Iñarrairaegui, M. (Mercedes)

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    Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients
    (Elsevier, 2021) Castells, L. (Lluis); Lladó, L. (Laura); Muñoz-Serrano, A. (Alejandro); García-Pajares, F. (Fernando); Otero, A. (Alejandra); González-Grande, R. (Rocío); Caballero, A. (Aránzazu); Graus, J. (Javier); Blanco-Fernández, G. (Gerardo); Fábrega, E. (Emilio); Navasa, M. (Miquel); González-Dieguez, M.L. (María Luisa); Cachero, A. (Alba); Bustamante-Schneider, J. (Javier); Rodriguez, M. (Manuel); Iñarrairaegui, M. (Mercedes); Arias-Milla, A. (Ana); Hierro, L. (Loreto); Vinaixa, C. (Carmen); Fondevila, C. (Constantino); Loinaz, C. (Carmelo); Nogueras, F. (Flor); Salcedo, M. (Magdalena); Ramírez, P. (Pablo); Colmenero, J. (Jordi); Pascual, S. (Sonia); Fernández-Yunquera, A. (Ainhoa); Álamo, J.M. (José María); Nuño, J. (Javier); Gastaca, M. (Mikel)
    In liver transplant patients, chronic immunosuppression increases the risk of acquiring COVID-19 but it could reduce disease severity. Com- plete immunosuppression with- drawal may not be justified. However, mycophenolate withdrawal or tem- porary conversion to calcineurin inhibitors or everolimus until disease resolution could be beneficial in hos- pitalised patients.
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    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.
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    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.
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    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
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    Is a Technetium-99m Macroaggregated Albumin Scan Essential in the Workup for Selective Internal Radiation Therapy with Yttrium-90? An Analysis of 532 Patients
    (Elsevier, 2017) Sancho, L. (Lidia); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Moran, V. (Verónica); Bilbao, J.I. (José I.); Rodriguez-Fraile, M. (Macarena); Beorlegui, C. (Carmen)
    Purpose: To determine if baseline patient, tumor, and pretreatment evaluation characteristics could help identify patients who require technetium-99m (99mTc) macroaggregated albumin (99mTc 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 99mTc MAA imaging results contraindicated/modified SIRT administration with yttrium-90 (90Y) resin microspheres and those who were treated as initially planned. The 99mTc MAA findings that contraindicated/modified SIRT were a lung shunt fraction (LSF) > 20%, gastrointestinal 99mTc MAA uptake, or a mismatch between 99mTc 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 99mTc 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 99mTc MAA is essential in SIRT workup because baseline characteristics may not adequately predict 99mTc 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.
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    Hepatic encephalopathy after liver transplantation in a patient with a normally functioning graft: Treatment with embolization of portosystemic collaterals
    (Wiley-Blackwell, 2009) Alegre, F. (Félix); Pardo, F. (Fernando); Iñarrairaegui, M. (Mercedes); Bilbao, J.I. (José I.); Herrero, J.I. (José Ignacio); Quiroga, J. (Jorge); Diaz-Dorronsoro, L. (Lourdes)
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    A new animal model of atrophy–hypertrophy complex and liver damage followingYttrium‐90 lobar selective internal radiation therapy in rabbits
    (Nature Research, 2022) Berasain, C. (Carmen); Páramo-Alfaro, M. (María); Peñuelas-Sanchez, I. (Ivan); Benito-Boíllos, A. (Alberto); Quincoces, G. (Gemma); Collantes-Martínez, M. (María); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Bilbao, J.I. (José I.); Santamaría, E. (Eva); Idoate, M.A. (Miguel Ángel); Quiroga, J. (Jorge); Argemí, J. (Josepmaria); Rodriguez, M. (Macarena)
    Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy–hypertrophy complex after SIRT. Three groups of 5–8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with diferent activities (0.3, 0.6 and 1.2GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced signifcant toxicity. Cranial SIRT with 0.3GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3GBq groups developed moderate damage with infammation and portal fbrosis at 15 days, partially recovering at 30 days. There was no diference in the expression of hepatocyte function and diferentiation genes between 0.3GBq and control groups. Cranial SIRT with 0.3GBq of 90Y resin microspheres in rabbits is a reliable animal model to analyse the atrophy–hypertrophy complex and liver damage without toxicity.
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    El hepatocarcinoma
    (Gobierno de Navarra, 2016) Iñarrairaegui, M. (Mercedes)
    El hepatocarcinoma (HCC) es la sexta neoplasia más frecuente a nivel mundial, y una de las principales causas de muerte por cáncer. Además, en la mayoría de las ocasiones, asienta sobre una enfermedad hepática previa, y se conocen muchos de los factores de riesgo para desarrollarlo (hepatitis virales, cirrosis alcohólica, esteatohepatitis no alcohólica, entre otros). Su diagnóstico en población cirrótica se basa en pruebas de imagen no invasivas, siendo la ecografía la técnica inicial que se utiliza para su detección, por su bajo coste y accesibilidad.
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    Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells
    (Elsevier, 2011) Berasain, C. (Carmen); D'Avola, D. (Delia); Kawa, M. (Milosz); Qian, C. (Cheng); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Prieto, J. (Jesús); Herrero, J.I. (José Ignacio); Quiroga, J. (Jorge); Schmitz, V. (Volker); Iñiguez, M. (María); Fernandez-Ruiz, V. (Verónica); Martinez-Anso, E. (Eduardo)
    BACKGROUND & AIMS: Cell therapy has been used to attenuate liver injury. Here we evaluated whether genetic engineering of either bone marrow-derived mononuclear cells (MNC) or endothelial progenitor cells (EPC) many enhance their hepatoprotective properties. METHODS: Mice with ConA-induced hepatitis or with lethal fulminant hepatitis resulting from administration of an adenovirus encoding CD40L (AdCD40L) received an intra-splenic injection of saline or 2 × 10(6) unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase (MNCLUC and EPCLUC) or encoding the hepatoprotective cytokine cardiotrophin-1 (CT-1) (MNCCT-1 and EPCCT-1). We analyzed the extent of liver damage, the intensity of inflammatory reaction, and animal survival. RESULTS: Luciferase immunohistochemistry showed that after injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis EPCCT-1, but not other forms of cell therapy, significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This superior therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNFα, and decreased granzyme B levels. In AdCD40L-induced lethal fulminant hepatitis, EPCCT-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% survival while mortality was 100% in the other treatment groups. CONCLUSIONS: Genetic engineering of EPC to overexpress CT-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for acute liver failure. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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    Liver resection and transplantation following Yttrium-90 radioembolization for primary malignant liver tumors: a 15-year single-center experience
    (2023) Rotellar, F. (Fernando); Pardo-Sanchez, F. (Fernando); Ortega-Montes, A. (Ana); Lopez-Olaondo, L. (Luis); Benito-Boíllos, A. (Alberto); Zozaya-Larequi, G. (Gabriel); Hidalgo, F. (Francisco); Martinez-de-la-Cuesta, A. (Antonio); Sangro, B. (Bruno); Ponz-Sarvise, M. (Mariano); Iñarrairaegui, M. (Mercedes); Bilbao, J.I. (José I.); Herrero, J.I. (José Ignacio); Marti-Cruchaga, P. (Pablo); Rodriguez-Fraile, M. (Macarena); Rodríguez-Rodríguez, J. (Javier); Aliseda, D. (Daniel)
    Simple Summary Radioembolization is a locoregional therapy used in primary liver malignancies with different applications depending on the treatment goal. The aim of this retrospective study was to evaluate postoperative and long-term survival outcomes of patients with unresectable or high biological risk HCC and ICC treated with RE that were finally rescued to liver surgery with curative intent. In a cohort of 34 patients, we assessed that liver resection and transplantation after RE seem safe and feasible with adequate short-term outcomes. Moreover, long-term outcomes after RE and LR were optimal, with a 10-year OS rate greater than 50% for HCC and ICC patients. On the other hand, the 10-year OS rates from RE were also greater than 50% for patients with HCC downstaged or bridged to LT. Radioembolization (RE) may help local control and achieve tumor reduction while hypertrophies healthy liver and provides a test of time. For liver transplant (LT) candidates, it may attain downstaging for initially non-candidates and bridging during the waitlist. Methods: Patients diagnosed with HCC and ICC treated by RE with further liver resection (LR) or LT between 2005-2020 were included. All patients selected were discarded for the upfront surgical approach for not accomplishing oncological or surgical safety criteria after a multidisciplinary team assessment. Data for clinicopathological details, postoperative, and survival outcomes were retrospectively reviewed from a prospectively maintained database. Results: A total of 34 patients underwent surgery following RE (21 LR and 13 LT). Clavien-Dindo grade III-IV complications and mortality rates were 19.0% and 9.5% for LR and 7.7% and 0% for LT, respectively. After RE, for HCC and ICC patients in the LR group, 10-year OS rates were 57% and 60%, and 10-year DFS rates were 43.1% and 60%, respectively. For HCC patients in the LT group, 10-year OS and DFS rates from RE were 51.3% and 43.3%, respectively. Conclusion: Liver resection after RE is safe and feasible with optimal short-term outcomes. Patients diagnosed with unresectable or high biological risk HCC or ICC, treated with RE, and rescued by LR may achieve optimal global and DFS rates. On the other hand, bridging or downstaging strategies to LT with RE in HCC patients show adequate recurrence rates as well as long-term survival.