Sangro, B. (Bruno)
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- Risk factors for recurrence of hepatitis C after liver transplantation.(Wiley-Blackwell, 1998) Civeira, M.P. (María Pilar); Peña, A. (Andrés) de la; Álvarez-Cienfuegos, J. (Javier); Sola, J. (Josu); Sangro, B. (Bruno); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Garcia, N. (Nicolás); Quiroga, J. (Jorge)Recurrent hepatitis C is a frequent complication after liver transplantation for hepatitis C virus– related cirrhosis, but risk factors related to its development remain ill defined. Twenty-three patients receiving a primary liver graft for hepatitis C virus–related cirrhosis and with an assessable biopsy performed at least 6 months after liver transplantation were studied retrospectively. The end point of this study was to look for risk factors associated with the development of histologic hepatitis C in the graft. Thirty-six major variables were studied, and those reaching significance by univariate analysis were included in a multivariate analysis. Eighteen patients (78%) developed posttransplant hepatitis C. On univariate analysis, six variables showed significant predictive value: increased immunosuppression for treatment of acute rejection; pretransplant hepatocellular carcinoma; cumulative doses of prednisone at 3, 6, and 12 months after transplantation; and mean blood trough levels of cyclosporine in the first 6 months posttransplantation. On multivariate analysis, two variables retained independent statistical significance as predictors of hepatitis C recurrence, namely receipt of antirejection therapy (P 5 .0087) and lower mean cyclosporine levels in the first 6 months after transplantation (P 5 .0134). Therefore, recurrence of hepatitis C after liver transplantation seems to be at least partially related to posttransplantation immunosuppressive therapy.
- A multicentre, international, observational study on transarterial chemoembolisation in colorectal cancer liver metastases: Design and rationale of CIREL(Elsevier, 2020) Pellerin, O. (Olivier); Kaufmann, N. (Nathalie); Iezzi, R. (Roberto); Arnold, D. (Dirk); Taieb, J. (Julien); Bauer, R. (Robert); Sangro, B. (Bruno); Maleux, G. (Geert); Nordlund, A. (Anders); Baere, T. (T.) de; Helmberger, T. (Thomas); Pereira, P.L. (Philippe L.); Prenen, H. (Hans); Zeka, B. (Bleranda); Gómez, F. (F.)Background: About 70–80% of patients with colorectal liver metastases appear as ineligible for a curative treatment approach. Transarterial chemoembolisation (TACE) using irinotecan-eluting beads has emerged as a promising treatment option in cases with irresectable liver metastases. Despite being in clinical practice for years, little is known about the treatment characteristics and outcomes when used as per routine hospital practice. Methods: Patients with hepatic metastases from colorectal cancer origin, admitted to contributing centres to receive TACE with drug-eluting LifePearl® Microspheres loaded with irinotecan, as part of their standard care, will be consecutively added to the registry. Data will be collected until the end of study, loss to follow-up or death. Primary endpoint is the characterisation of the treatment usage at the selected sites in Europe. Secondary endpoints include outcome parameters, safety and toxicity, as well as quality of life. Conclusion and AIMS: This multicentre, international, prospective observational study conducted in European centres plans to collect real-life data. This data will form an evidence-base from which conclusions can be drawn on how to improve patient selection and optimise treatment protocols when treating with TACE using irinotecan-eluting microspheres.
- Metabolic dysfunction–associated fatty liver disease (MAFLD): an update of the recent advances in pharmacological treatment(Springer, 2023) D'Avola, D. (Delia); Sangro, B. (Bruno); Sangro, P. (Paloma); Torre-Aláez, M.A. (Manuel Antonio) de laMetabolic dysfunction-associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.
- Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study(Bmj, 2022) Reig, M. (Maria); Sangro, B. (Bruno); Testillano, M. (Milagros); Lledó, J.L. (José Luis); Iñarrairaegui, M. (Mercedes); Matilla, A. (Ana); Bilbao, J.I. (José I.); Da-Fonseca, L. (Leonardo); Márquez, L. (Laura); Rodriguez-Fraile, M. (Macarena); Lorente, S. (Sara); Varela, M.R. (María Rosario); Arenas, J.I. (Juan Ignacio); Torre-Aláez, M.A. (Manuel Antonio) de la; Argemí, J. (Josepmaria); Gómez-Martin, C. (Carlos)Purpose: To evaluate the safety and efficacy of selective internal radiation therapy (SIRT) in combination with a PD-1 inhibitor in patients with unresectable hepatocellular carcinoma (uHCC) and liver-only disease ineligible for chemoembolization. Patients and methods: NASIR-HCC is a single-arm, multicenter, open-label, phase 2 trial that recruited from 2017 to 2019 patients who were naïve to immunotherapy and had tumors in the BCLC B2 substage (single or multiple tumors beyond the up-to-7 rule), or unilobar tumors with segmental or lobar portal vein invasion (PVI); no extrahepatic spread; and preserved liver function. Patients received SIRT followed 3 weeks later by nivolumab (240 mg every 2 weeks) for up to 24 doses or until disease progression or unacceptable toxicity. Safety was the primary endpoint. Secondary objectives included objective response rate (ORR), time to progression (TTP), and overall survival (OS). Results: 42 patients received SIRT (31 BCLC-B2, 11 with PVI) and were followed for a median of 22.2 months. 27 patients discontinued and 1 never received Nivolumab. 41 patients had any-grade adverse events (AE) and 21 had serious AEs (SAE). Treatment-related AEs and SAEs grade 3-4 occurred in 8 and 5 patients, respectively. Using RECIST 1.1 criteria, ORR reported by investigators was 41.5% (95% CI 26.3% to 57.9%). Four patients were downstaged to partial hepatectomy. Median TTP was 8.8 months (95% CI 7.0 to 10.5) and median OS was 20.9 months (95% CI 17.7 to 24.1). Conclusions: The combination of SIRT and nivolumab has shown an acceptable safety profile and signs of antitumor activity in the treatment of patients with uHCC that were fit for SIRT.
- Gene therapy of cancer based on interleukin 12(Bentham Science Publishers, 2005) Qian, C. (Cheng); Sangro, B. (Bruno); Melero, I. (Ignacio); Prieto, J. (Jesús)Tumor formation and growth depends mainly on the inability of the organism to elicit a potent immune response, and on the formation of new blood vessels that enable tumor nutrition. Interleukin-12 (IL-12) therapy can target both processes. And IL-12-based gene therapy may restrict IL-12 production to the relevant site in order to obtain enhanced antitumor activity and reduced toxicity. In the clinical setting, IL-12 gene transfer can be used either to improve the pharmacokinetic/pharmacodynamic profile of the cytokine, to transduce dendritic cells or to enhance the efficiency of antitumor vaccination. It can also synergize with other procedures involving the simultaneous transfer of other transgenes or non-gene based strategies. The strong anti-tumoral power shown in many different animal models has not been found in early clinical trials in which cancer patients were treated by peritumoral injections of autologous fibroblasts producing IL-12, intratumoral injections of an adenoviral vector encoding human IL-12 genes, or intratumoral injection of autologous dendritic cells transduced ex vivo with this same adenoviral vector. However, these trials have set the proof-of-concept that local production of IL-12 inside a tumor can stimulate tumor infiltration by effector immune cells and that in some cases it is followed by tumor regression. From the many questions that arise after these disappointing results the most relevant concerns the duration and intensity of transgene expression and the capability to monitor this topics in vivo. New vectors that might achieve regulated, long-term production of this cytokine might have better results and merit clinical testing.
- Serum metabolites as diagnostic biomarkers for cholangiocarcinoma, hepatocellular carcinoma and primary sclerosing cholangitis(Wiley, 2019) Banales, J.M. (Jesús M.); Muñoz-Bellvis, L. (Luis); Martínez-Arranz, I. (Ibon); Arbelaiz, A. (Ander); Flores-González, L.M. (Luis Manuel); Muntane, J. (Jordi); Avila, M.A. (Matías Antonio); Alonso, C. (Cristina); Lapitz, A. (Ainhoa); La-Casta-Muñoa, A. (Adelaida); Sangro, B. (Bruno); Arretxe, A. (Anere); Iñarrairaegui, M. (Mercedes); Bujanda, L. (Luis); Milkiewicz, P. (Piotr); Macias, R. (Rocío); Santos-Laso, A. (Alvaro); Martinez-Chantar, M.L. (María Luz); Marin, J.J.G (Jose J.G.)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.
- Liver transplantation in cirrhotic patients with diabetes mellitus: Midterm results, survival, and adverse events(Wiley-Blackwell, 2001) Pardo, F. (Fernando); Álvarez-Cienfuegos, J. (Javier); Gomez-Manero, N. (Noemí); Sangro, B. (Bruno); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Quiroga, J. (Jorge); Blanco, J.J. (Jose J.)Liver cirrhosis is frequently associated with diabetes mellitus (DM), and this metabolic complication is also frequent after orthotopic liver transplantation (OLT). The aim of our study is to investigate which factors are associated with DM before and after OLT and their impact on post-OLT evolution. We evaluated the prevalence of DM among 115 liver transplant candidates with cirrhosis and assessed their evolution after OLT (median follow-up, 41 months). Sixteen candidates had DM requiring pharmacological therapy (group A), 45 candidates had DM controlled with diet (group B), and 54 candidates did not have DM (group C). One-year and 3-year actuarial survival rates were 100% and 100% for group A, 91% and 85% for group B, and 77% and 74% for group C, respectively (P <.03). Post-OLT DM was more frequent in group A. The incidence of other metabolic complications, major infections, rejection, and arterial hypertension; the need for hospitalization; and renal and graft function of patients in groups A, B, and C were similar. The only risk factor for DM 1 year after OLT on multivariate analysis was pre-OLT DM requiring pharmacological treatment. The incidence of complications, need for hospitalization, and renal and graft function 1 year after OLT for patients with post-OLT DM were similar to those of patients without post-OLT DM. In conclusion, patients with cirrhosis who have DM have a greater risk for post-OLT DM, but their midterm survival is not worse than the survival of those without DM.
- In Vitro Model for Simulating Drug Delivery during Balloon-Occluded Transarterial Chemoembolization.(MDPI, 2021) Aramburu-Montenegro, J. (Jorge); Antón-Remírez, R. (Raúl); Fukamizu, J. (Junichi); Nozawa, D. (Daiki); Ramos-González, J. (Juan Carlos); Sangro, B. (Bruno); Bilbao-Jaureguízar, J. (José Ignacio); Tomita, K. (Kosuke); Matsumoto, T. (Tomohiro); Hasebe, T. (Teremitsu)Simple Summary Liver cancer is one of the leading causes of cancer-related deaths worldwide and balloon-occluded transarterial chemoembolization (B-TACE) has emerged as a safe and effective treatment for liver cancer. However, the hemodynamic alterations that are responsible for the successfulness of the treatment and are produced by the microballoon catheter used during the treatment are not yet well understood. In this study, we developed an in vitro model (IVM) that can simulate B-TACE. We designed clinically relevant experiments, and we obtained clinically realistic results. We conclude that the IVM allows for a visual understanding of a complex phenomenon (i.e., the blood flow redistribution after balloon occlusion) and it could be used as a base for future sophisticated and even patient-specific IVMs; in addition, it could be used to conduct IVM-based research on B-TACE. Background: Balloon-occluded transarterial chemoembolization (B-TACE) has emerged as a safe and effective procedure for patients with liver cancer, which is one of the deadliest types of cancer worldwide. B-TACE consist of the transcatheter intraarterial infusion of chemotherapeutic agents, followed by embolizing particles, and it is performed with a microballoon catheter that temporarily occludes a hepatic artery. B-TACE relies on the blood flow redistribution promoted by the balloon-occlusion. However, flow redistribution phenomenon is not yet well understood. Methods: This study aims to present a simple in vitro model (IVM) where B-TACE can be simulated. Results: By visually analyzing the results of various clinically-realistic experiments, the IVM allows for the understanding of balloon-occlusion-related hemodynamic changes and the importance of the occlusion site. Conclusion: The IVM can be used as an educational tool to help clinicians better understand B-TACE treatments. This IVM could also serve as a base for a more sophisticated IVM to be used as a research tool.
- Factors related to increased resting energy expenditure in men with liver cirrhosis(2016) Prieto-Frías, C. (Cesár); Conchillo, M. (M.); Payeras, M. (Marina); Iñarrairaegui, M. (Mercedes); D'Avola, D. (Delia); Frühbeck, G. (Gema); Salvador, J. (Javier); Rodriguez, M. (Macarena); Richter, J.A. (José Ángel); Mugueta, C. (Carmen); Gil-Maria, J. (Jesús); Herrero, I. (Ignacio); Prieto, J. (Jesús); Sangro, B. (Bruno); Quiroga, J. (Jorge)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, β-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
- Minimally invasive liver surgery for hepatocellular carcinoma in patients with portal hypertension(Oxford University Press, 2023) Rotellar, F. (Fernando); Almeida, A. (Ana); Luján-Colás, J. (Juan); Zozaya-Larequi, G. (Gabriel); Sangro, B. (Bruno); Blanco, N. (Nuria); Sabatella, L. (Lucas); Marti-Cruchaga, P. (Pablo); Aliseda, D. (Daniel)For patients with early stage hepatocellular carcinoma (HCC), liver resection is a mainstay of curative treatment. Patients with a solitary tumour, Child–Pugh A cirrhosis and serum bilirubin of 1 mg/dl are considered ideal candidates for liver resection1,2 . For patients with portal hypertension, current guidelines recommend careful consideration of liver resection based on the hierarchical interaction of portal hypertension, liver function and resection extent1,3 . Open liver resection has been used in the majority of published studies on liver resection and portal hypertension. Although there is limited published experience of minimally invasive liver resection (MILR), using MILR in these patients appears to be associated with favourable outcomes4 . Particularly in patients with Child–Pugh A cirrhosis, but also in patients with more advanced cirrhosis5 , MILR offers significant advantages in the surgical treatment of HCC including reduced intraoperative bleeding, fewer complications and minimized surgical aggression, which improves recovery6,7 . If these benefits are also found in patients with portal hypertension, MILR may represent a step forward in the surgical treatment of patients with HCC and portal hypertension. This systematic review and meta-analysis aimed to summarize the intraoperative, postoperative and survival outcomes of MILR in patients with HCC and portal hypertension.