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- New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study(Elsevier B.V., 2024) Latasa, M.U. (María Ujué); Lopez-Pascual, A. (Amaya); Corrales, F.J. (Fernando José); Lucena-Ramírez, J.F. (Juan Felipe); Berasain, C. (Carmen); Arechederra, M. (María); Rotellar, F. (Fernando); Fernández-Barrena, M.G. (Maite G.); Pardo, F. (Fernando); Uriarte, I. (Iker); Irigaray-Miramon, A. (Ainara); Avila, M.A. (Matías Antonio); Sangro, B. (Bruno); Basualdo, J. (Jorge); Monte, M.J. (María J.); Herranz, J.M. (José M.); Merlen, G. (Gregory); Santamaría, E. (Eva); Tordjmann, T. (Thierry); Adán-Villaescusa, E. (Elena); Herrero, I. (Ignacio); Rainteau, D. (Dominique); Argemí, J. (Josepmaria); Marin, J.J.G (Jose J.G.)Background and aims: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. Methods: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. Results: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in shamoperated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. Conclusions: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.
- 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.
- Comprehensive analysis of epigenetic and epitranscriptomic genes’ expression in human NAFLD(Springer, 2023) Latasa, M.U. (María Ujué); Lopez-Pascual, A. (Amaya); Berasain, C. (Carmen); Arechederra, M. (María); Fernández-Barrena, M.G. (Maite G.); Uriarte, I. (Iker); Irigaray-Miramon, A. (Ainara); Avila, M.A. (Matías Antonio); Sangro, B. (Bruno); Herranz, J.M. (José M.); Adán-Villaescusa, E. (Elena); Castelló-Uribe, B. (Borja); Claveria-Cabello, A. (Alex)Non-alcoholic fatty liver disease (NAFLD) is a multifactorial condition with a complex etiology. Its incidence is increasing globally in parallel with the obesity epidemic, and it is now considered the most common liver disease in Western countries. The precise mechanisms underlying the development and progression of NAFLD are complex and still poorly understood. The dysregulation of epigenetic and epitranscriptomic mechanisms is increasingly recognized to play pathogenic roles in multiple conditions, including chronic liver diseases. Here, we have performed a comprehensive analysis of the expression of epigenetic and epitranscriptomic genes in a total of 903 liver tissue samples corresponding to patients with normal liver, obese patients, and patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), advancing stages in NAFLD progression. We integrated ten transcriptomic datasets in an unbiased manner, enabling their robust analysis and comparison. We describe the complete landscape of epigenetic and epitranscriptomic genes’ expression along the course of the disease. We identify signatures of genes significantly dysregulated in association with disease progression, particularly with liver fibrosis development. Most of these epigenetic and epitranscriptomic effectors have not been previously described in human NAFLD, and their altered expression may have pathogenic implications. We also performed a comprehensive analysis of the expression of enzymes involved in the metabolism of the substrates and cofactors of epigenetic and epitranscriptomic effectors. This study provides novel information on NAFLD pathogenesis and may also guide the identification of drug targets to treat this condition and its progression towards hepatocellular carcinoma.
- 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.
- Artificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab–bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study(Elsevier, 2023) Boulagnon-Rombi, C. (Camille); Allende, D.S. (Daniela S.); Zeng, Q. (Qinghe); Campani, C. (Claudia); Baulande, S. (Sylvain); Maille, P. (Pascale); Casadei-Gardini, A. (Andrea); Park, Y.N. (Young Nyun); Iavarone, M. (Massimo); Vij, M. (Mukul); Ningarhari, M. (Massih); Maggioni, M. (Marco); Nault, J.C. (Jean-Charles); Rela, M. (Mohamed); Perbellini, R. (Riccardo); Heurgué, A. (Alexandra); D’Alessio, A. (Antonio); Sangro, B. (Bruno); Bruges, L. (Léa); Pedica, F. (Federica); Iñarrairaegui, M. (Mercedes); Lameiras, S. (Sonia); Rimini, M. (Margherita); Rhee, H. (Hyungjin); Garcia-Porrero, G. (Guillermo); Klein, C. (Christophe); Mínguez, B. (Beatriz); Legoix, P. (Patricia); Argemí, J. (Josepmaria); Caruso, S. (Stefano)Background Clinical benefits of atezolizumab plus bevacizumab (atezolizumab–bevacizumab) are observed only in a subset of patients with hepatocellular carcinoma and the development of biomarkers is needed to improve therapeutic strategies. The atezolizumab–bevacizumab response signature (ABRS), assessed by molecular biology profiling techniques, has been shown to be associated with progression-free survival after treatment initiation. The primary objective of our study was to develop an artificial intelligence (AI) model able to estimate ABRS expression directly from histological slides, and to evaluate if model predictions were associated with progression-free survival. Methods In this multicentre retrospective study, we developed a model (ABRS-prediction; ABRS-P), which was derived from the previously published clustering-constrained attention multiple instance learning (or CLAM) pipeline. We trained the model fit for regression analysis using a multicentre dataset from The Cancer Genome Atlas (patients treated by surgical resection, n=336). The ABRS-P model was externally validated on two independent series of samples from patients with hepatocellular carcinoma (a surgical resection series, n=225; and a biopsy series, n=157). The predictive value of the model was further tested in a series of biopsy samples from a multicentre cohort of patients with hepatocellular carcinoma treated with atezolizumab–bevacizumab (n=122). All samples in the study were from adults (aged ≥18 years). The validation sets were sampled between Jan 1, 2008, to Jan 1, 2023. For the multicentre validation set, the primary objective was to assess the association of high versus low ABRS-P values, defined relative to cross-validation median split thresholds in the first biopsy series, with progression-free survival after treatment initiation. Additionally, we performed spatial transcriptomics and matched prediction heatmaps with in situ expression profiles. Findings Of the 840 patients sampled, 641 (76%) were male and 199 (24%) were female. Across the development and validation datasets, hepatocellular carcinoma risk factors included alcohol intake, hepatitis B and C virus infections, and non-alcoholic steatohepatitis. Using cross-validation in the development series, the mean Pearson’s correlation between ABRS-P values and ABRS score (mean expression of ABRS genes) was 0·62 (SD 0·09; mean p<0·0001, SD<0·0001). The ABRS-P generalised well on the external validation series (surgical resection series, r=0·60 [95% CI 0·51–0·68], p<0·0001; biopsy series, r=0·53 [0·40–0·63], p<0·0001). In the 122 patients treated with atezolizumab–bevacizumab, those with ABRS-P-high tumours (n=74) showed significantly longer median progression-free survival than those with ABRS-P-low tumours (n=48) after treatment initiation (12 months [95% CI 7–not reached] vs 7 months [4–9]; p=0·014). Spatial transcriptomics showed significantly higher ABRS score, along with upregulation of various other immune effectors, in tumour areas with high ABRS-P values versus areas with low ABRS-P values. Interpretation Our study indicates that AI applied on hepatocellular carcinoma digital slides is able to serve as a biomarker for progression-free survival in patients treated with atezolizumab–bevacizumab. This approach could be used in the development of inexpensive and fast biomarkers for targeted therapies. The combination of AI heatmaps with spatial transcriptomics provides insight on the molecular features associated with predictions. This methodology could be applied to other cancers or diseases and improve understanding of the biological mechanisms that drive responses to treatments.
- Segmental Pneumonitis after Radioembolization(Elsevier, 2018) Chopitea, A. (Ana); Páramo-Alfaro, M. (María); Sancho, L. (Lidia); Benito-Boíllos, A. (Alberto); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Bilbao, J.I. (José I.); Rodriguez-Fraile, M. (Macarena)Radiation pneumonitis, although infrequent, is a dreaded complication of radioembolization (RE) with yttrium-90 ( 90 Y) microspheres (1). Only 6 cases have been reported so far (1,2). It develops when 90 Y microspheres reach the lung filter owing to circumvention of the liver sinusoidal network through the tumor or arteriovenous channels. Risk of pneumonitis increases when the lung shunt frac- tion is > 20% or when the estimated absorbed dose by the lungs is > 30 Gy (3). During 90 Y RE, occlusion of extrahepatic arterial branches that feed the tumor from the systemic vasculature is commonly performed with the aim to redistribute tumor afferents and administer the treatment through the hepatic arteries.
- 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.
- 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.
- 3D voxel-based dosimetry to predict contralateral hypertrophy and an adequate future liver remnant after lobar radioembolization(Springer, 2021) Sancho, L. (Lidia); Prieto-Azcárate, E. (Elena); Sangro, B. (Bruno); Iñarrairaegui, M. (Mercedes); Grisanti-Vollbracht, F. (Fabiana); Bastidas, J.F. (Juan Fernando); Bilbao, J.I. (José I.); Rodrigo, P. (Pablo); Rodriguez-Fraile, M. (Macarena); Beorlegui, C. (Carmen)Introduction Volume changes induced by selective internal radiation therapy (SIRT) may increase the possibility of tumor resection in patients with insufficient future liver remnant (FLR). The aim was to identify dosimetric and clinical parameters associated with contralateral hepatic hypertrophy after lobar/extended lobar SIRT with 90Y-resin microspheres. Materials and methods Patients underwent 90Y PET/CT after lobar or extended lobar (right + segment IV) SIRT. 90Y voxel dosimetry was retrospectively performed (PLANET Dose; DOSIsoft SA). Mean absorbed doses to tumoral/non-tumoral-treated volumes (NTL) and dose-volume histograms were extracted. Clinical variables were collected. Patients were stratified by FLR at baseline (T0-FLR): < 30% (would require hypertrophy) and ≥ 30%. Changes in volume of the treated, non-treated liver, and FLR were calculated at < 2 (T1), 2–5 (T2), and 6–12 months (T3) post-SIRT. Univariable and multivariable regression analyses were performed to identify predictors of atrophy, hypertrophy, and increase in FLR. The best cut-off value to predict an increase of FLR to ≥ 40% was defined using ROC analysis. Results Fifty-six patients were studied; most had primary liver tumors (71.4%), 40.4% had cirrhosis, and 39.3% had been previously treated with chemotherapy. FLR in patients with T0-FLR < 30% increased progressively (T0: 25.2%; T1: 32.7%; T2: 38.1%; T3: 44.7%). No dosimetric parameter predicted atrophy. Both NTL-Dmean and NTL-V30 (fraction of NTL exposed to ≥ 30 Gy) were predictive of increase in FLR in patients with T0 FLR < 30%, the latter also in the total cohort of patients. Hypertrophy was not significantly associated with tumor dose or tumor size. When ≥ 49% of NTL received ≥ 30 Gy, FLR increased to ≥ 40% (accuracy: 76.4% in all patients and 80.95% in T0-FLR < 30% patients). Conclusion NTL-Dmean and NTL exposed to ≥ 30 Gy (NTL-V30) were most significantly associated with increase in FLR (particularly among patients with T0-FLR < 30%). When half of NTL received ≥ 30 Gy, FLR increased to ≥ 40%, with higher accuracy among patients with T0-FLR < 30%.
- Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial(Lancet Pub. Group, 2022) Yau, T. (Thomas); El-Khoueiry, A. (Anthony); Edeline, J. (Julien); Chen, G. (Gong); Park, J.W. (Joong-Won); Wyrwicz, L. (Lucjan); Choo, S.P. (Su-Pin); Wisniewski, T. (Tami); Harding, J.J. (James J.); Schott, E. (Eckart); Begic, D. (Damir); Furuse, J. (Junji); Assenat, E. (Eric); Sieghart, W. (Wolfgang); Kate-Kelley, R. (Robin); Sangro, B. (Bruno); Kudo, M. (Masatoshi); Neely, J. (Jaclyn); Zaucha, R. (Renata); Melero, I. (Ignacio); Rosmorduc, O. (Olivier); Merle, P. (Philippe); Tschaika, M. (Marina); Finn, R.S. (Richard S.); Cheng, A.L. (Ann-Lii); Mathurin, P. (Philippe); Abou-Alfa, G.K. (Ghassan K.)Background: Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. Methods: In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Findings: Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. Interpretation: First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.