due to unintended deployment of Y-90 particles.
Autores: Chopitea, Ana; Iñarrairaegui, Mercedes; et al.
Revista: Hepatology
ISSN 0270-9139  Vol. 57  Nº 3  2013  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)
Autores: Sarobe, Pablo; Merino, J; et al.
Revista: LIVER TRANSPLANTATION
ISSN 1527-6465  Vol. 19  Nº 9  2013  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.
Autores: Rotellar, Fernando; Pardo, Fernando; Benito, Alberto; et al.
Revista: AMERICAN JOURNAL OF TRANSPLANTATION
ISSN 1600-6135  Vol. 13  Nº 12  2013  págs. 3269-3273
The overriding concern in living donor liver transplantation is donor safety. A totally laparoscopic right hepatectomy without middle hepatic vein for adult living donor liver transplantation is presented. The surgical procedure is described in detail, focusing on relevant technical aspects to enhance donor safety, specifically the hanging maneuver and dynamic fluoroscopy-controlled bile duct division.
Autores: Sangro, Bruno; Iñarrairaegui, Mercedes; Bilbao, José Ignacio;
Revista: JOURNAL OF HEPATOLOGY
ISSN 0168-8278  Vol. 58  Nº 5  2013  págs. 1056-1057
Autores: Martínez, Diego; Sangro, Bruno;
Revista: GASTROENTEROLOGIA Y HEPATOLOGIA
ISSN 0210-5705  Vol. 36  Nº 9  2013  págs. 606-07
Autores: Iñarrairaegui, Mercedes; Pardo, Fernando; Sangro, Bruno;
Revista: EJSO
ISSN 0748-7983  Vol. 39  Nº 8  2013  págs. 920-921
Autores: Wasan, H.; Kennedy, A.; Coldwell, D.; et al.
Revista: AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS
ISSN 0277-3732  Vol. 35  Nº 3  2012  págs. 293 - 301
Clinical decisions regarding the treatment of metastatic colorectal cancer require consideration of current and evolving modalities to best achieve prolonged patient survival. Clinical trials have established that for first-line treatment of patients with or without extrahepatic metastases, radioembolization augments the response produced by chemotherapy in patients with unresectable liver metastases. This includes progression-free and overall survivals that compare favorably with phase II to III data of current chemotherapy regimens. The increased response rate with radioembolization and first-line chemotherapy may improve the likelihood for potentially curative hepatic lesion resection or ablation. Application of an innovative multidisciplinary treatment approach that integrates radioembolization and local ablative therapy may enable the benefits of curative hepatic resection to be extended to a broader group of patients.
Autores: Coldwell, D.; Sangro, Bruno; Salem, R.; et al.
Revista: American Journal of Clinical Oncology
ISSN 0277-3732  Vol. 35  Nº 2  2012  págs. 167 - 177
Radioembolization is a proven treatment to slow disease progression and improve survival in patients with colorectal cancer liver metastases and hepatocellular carcinoma. Accumulating evidence supports its use in metastases from neuroendocrine tumors and breast cancer. Cancers with radiobiologic profiles similar to those of colorectal and breast cancer, including melanoma, lung cancer, and nodular cholangiocarcinoma, are being studied as candidates for radioembolization. This treatment modality has also been shown to downsize hepatic tumors for potentially curative ablation in patients with breast, pancreatic, and colorectal cancer. Radioembolization using either yttrium-90 (Y-90)-labeled resin or glass microspheres represents a promising therapy for liver-only or liver-predominant tumors in patients with 1 or more variables, including adequate or sufficient functional liver reserve, good performance status, and absence of other significant comorbidities. Therapeutic efficacy and safety can be best achieved by use of careful dosimetric techniques and treatment planning. Radioembolization could be considered after progression of liver metastases during treatment hiatus, at an early therapeutic line in tumors that respond poorly to chemotherapy, or in treatment-refractory disease.
Autores: D'Avola, Delia; Bilbao, José Ignacio; et al.
Revista: Transplantation Proceedings
ISSN 0041-1345  Vol. 44  Nº 9  2012  págs. 2603 - 26058
Autores: Sangro, Bruno; Iñarrairaegui, Mercedes; Bilbao, José Ignacio;
Revista: Journal of Hepatology
ISSN 0168-8278  Vol. 56  Nº 2  2012  págs. 464 - 473
Autores: Gómez-Martín, Carlos; Bustamante, Javier; Castroagudin, Javier F.; et al.
Revista: Liver Transplantation
ISSN 1527-6465  Vol. 18  Nº 1  2012  págs. 45 - 52
There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preli
Autores: D'Avola, Delia; Iñarrairaegui, Mercedes; et al.
Revista: JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY RESEARCH
ISSN 2224-3992  Vol. 1  Nº 6  2012  págs. 111 - 113
Autores: Wasan, Harpreet; Kennedy, Andrew; Coldwell, Douglas; et al.
Revista: American Journal of Clinical Oncology
ISSN 0277-3732  Vol. 35  Nº 3  2012  págs. 293 - 301
Clinical decisions regarding the treatment of metastatic colorectal cancer require consideration of current and evolving modalities to best achieve prolonged patient survival. Clinical trials have established that for first-line treatment of patients with or without extrahepatic metastases, radioembolization augments the response produced by chemotherapy in patients with unresectable liver metastases. This includes progression-free and overall survivals that compare favorably with phase II to III data of current chemotherapy regimens. The increased response rate with radioembolization and first-line chemotherapy may improve the likelihood for potentially curative hepatic lesion resection or ablation. Application of an innovative multidisciplinary treatment approach that integrates radioembolization and local ablative therapy may enable the benefits of curative hepatic resection to be extended to a broader group of patients.
Autores: Kennedy, Andrew; Coldwell, Douglas; Sangro, Bruno; et al.
Revista: American Journal of Clinical Oncology
ISSN 0277-3732  Vol. 35  Nº 1  2012  págs. 91 - 99
Autores: Kennedy, A.; Coldwell, D.; Sangro, Bruno; et al.
Revista: American Journal of Clinical Oncology
ISSN 0277-3732  Vol. 35  Nº 4  2012  págs. 393 - 398
Surgical resection of hepatic metastases from neuroendocrine tumors (mNETs) is controversial because the potential survival benefit of this intervention must be balanced against the risk of surgical morbidity and mortality. In patients with unresectable mNETs in the liver, radioembolization has been used to treat tumors from a range of primary sites, including carcinoid and islet cell carcinomas as well as nonfunctional, asymptomatic tumors. Initial clinical studies and retrospective studies on a large cohort of patients indicate that radioembolization is well tolerated and highly effective in achieving a durable hepatic tumor response and ameliorating symptoms. Radio-embolization using Yttrium-90 (Y-90)-labeled resin or glass microspheres offers effective disease control and possible improved quality of life and thus merits consideration as an option for both functional and nonfunctional mNETs. Benefits of this intervention seem to extend from use in early lines of treatment to salvage of refractory disease. Radioembolization also offers a potential somatostatin analog-sparing effect in symptomatic disease.
Autores: Kennedy, Andrew; Coldwell, Douglas; Sangro, Bruno; et al.
Revista: American Journal of Clinical Oncology
ISSN 0277-3732  Vol. 35  Nº 1  2012  págs. 81 - 90
Autores: Iñarrairaegui, Mercedes; Pardo, Fernando; Bilbao, José Ignacio; et al.
Revista: European Journal of surgical Oncology
ISSN 0748-7983  Vol. 38  Nº 7  2012  págs. 594 - 601
Autores: Martínez-Becerra, P.; J. Vaquero; Romero, M. R.; et al.
Revista: MOLECULAR PHARMACEUTICS
ISSN 1543-8384  Vol. 9  Nº 6  2012  págs. 1693 - 1704
Farnesoid X receptor (FXR) has been recently reported to enhance chemoresistance through bile acid-independent mechanisms. Thus, FXR transfection plus activation with GW4064 resulted in reduced sensitivity to cisplatin-induced toxicity. This is interesting because primary tumors of the liver, an organ where FXR is expressed, exhibit marked refractoriness to pharmacological treatment. Here we have determined whether FXR is upregulated in hepatocellular carcinoma (HCC), cholangiocarcinoma (CGC) and hepatoblastoma (HPB) and whether this is related with the expression of genes involved in mechanisms of chemoresistance. Using RT-QPCR and Taqman low density arrays we have analyzed biopsies from healthy livers or surgically removed tumors from naive patients and cell lines derived from HCC (SK-HEP-1, Alexander and Huh7), CGC (TFK1) and HPB (HepG2), before and after exposure to cisplatin at IC50 for 72 h. In liver tumors FXR expression was not enhanced but significantly decreased (healthy liver > HCC > HPB ¿ CGC). Except for CGC, this was not accompanied by changes in the proportions of FXR isoforms. Changes in 36 genes involved in drug uptake/efflux and metabolism, expression/function of molecular targets, and survival/apoptosis balance were found. Changes affecting SLC22A1, CYP2A1 and BIRC5 were shared by HCC, CGC and HPB. Similarity in gene expression profiles between cell lines and parent tumors was found. Pharmacological challenge with cisplatin induced changes that increased this resemblance. This was not dependent upon FXR expression. Thus, although FXR may play a role in inducing chemoresistance under certain circumstances, its upregulation does not seem to be involved in the multidrug resistance phenotype characteristic of HCC, CGC and HPB.
Autores: Sangro, Bruno; Iñarrairaegui, Mercedes;
Revista: RARE TUMORS
ISSN 2036-3605  Vol. 4  Nº 2  2012  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
Autores: Herrero, José Ignacio; España, Agustín; D'Avola, Delia; et al.
Revista: Transplantation Proceedings
ISSN 0041-1345  Vol. 44  Nº 6  2012  págs. 1568 - 1570
Autores: Lau, Wan-Yee; Kennedy, Andrew; Kim, Yun Hwan; et al.
Revista: International Journal of Radiation Oncology, Biology, Physics
ISSN 0360-3016  Vol. 82  Nº 1  2012  págs. 401 - 407
Selective internal radiotherapy (SIRT) with yttrium-90 ((90)Y) resin microspheres can improve the clinical outcomes for selected patients with inoperable liver cancer. This technique involves intra-arterial delivery of ß-emitting microspheres...
Autores: Sangro, Bruno; Salem, Riad; Kennedy, Andrew; et al.
Revista: American Journal of Clinical Oncology
ISSN 0277-3732  Vol. 34  Nº 4  2011  págs. 422 - 431
Autores: Sangro, Bruno; D'Avola, Delia; Iñarrairaegui, Mercedes; et al.
Revista: Expert Opinion on Pharmacotherapy
ISSN 1465-6566  Vol. 12  Nº 7  2011  págs. 1057 - 1073
Autores: Schröder, Paul C; Segura, Victoriano; Riezu-Boj, José Ignacio; et al.
Revista: Functional & Integrative Genomics
ISSN 1438-793X  Vol. 11  Nº 3  2011  págs. 419 - 429
Autores: Berasain, C; Schmitz, Volker; et al.
Revista: Journal of Hepatology
ISSN 0168-8278  Vol. 55  Nº 4  2011  págs. 828 - 837
Autores: Sangro, Bruno; Carpanese, Livio; Cianni, Roberto; et al.
Revista: Hepatology
ISSN 0270-9139  Vol. 54  Nº 3  2011  págs. 868 - 878
Autores: Coldwell, Douglas; Sangro, Bruno; Wasan, Harpreet; et al.
Revista: American Journal of Clinical Oncology
ISSN 0277-3732  Vol. 34  Nº 3  2011  págs. 337 - 341
Autores: Riezu-Boj, José Ignacio; Larrea, Esther; Aldabe, R; et al.
Revista: JOURNAL OF HEPATOLOGY
ISSN 0168-8278  Vol. 54  Nº 3  2011  págs. 422 - 431
Autores: Sangro, Bruno; Iñarrairaegui, Mercedes;
Revista: Nuclear Medicine & Radiation Therapy
ISSN 2155-9619  Vol. 2  Nº 1  2011  págs. 1 - 6
Autores: Salem, Riad; Lewandowski, Robert J; Gates, Vanessa L; et al.
Revista: Journal of vascular and interventional radiology (Print)
ISSN 1051-0443  Vol. 22  Nº 3  2011  págs. 265 - 278
Autores: Herrero, José Ignacio; Pardo, Fernando; D'Avola, Delia; et al.
Revista: Liver Transplantation
ISSN 1527-6465  Vol. 17  Nº 4  2011  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: Suárez Fuentetaja, N.; Alfaro Alegría, C.; Dubrot Armendáriz, J.; et al.
Revista: International Journal of Cancer (Print)
ISSN 0020-7136  Vol. 129  Nº 2  2011  págs. 374 - 386
The synergy mechanism can be traced to enhanced CTLA-4 expression in effector cells as a result of T(reg) elimination, thereby offering more targets to the blocking antibody. Human T cells and allogenic DCs (derived both from healthy donors and advanced cancer patients) were coinjected in the peritoneum of Rag2(-/-) IL-2R¿(-/-) mice. In these conditions, tremelimumab injected intravenously did not significantly enhance alloreactive proliferation unless T(reg) cells had been predepleted. Synergistic effects in vivo were again largely restricted to the CD4 T-cell compartment. In addition, T(reg) depletion and CTLA-4 blockade synergistically enhanced specific cytotoxicity raised in culture against autologous EBV-transformed cell lines. Taken together, these experiments indicate that tremelimumab therapy may benefit from previous or concomitant T(reg) depletion
Autores: Alfaro, Carlos; Pérez, José Luis; et al.
Revista: The Journal of Immunology
ISSN 0022-1767  Vol. 187  Nº 11  2011  págs. 6130 - 6142
Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-alpha, TNF-alpha, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-gamma-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.
Autores: D'Avola, Delia; Iñarrairaegui, Mercedes; Pardo, Fernando; et al.
Revista: ANNALS OF SURGICAL ONCOLOGY
ISSN 1068-9265  Vol. 18  Nº 7  2011  págs. 1964 - 1971
Autores: Raoul, JL; Sangro, Bruno; Forner, A; et al.
Revista: Cancer Treatment Reviews
ISSN 0305-7372  Vol. 37  Nº 3  2011  págs. 212 - 220
Autores: Lau, Wan-Yee; Kennedy, Andrew; Kim, Yun Hwan; et al.
Revista: International Journal of Radiation Oncology, Biology, Physics
ISSN 0360-3016  Vol. 80  Nº 4  2011  págs. 1280 - 1281
Autores: Sangro, Bruno; Prieto, Jesús María;
Revista: Current Opinion in molecular therapheutics
ISSN 1464-8431  Vol. 12  Nº 5  2010  págs. 561 - 569
In contrast to the large quantity of preclinical evidence for efficacy, few gene therapy agents have reached clinical development for the treatment of primary and secondary liver cancer. This review discusses the published clinical trials that have explored the feasibility, safety and efficacy of gene therapy strategies for the treatment of liver cancer. Strategies include restoration of tumor suppressor genes, genetic prodrug-activating therapy, genetic immunotherapy and oncolytic virotherapy. In these trials, transgene expression of varying degrees has been detected. Globally, gene therapy has proven to be safe, with none of the agents tested reaching the MTD. Although none of the phase II trials provided significant response rates, objective remissions have occasionally been observed and proof-of-concept for the ability of gene therapy to produce significant tumor cell killing has been determined. Insufficient delivery following intravascular administration and short-lived transgene expression are likely to be the cause of this limited antitumor efficacy. The development of new gene therapy vectors with improved characteristics will increase the probability of success of gene therapy for the treatment of liver cancer.
Autores: Iñarrairaegui, Mercedes; Rodríguez-Fraile, M; et al.
Revista: International Journal of Radiation Oncology, Biology, Physics
ISSN 0360-3016  Vol. 77  Nº 5  2010  págs. 1441 - 1448
Autores: Sangro, Bruno; Mazzolini Rizzo, G.D.; et al.
Revista: Cancer Gene Therapy (Print)
ISSN 0929-1903  Vol. 17  Nº 12  2010  págs. 837 - 843
Autores: Iñarrairaegui, Mercedes; Bilbao, José Ignacio; Rodríguez-Fraile, M; et al.
Revista: HOSPITAL PRACTICE
ISSN 2154-8331  Vol. 38  Nº 3  2010  págs. 103 - 109
Autores: Bilbao, José Ignacio; et al.
Revista: Cardiovascular and Interventional Radiology
ISSN 0174-1551  Vol. 33  Nº 3  2010  págs. 523 - 531
Autores: Peck-Radosavljevic, M; Greten, Tim F; Lammer, J; et al.
Revista: European Journal of Gastroenterology and Hepatology
ISSN 0954-691X  Vol. 22  Nº 4  2010  págs. 391 - 398
Autores: Iñarrairaegui, Mercedes; Thurston Kenneth, G; Bilbao, José Ignacio; et al.
Revista: Journal of vascular and interventional radiology (Print)
ISSN 1051-0443  Vol. 21  Nº 8  2010  págs. 1205 - 1212
Autores: Quiroga, Jorge Augusto; Sangro, Bruno; et al.
Libro:  Tratado de Medicina Farmacéutica
2010  págs. 261 - 277