RESUMEN
Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute the human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored in fibroblast plasticity, with regional relationships to tumor immunity, subtypes, differentiation, and treatment response. "Reactive" subTMEs rich in complex but functionally coordinated fibroblast communities were immune hot and inhabited by aggressive tumor cell phenotypes. The matrix-rich "deserted" subTMEs harbored fewer activated fibroblasts and tumor-suppressive features yet were markedly chemoprotective and enriched upon chemotherapy. SubTMEs originated in fibroblast differentiation trajectories, and transitory states were notable both in single-cell transcriptomics and in situ. The intratumoral co-occurrence of subTMEs produced patient-specific phenotypic and computationally predictable heterogeneity tightly linked to malignant biology. Therefore, heterogeneity within the plentiful, notorious pancreatic TME is not random but marks fundamental tissue organizational units.
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Neoplasias Pancreáticas/patología , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Diferenciación Celular , Proliferación Celular , Epitelio/patología , Matriz Extracelular/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Fenotipo , Células del Estroma/patología , Análisis de Supervivencia , Microambiente Tumoral/inmunologíaRESUMEN
The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
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Rechazo de Injerto , Trasplante de Hígado , Humanos , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Supervivencia de Injerto , AloinjertosRESUMEN
BACKGROUND AND AIMS: Bacterial species and microbial pathways along with metabolites and clinical parameters may interact to contribute to non-alcoholic fatty liver disease (NAFLD) and disease severity. We used integrated machine learning models and a cross-validation approach to assess this interaction in bariatric patients. METHODS: 113 patients undergoing bariatric surgery had clinical and biochemical parameters, blood and stool metabolite measurements as well as faecal shotgun metagenome sequencing to profile the intestinal microbiome. Liver histology was classified as normal liver obese (NLO; n = 30), simple steatosis (SS; n = 41) or non-alcoholic steatohepatitis (NASH; n = 42); fibrosis was graded F0 to F4. RESULTS: We found that those with NASH versus NLO had an increase in potentially harmful E. coli, a reduction of potentially beneficial Alistipes putredinis and an increase in ALT and AST. There was higher serum glucose, faecal 3-(3-hydroxyphenyl)-3-hydroxypropionic acid and faecal cholic acid and lower serum glycerophospholipids. In NAFLD, those with severe fibrosis (F3-F4) versus F0 had lower abundance of anti-inflammatory species (Eubacterium ventriosum, Alistipes finegoldii and Bacteroides dorei) and higher AST, serum glucose, faecal acylcarnitines, serum isoleucine and homocysteine as well as lower serum glycerophospholipids. Pathways involved with amino acid biosynthesis and degradation were significantly more represented in those with NASH compared to NLO, with severe fibrosis having an overall stronger significant association with Superpathway of menaquinol-10 biosynthesis and Peptidoglycan biosynthesis IV. CONCLUSIONS: In bariatric patients, NASH and severe fibrosis were associated with specific bacterial species, metabolic pathways and metabolites that may contribute to NAFLD pathogenesis and disease severity.
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Cirugía Bariátrica , Microbioma Gastrointestinal , Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida , Humanos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Escherichia coli , Hígado/patología , Fibrosis , Metaboloma , Glicerofosfolípidos/metabolismo , Glucosa/metabolismo , Obesidad Mórbida/complicacionesRESUMEN
Integration and mining of bioimaging data remains a challenge and lags behind the rapidly expanding digital pathology field. We introduce Hourglass, an open-access analytical framework that streamlines biology-driven visualization, interrogation, and statistical assessment of multiparametric datasets. Cognizant of tissue and clinical heterogeneity, Hourglass systematically organizes observations across spatial and global levels and within patient subgroups. Applied to an extensive bioimaging dataset, Hourglass promptly consolidated a breadth of known interleukin-6 (IL-6) functions via its downstream effector STAT3 and uncovered a so-far unknown sexual dimorphism in the IL-6/STAT3-linked intratumoral T-cell response in human pancreatic cancer. As an R package and cross-platform application, Hourglass facilitates knowledge extraction from multi-layered bioimaging datasets for users with or without computational proficiency and provides unique and widely accessible analytical means to harness insights hidden within heterogeneous tissues at the sample and patient level. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Interleucina-6 , Neoplasias Pancreáticas , Humanos , Interleucina-6/genética , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Fenotipo , Reino Unido , Factor de Transcripción STAT3/genéticaRESUMEN
BACKGROUND: Systemic inflammatory scores may aid prognostication and patient selection for trials. We compared five scores in advanced pancreatic adenocarcinoma (PDAC). METHODS: Unresectable/metastatic PDAC patients enrolled in the Comprehensive Molecular Characterisation of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selection trial (NCT02750657) were included. Patients had pre-treatment biopsies for whole genome and RNA sequencing. CD8 immunohistochemistry was available in a subset. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, Prognostic Nutritional Index, Gustave Roussy Immune Score (GRIm-S), and Memorial Sloan Kettering Prognostic Score (MPS) were calculated. Overall survival (OS) was estimated using Kaplan-Meier methods. Associations between inflammatory scores, clinical/genomic characteristics, and OS were analysed. RESULTS: We analysed 263 patients. High-risk NLR, GRIm-S and MPS were poorly prognostic. The GRIm-S had the highest predictive ability: median OS 6.4 vs. 10 months for high risk vs. low-risk (P < 0.001); HR 2.26 (P < 0.001). ECOG ≥ 1, the basal-like subtype, and low-HRDetect were additional poor prognostic factors (P < 0.01). Inflammatory scores did not associate with RNA-based classifiers or homologous recombination repair deficiency genotypes. High-risk MPS (P = 0.04) and GRIm-S (P = 0.02) patients had lower median CD8 + tumour-infiltrating lymphocytes. CONCLUSIONS: Inflammatory scores incorporating NLR have prognostic value in advanced PDAC. Understanding immunophenotypes of poor-risk patients and using these scores in trials will advance the field.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patología , Pronóstico , Adenocarcinoma/genética , Adenocarcinoma/patología , Linfocitos/patología , Neutrófilos/patología , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
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Carcinoma Ductal Pancreático/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Pancreáticas/genética , Reparación del ADN por Recombinación , Anciano , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/terapia , Cisplatino/administración & dosificación , Proteínas de Unión al ADN/genética , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Femenino , Fluorouracilo/uso terapéutico , Inestabilidad Genómica , Mutación de Línea Germinal , Recombinación Homóloga , Humanos , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/uso terapéutico , Pancreatectomía , Neoplasias Pancreáticas/terapia , Pronóstico , Sensibilidad y Especificidad , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genética , Secuenciación Completa del Genoma , GemcitabinaRESUMEN
BACKGROUND: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance. METHODS: A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months. RESULTS: Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. One patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole-genome sequencing of this patient's PC and of a second patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the malignant transformation of an underlying BD-IPMN in <6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN that harbored polyclonal KRAS mutations. CONCLUSIONS: PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Carcinoma , Carcinoma Ductal Pancreático/patología , Humanos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Síndrome , Neoplasias PancreáticasRESUMEN
Patients with primary sclerosing cholangitis (PSC) constitute 5 to 15% of patients listed for liver transplantation worldwide. Although post-transplant outcomes are favorable, recurrent PSC (rPSC) occurs in an important subset of patients, with higher prevalence rates reported with increasing time from transplant. Given its association with poor graft outcomes and risk of retransplant, effort has been made to understand rPSC, its pathophysiology, and risk factors. This review covers these facets of rPSC and focuses on implicated risk factors including pretransplant recipient characteristics, inflammatory bowel-disease-related factors, and donor-specific and transplant-specific factors. Confirming a diagnosis of rPSC requires thoughtful consideration of alternative etiologies so as to ensure confidence in diagnosis, management, subsequent risk assessment, and counseling for patients. Unfortunately, no cure exists for rPSC; however, future large-scale efforts are underway to better characterize the natural history of rPSC and its associated risk factors with hopes of identifying potential key targets for novel therapies.
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Colangitis Esclerosante , Trasplante de Hígado , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/epidemiología , Colangitis Esclerosante/terapia , Humanos , Trasplante de Hígado/efectos adversos , Recurrencia , Factores de Riesgo , Donantes de TejidosRESUMEN
OBJECTIVE: To prospectively compare the diagnostic performance of gadoxetic acid-enhanced MRI (EOB-MRI) and contrast-enhanced CT (CECT) for preoperative detection of colorectal liver metastases (CRLM) following chemotherapy and to evaluate the potential change in the hepatic resection plan. METHODS: 51 patients with CRLM treated with preoperative chemotherapy underwent liver imaging by EOB-MRI and CECT prospectively. Two independent blinded readers characterized hepatic lesions on each imaging modality using a 5-point scoring system. 41 patients underwent hepatic resection and histopathological evaluation. RESULTS: 151 CRLM were confirmed by histology. EOB-MRI, compared to CECT, had significantly higher sensitivity in detection of CRLM ≤1.0 cm (86% vs. 45.5%; p < 0.001), significantly lower indeterminate lesions diagnosis (7% vs. 33%; p < 0.001) and significantly higher interobserver concordance rate in characterizing the lesions ≤1.0 cm (72% vs. 51%; p = 0.041). The higher yield of EOB-MRI could have changed the surgical plan in 45% of patients. CONCLUSION: Following preoperative chemotherapy, EOB-MRI is superior to CECT in detection of small CRLM (≤1 cm) with significantly higher sensitivity and diagnostic confidence and interobserver concordance in lesion characterization. This improved diagnostic performance can alter the surgical plan in almost half of patients scheduled for liver resection.
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Neoplasias Colorrectales/patología , Medios de Contraste/administración & dosificación , Hepatectomía , Ácido Yotalámico/análogos & derivados , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Imagen por Resonancia Magnética , Tomografía Computarizada Multidetector , Terapia Neoadyuvante , Ácidos Triyodobenzoicos/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Quimioterapia Adyuvante , Toma de Decisiones Clínicas , Femenino , Gadolinio DTPA , Humanos , Ácido Yotalámico/administración & dosificación , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Carga TumoralRESUMEN
UNLABELLED: In nonalcoholic fatty liver disease, hepatic gene expression and fatty acid (FA) composition have been reported independently, but a comprehensive gene expression profiling in relation to FA composition is lacking. The aim was to assess this relationship. In a cross-sectional study, hepatic gene expression (Illumina Microarray) was first compared among 20 patients with simple steatosis (SS), 19 with nonalcoholic steatohepatitis (NASH), and 24 healthy controls. The FA composition in hepatic total lipids was compared between SS and NASH, and associations between gene expression and FAs were examined. Gene expression differed mainly between healthy controls and patients (SS and NASH), including genes related to unsaturated FA metabolism. Twenty-two genes were differentially expressed between NASH and SS; most of them correlated with disease severity and related more to cancer progression than to lipid metabolism. Biologically active long-chain polyunsaturated FAs (PUFAs; eicosapentaenoic acid + docosahexaenoic acid, arachidonic acid) in hepatic total lipids were lower in NASH than in SS. This may be related to overexpression of FADS1, FADS2, and PNPLA3. The degree and direction of correlations between PUFAs and gene expression were different among SS and NASH, which may suggest that low PUFA content in NASH modulates gene expression in a different way compared with SS or, alternatively, that gene expression influences PUFA content differently depending on disease severity (SS versus NASH). CONCLUSION: Well-defined subjects with either healthy liver, SS, or NASH showed distinct hepatic gene expression profiles including genes involved in unsaturated FA metabolism. In patients with NASH, hepatic PUFAs were lower and associations with gene expression were different compared to SS.
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Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-3/genética , Ácidos Grasos Omega-6/sangre , Ácidos Grasos Omega-6/genética , Regulación de la Expresión Génica , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Adulto , Estudios Transversales , delta-5 Desaturasa de Ácido Graso , Femenino , Humanos , MasculinoRESUMEN
UNLABELLED: Despite evidence that the intestinal microbiota (IM) is involved in the pathogenesis of obesity, the IM composition of patients with nonalcoholic fatty liver disease (NAFLD) has not been well characterized. This prospective, cross-sectional study was aimed at identifying differences in IM between adults with biopsy-proven NAFLD (simple steatosis [SS] or nonalcoholic steatohepatitis [NASH]) and living liver donors as healthy controls (HC). Fifty subjects were included: 11 SS, 22 NASH, and 17 HC. One stool sample was collected from each participant. Quantitative real-time polymerase chain reaction was used to measure total bacterial counts, Bacteroides/Prevotella (herein referred to as Bacteroidetes), Clostridium leptum, C. coccoides, bifidobacteria, Escherichia coli and Archaea in stool. Clinical and laboratory data, food records, and activity logs were collected. Patients with NASH had a lower percentage of Bacteroidetes (Bacteroidetes to total bacteria counts) compared to both SS and HC (P = 0.006) and higher fecal C. coccoides compared to those with SS (P = 0.04). There were no differences in the remaining microorganisms. As body mass index (BMI) and dietary fat intake differed between the groups (P < 0.05), we performed linear regression adjusting for these variables. The difference in C. coccoides was no longer significant after adjusting for BMI and fat intake. However, there continued to be a significant association between the presence of NASH and lower percentage Bacteroidetes even after adjusting for these variables (P = 0.002; 95% confidence interval = -0.06 to -0.02). CONCLUSION: There is an inverse and diet-/BMI-independent association between the presence of NASH and percentage Bacteroidetes in the stool, suggesting that the IM may play a role in the development of NAFLD.
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Hígado Graso/microbiología , Intestinos/microbiología , Metagenoma , Adulto , Anciano , Índice de Masa Corporal , Estudios Transversales , Dieta , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico , Obesidad/microbiologíaRESUMEN
OBJECTIVE: Both Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) are effective at inducing weight loss, but more information is needed on their comparative effectiveness at improving clinical/biochemical outcomes related to the presence of hyperlipidemia, metabolic dysfunction-associated steatotic liver disease (MASLD), or type 2 diabetes (T2D) at baseline. Here we aimed to assess this in real-world practice. METHODS: This is a prospective cross-sectional and cohort study of 142 patients who underwent RYGB or LSG as per clinical practice. Clinical/biochemical data were collected at baseline, prior to surgery and 12 months post-bariatric surgery. Liver biopsy was performed during surgery to diagnose MASLD. The main outcome was 12-month changes in lipid parameters, mainly total cholesterol, between types of surgery. RESULTS: A TOTAL OF: 107 participants underwent RYGB and 35 underwent LSG. Both groups were similar at baseline except for a higher proportion of males and waist circumference in the LSG group. At 12 months postsurgery, RYGB versus LSG resulted in a significantly lower body mass index, triglycerides, total cholesterol, and low-density lipoprotein. However, alanine aminotransferase was significantly lower in those who underwent LSG. In subgroup analyses RYGB was superior at improving lipid-related parameters in those with hyperlipidemia, whereas LSG was superior at reducing alanine aminotransferase in those with MASLD. CONCLUSIONS: RYGB versus LSG leads to greater reductions in body mass index and lipid parameters, especially in those with hyperlipidemia, whereas LSG showed greater improvements in liver enzymes in those with MASLD.
RESUMEN
PURPOSE: Liver biopsy (LBx) remains the gold standard to assess fibrosis in non-alcoholic fatty liver disease (NAFLD). Biochemical markers are also useful, but their reliability is not clear in patients with morbid obesity. We assessed the performance of six non-invasive fibrosis assessment tools before and after bariatric surgery (BSx) using LBx. MATERIALS AND METHODS: This is a cross-sectional and prospective cohort study. LBx was performed at the time of BSx and 12-month post-operatively and assessed using the Brunt system. Clinical and biochemical measurements were collected at the same time points and six non-invasive fibrosis assessment tools were calculated. RESULTS: One hundred seventy patients had BSx; 79.4% female; age was 46.6 ± 9.8 years, and BMI was 48.6 ± 7.5 kg/m2. From liver histology, 88% had F0-F2 and 11.2% F3-F4. At BSx, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 had better accuracy (0.86 and 0.88) with specificity of 96.6% and 94.0% and negative predictive values (NPV) of 88.9% and 93.7%. However, sensitivity (6.7% and 40.0%) and positive predictive values (PPV) (20.0% and 46.2%) were low. Twelve months post-surgery (n = 54), 88.9% of patients had F0-F2 and 11.1% had F3-F4. Fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) had the best accuracy (0.79 and 0.77) with specificity of 83.7% and 86.9% and NPV of 92.3% and 86.9%. However, sensitivity (25% and 0%) and PPV (12.5% and 0%) were low. CONCLUSION: Overall, FIB-4, APRI, and NFS showed similar performances with higher accuracy, specificity, and NPV. Sensitivity and PPV were low. These tests are more useful at excluding advanced fibrosis.
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Cirugía Bariátrica , Enfermedad del Hígado Graso no Alcohólico , Obesidad Mórbida , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Enfermedad del Hígado Graso no Alcohólico/patología , Cirrosis Hepática/cirugía , Cirrosis Hepática/patología , Estudios Prospectivos , Estudios Transversales , Reproducibilidad de los Resultados , Obesidad Mórbida/cirugía , Hígado/patología , Fibrosis , Biopsia , Aspartato AminotransferasasRESUMEN
BACKGROUND: We aimed to prospectively compare the diagnostic performance of gadoxetic acid-enhanced MRI (EOB-MRI) and contrast-enhanced Computed Tomography (CECT) for hepatocellular carcinoma (HCC) detection and liver transplant (LT) eligibility assessment in cirrhotic patients with explant histopathology correlation. METHODS: In this prospective, single-institution ethics-approved study, 101 cirrhotic patients were enrolled consecutively from the pre-LT clinic with written informed consent. Patients underwent CECT and EOB-MRI alternately every 3 months until LT or study exclusion. Two blinded radiologists independently scored hepatic lesions on CECT and EOB-MRI utilizing the liver imaging reporting and data system (LI-RADS) version 2018. Liver explant histopathology was the reference standard. Pre-LT eligibility accuracies with EOB-MRI and CECT as per Milan criteria (MC) were assessed in reference to post-LT explant histopathology. Lesion-level and patient-level statistical analyses were performed. RESULTS: Sixty patients (49 men; age 33-72 years) underwent LT successfully. One hundred four non-treated HCC and 42 viable HCC in previously treated HCC were identified at explant histopathology. For LR-4/5 category lesions, EOB-MRI had a higher pooled sensitivity (86.7% versus 75.3%, p < 0.001) but lower specificity (84.6% versus 100%, p < 0.001) compared to CECT. EOB-MRI had a sensitivity twice that of CECT (65.9% versus 32.2%, p < 0.001) when all HCC identified at explant histopathology were included in the analysis instead of imaging visible lesions only. Disregarding the hepatobiliary phase resulted in a significant drop in EOB-MRI performance (86.7 to 72.8%, p < 0.001). EOB-MRI had significantly lower pooled sensitivity and specificity versus CECT in the LR5 category with lesion size < 2 cm (50% versus 79%, p = 0.002 and 88.9% versus 100%, p = 0.002). EOB-MRI had higher sensitivity (84.8% versus 75%, p < 0.037) compared to CECT for detecting < 2 cm viable HCC in treated lesions. Accuracies of LT eligibility assessment were comparable between EOB-MRI (90-91.7%, p = 0.156) and CECT (90-95%, p = 0.158). CONCLUSION: EOB-MRI had superior sensitivity for HCC detection; however, with lower specificity compared to CECT in LR4/5 category lesions while it was inferior to CECT in the LR5 category under 2 cm. The accuracy for LT eligibility assessment based on MC was not significantly different between EOB-MRI and CECT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03342677 , Registered: November 17, 2017.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Hepatocelular/patología , Medios de Contraste , Gadolinio DTPA , Cirrosis Hepática , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: Non-alcoholic fatty liver disease is highly prevalent in the bariatric population but not all patients develop liver fibrosis. Considering that fibrosis may affect clinical outcomes, it is important to assess and treat contributing factors. In this population, it is not clear whether dietary intake is a contributor. The objective was to determine the relationship between dietary intake components and liver fibrosis before and 1 y after Roux-en-Y gastric bypass (RYGB). METHODS: This was a prospective cross-sectional (n = 133) study conducted between 2013 and 2022. In addition, a subgroup of 44 patients were followed for 1 y post-RYGB. Anthropometrics, biochemical measurements, and 3-d food records and liver biopsies were obtained presurgery and, in a subgroup of patients, as for the cohort, 1 y post-RYGB. RESULTS: In the cross-sectional study, 78.2% were female, with a median age of 48 y and body mass index of 46.8 kg/m2; 33.8% had type 2 diabetes mellitus and 57.1% had metabolic syndrome. In a multivariate analysis, age (odds ratio; 95% CI) (1.076; 1.014-1.141), alanine transaminase (1.068; 1.025-1.112), calorie intake (1.001; 1.000-1.002), and dietary copper (0.127; 0.022-0.752) were independently associated with fibrosis (<0.05). At 1 y post-RYGB, no independent risk factors were associated with persistent fibrosis. CONCLUSIONS: In bariatric patients before surgery, higher age, alanine transaminase, and total calorie and lower copper intakes were independent risk factors associated with liver fibrosis. These relationships were no longer observed after RYGB, likely due to the effect of surgery on weight and similar postsurgery diet among patients.
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Cirugía Bariátrica , Diabetes Mellitus Tipo 2 , Derivación Gástrica , Obesidad Mórbida , Humanos , Femenino , Masculino , Estudios Transversales , Diabetes Mellitus Tipo 2/etiología , Alanina Transaminasa , Estudios Prospectivos , Cobre , Obesidad/etiología , Cirugía Bariátrica/efectos adversos , Derivación Gástrica/efectos adversos , Cirrosis Hepática/etiología , Cirrosis Hepática/cirugía , Ingestión de Alimentos , Obesidad Mórbida/complicaciones , Obesidad Mórbida/cirugíaRESUMEN
PURPOSE: Obesity can be associated with chronic inflammation and dysregulated expression of inflammatory adipokines that contribute to insulin resistance and type 2 diabetes. This may also affect the clinical response to bariatric surgery. Our objective was whether baseline visceral adipose tissue features and plasma adipokine are associated with HbA1c ≥0.06 at the time of Roux-en-Y gastric bypass (RYGB) surgery and with persistently elevated HbA1c at 12 months post-RYGB. METHODS: During the surgery, adipose biopsies and plasma were collected for adipokine/cytokine profile. Clinical and biochemical measurements were also collected at the time of RYGB and, in those with baseline elevated HbA1c, at 12 months post-RYGB. RESULTS: In the cross-sectional study, 109 patients (82.6% female; age 49 years; BMI 46.98 kg/m2) participated. Of those with elevated HbA1c at baseline (n = 61), 47 patients had repeated measurements at 12 months post-RYGB (23% drop-out). Using a multivariate logistic regression model, older age (adjusted odds ratio (aOR), 1.14; 95% confidence interval (CI), 1.06-1.22) and higher plasma resistin (aOR, 5.30; 95% CI, 1.25-22.44) were associated with higher odds of HbA1c ≥ 0.06, whereas higher plasma adiponectin (aOR, 0.993; 95% CI, 0.99-0.996) was associated with lower odds of HbA1c ≥0.06. In addition, baseline higher average adipose cell area (aOR, 1.0017; 95% CI, 1.0002-1.0032) and plasma resistin (aOR, 1.0004; 95% CI, 1.0000-1.0009) were associated with higher odds of having persistently elevated HbA1c at 12 months post-RYGB. CONCLUSION: Our study suggests that baseline plasma adipokine dysregulation, specifically high resistin, and adipocyte hypertrophy may affect the clinical response to RYGB.
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Cirugía Bariátrica , Diabetes Mellitus Tipo 2 , Derivación Gástrica , Obesidad Mórbida , Humanos , Femenino , Persona de Mediana Edad , Masculino , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Obesidad Mórbida/cirugía , Hemoglobina Glucada , Resistina/metabolismo , Estudios de Cohortes , Obesidad/cirugía , Tejido Adiposo/metabolismo , AdipoquinasRESUMEN
AIMS: The majority of pancreatic ductal adenocarcinomas (PDACs) harbour oncogenic mutations in KRAS with variants in TP53, CDKN2A and SMAD4 also prevalent. The presence of oncogenic fusions including NTRK fusions are rare but important to identify. Here we ascertain the prevalence of NTRK fusions and document their genomic characteristics in a large series of PDAC. METHODS: Whole genome sequencing and RNAseq were performed on a series of patients with resected or locally advanced/metastatic PDAC collected between 2008 and 2020 at a single institution. A subset of specimens underwent immunohistochemistry (IHC) analysis. Clinical and molecular characterisation and IHC sensitivity and specificity were evaluated. RESULTS: 400 patients were included (resected n=167; locally advanced/metastatic n=233). Three patients were identified as harbouring an NTRK fusion, two EML4-NTRK3 (KRAS-WT) and a single novel KANK1-NTRK3 fusion. The latter occurring in the presence of a subclonal KRAS mutation. Typical PDAC drivers were present including mutations in TP53 and CDKN2A. Substitution base signatures and tumour mutational burden were similar to typical PDAC. The prevalence of NTRK fusions was 0.8% (3/400), while in KRAS wild-type tumours, it was 6.25% (2/32). DNA prediction alone documented six false-positive cases. RNA analysis correctly identified the in-frame fusion transcripts. IHC analysis was negative in the KANK1-NTRK3 fusion but positive in a EML4-NTRK3 case, highlighting lower sensitivity of IHC. CONCLUSION: NTRK fusions are rare; however, with emerging therapeutic options targeting these fusions, detection is vital. Reflex testing for KRAS mutations and subsequent RNA-based screening could help identify these cases in PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Mutación , Proteínas de Fusión Oncogénica/genética , Proteínas del Citoesqueleto/genética , Proteínas Adaptadoras Transductoras de Señales , Neoplasias PancreáticasRESUMEN
Patients with autoimmune hepatitis (AIH) who have antibodies against mitochondrial proteins (AMA positive) are believed to have an autoimmune syndrome that should be managed as AIH. Of patients with AMA-positive AIH, we report on 3 individuals to demonstrate how autoimmune liver disease can progress over time. Specific features of primary biliary cirrhosis (PBC) overlapped in time in these patients. Our observations indicate the importance of careful follow up of patients with AMA-positive AIH; health care professionals that treat such patients should therefore be aware of longitudinal clinical changes that might indicate development of PBC in this setting.
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Anticuerpos/sangre , Hepatitis Autoinmune/complicaciones , Cirrosis Hepática Biliar/diagnóstico , Mitocondrias/inmunología , Anciano , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Histocitoquímica , Humanos , Inmunohistoquímica , Hígado/patología , Microscopía , Persona de Mediana EdadRESUMEN
OBJECTIVE: Non-alcoholic fatty liver disease is a leading cause of liver disease worldwide and includes nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis. Because NASH is associated with obesity severity, routine evaluation of obesity/body fat in clinical settings may help detect patients at risk. The aim of this study was to determine whether assessing body fat by bioelectrical impedance analysis (BIA) is superior to body mass index (BMI) and waist circumference (WC) in assessing the risk for NASH. METHODS: In this cross-sectional study, patients were recruited and gave consent from a local hospital. All had a liver biopsy. Measurements before the biopsy included BMI, WC, and BIA. BIA was used to measure percentage body fat and fat mass (kg). Based on histology, patients were grouped into one of three categories: simple steatosis (SS), NASH, or normal liver (NL). RESULTS: Of the 139 participants who participated, 39 were classified as SS, 53 as NASH, and 47 as NL. Regardless of sex, patients with NASH had significantly higher BMI, WC, percentage body fat and fat mass than those with NL or SS. These four parameters were significantly positively correlated with liver histology measurements. In all patients, when controlling for sex and age we found that BMI, WC, and BIA were equal at predicting the presence of NASH (P = 0.0571). CONCLUSION: All three methods, BIA, BMI, and WC, were comparable in assessing the risk for NASH. For practical purpose in clinical settings, using BMI is acceptable.
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Enfermedad del Hígado Graso no Alcohólico , Índice de Masa Corporal , Estudios Transversales , Impedancia Eléctrica , Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Circunferencia de la CinturaRESUMEN
OBJECTIVES: To compare the diagnostic performance of international hepatocellular carcinoma (HCC) guidelines with gadoxetic acid-enhanced MRI (EOB-MRI) and contrast-enhanced Computed tomography (CECT) and their impact on liver transplant (LT) allocation in cirrhotic patients with explant histopathology correlation. METHODS: In this prospective single-centre ethics-approved study, 101 cirrhotic patients were consecutively enrolled with informed consent from the pre-LT clinic. They underwent CECT and EOB-MRI alternately at three monthly intervals until LT or removal from LT list. Two abdominal radiologists, blinded to explant histopathology, independently recorded liver lesions visible on CECT and EOB-MRI. Imaging-based HCC scores were assigned to non-treated liver lesions utilizing Liver Imaging Reporting and Data System (LI-RADS), European Association for the Study of the Liver (EASL), Asian-Pacific Association for the Study of the Liver (APASL) and Korean Liver Cancer Association-National Cancer Center (KLCA) guidelines. Liver explant histopathology was the reference standard. Simulated LT eligibility was assessed as per Milan criteria (MC) in reference to explant histopathology. RESULTS: One hundred and three non-treated HCC and 12 non-HCC malignancy were identified at explant histopathology in 34 patients (29 men, 5 women, age 55-73 years). Higher HCC sensitivities of statistical significance were observed with EOB-MRI for LI-RADS 4 + 5, APASL and KLCA compared to LI-RADS 5 and EASL with greatest sensitivity obtained for LIRADS 4 + 5 lesions. HCC sensitivities by all guidelines with both EOB-MRI and CECT were significantly lower if all histopathology-detected HCCs were included in the analysis, compared to imaging-visible lesions only. A significantly greater variation in HCC sensitivity was noted across the guidelines with EOB-MRI compared to CECT. No significant differences in simulated LT eligibility based on MC were observed across the HCC scoring guidelines with EOB-MRI or CECT. CONCLUSION: HCC sensitivities are variable depending on scoring guideline, lesion size and imaging modality utilised. Prior studies that included only lesions visible on pre-operative imaging overestimate the diagnostic performance of HCC scoring guidelines. Per-lesion differences in HCC diagnosis across these guidelines did not impact patient-level LT eligibility based on MC.