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1.
Clin Gastroenterol Hepatol ; 22(9): 1774-1789.e8, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38604295

RESUMO

Hepatocellular carcinoma (HCC) typically develops as a consequence of liver cirrhosis, but HCC epidemiology has evolved drastically in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis, has emerged as the most common chronic liver disease worldwide and a leading cause of HCC. A substantial proportion of MASLD-associated HCC (MASLD-HCC) also can develop in patients without cirrhosis. The specific pathways that trigger carcinogenesis in this context are not elucidated completely, and recommendations for HCC surveillance in MASLD patients are challenging. In the era of precision medicine, it is critical to understand the processes that define the profiles of patients at increased risk of HCC in the MASLD setting, including cardiometabolic risk factors and the molecular targets that could be tackled effectively. Ideally, defining categories that encompass key pathophysiological features, associated with tailored diagnostic and treatment strategies, should facilitate the identification of specific MASLD-HCC phenotypes. In this review, we discuss MASLD-HCC, including its epidemiology and health care burden, the mechanistic data promoting MASLD, metabolic dysfunction-associated steatohepatitis, and MASLD-HCC. Its natural history, prognosis, and treatment are addressed specifically, as the role of metabolic phenotypes of MASLD-HCC as a potential strategy for risk stratification. The challenges in identifying high-risk patients and screening strategies also are discussed, as well as the potential approaches for MASLD-HCC prevention and treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Fenótipo , Humanos , Carcinoma Hepatocelular/epidemiologia , Neoplasias Hepáticas/epidemiologia , Fígado Gorduroso/complicações
2.
Gastroenterology ; 164(1): 72-88.e18, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36108710

RESUMO

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Biomarcadores
3.
Lancet Oncol ; 24(12): 1411-1422, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37951222

RESUMO

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. Finally, 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 r=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. FUNDING: Institut National du Cancer, Fondation ARC, China Scholarship Council, Ligue Contre le Cancer du Val de Marne, Fondation de l'Avenir, Ipsen, and Fondation Bristol Myers Squibb Pour la Recherche en Immuno-Oncologie.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Adolescente , Adulto , Feminino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inteligência Artificial , Bevacizumab/uso terapêutico , Biomarcadores , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Estudos Retrospectivos
4.
J Hepatol ; 75(4): 865-878, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33992698

RESUMO

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. METHODS: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. RESULTS: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-ß proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. CONCLUSIONS: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. LAY SUMMARY: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.


Assuntos
Carcinoma Hepatocelular/genética , Biologia Molecular/estatística & dados numéricos , Hepatopatia Gordurosa não Alcoólica/genética , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/etiologia , Feminino , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Biologia Molecular/métodos , Hepatopatia Gordurosa não Alcoólica/complicações , Fatores de Risco
5.
J Hepatol ; 72(3): 472-480, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31629779

RESUMO

BACKGROUND & AIMS: It is important to know which patients with hepatitis C are likely to develop liver-related complications after achieving a sustained virological response (SVR) to direct-acting antiviral (DAA) therapy. We aimed to describe the incidence of liver-related events in a population of patients with HCV-associated compensated advanced chronic liver disease (cACLD) who achieved SVR and to identify non-invasive parameters that predict the occurrence of liver-related events. METHODS: This 2-center prospective study included 572 patients with cACLD who had been treated with DAAs and had achieved SVR. Patients had liver stiffness measurement (LSM) ≥10 kPa at baseline and had never decompensated (Child-Pugh class A). Laboratory work-up and LSM were performed at baseline and at 1 year of follow-up. RESULTS: The median follow-up was 2.8 years during which 32 patients (5.6%) presented with a liver-related event. The incidence rate (IR) of portal hypertension-related decompensation was 0.34/100 patient-years. These patients all had baseline LSM >20 kPa, and LSM did not improve during follow-up in 4 out of 5 of them. Hepatocellular carcinoma (HCC) occurred in 25 patients (IR 1.5/100 patient-years). Albumin levels at follow-up (hazard ratio [HR] 0.08; 95% CI 0.02-0.25) and LSM <10 kPa at follow-up (HR 0.33; 95% CI 0.11-0.96) were independently associated with the risk of HCC. Combining both predictors identified 2 groups with differing risk of HCC occurrence: those with LSM ≥20 kPa at follow-up or those with LSM between 10-20 kPa and albumin levels <4.4 g/dl were at the highest risk (IR ≥1.9/100 patient-years). Visual nomograms predicting HCC risk based on LSM and albumin at 1 year of follow-up were constructed. CONCLUSION: In patients with HCV-related cACLD who have achieved SVR with DAAs, HCC is the most frequent liver-related event. Both albumin levels and LSM are useful for stratifying patients based on their risk of developing HCC during follow-up. LAY SUMMARY: New oral antivirals can cure chronic hepatitis C infection, however patients with advanced chronic liver disease are still at risk of presenting with liver-related complications. The most frequent complication after oral antiviral therapy in asymptomatic patients with advanced chronic liver disease was liver cancer. The use of simple parameters such liver stiffness and albumin levels after treatment can help to identify patients at higher or lower risk of liver cancer.


Assuntos
Antivirais/administração & dosagem , Carcinoma Hepatocelular/epidemiologia , Técnicas de Imagem por Elasticidade/métodos , Hepacivirus/genética , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Hipertensão Portal/epidemiologia , Neoplasias Hepáticas/epidemiologia , Albumina Sérica/análise , Administração Oral , Idoso , Feminino , Seguimentos , Hepatite C Crônica/virologia , Humanos , Incidência , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Nomogramas , Estudos Prospectivos , RNA Viral/genética , Medição de Risco , Resposta Viral Sustentada
6.
J Hepatol ; 72(4): 702-710, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31726116

RESUMO

BACKGROUND & AIMS: Fontan surgery is used to treat a variety of congenital heart malformations, and may lead to advanced chronic liver disease in the long-term. This study examines the prevalence, characteristics and predictors of liver nodules in patients following Fontan surgery. METHODS: This was a prospective, cross-sectional, observational study conducted at 8 European centres. Consecutive patients who had undergone Fontan surgery underwent blood tests, abdominal ultrasonography (US), transient elastography (Fibroscan®), echocardiography, haemodynamic assessments, and abdominal MRI/CT scan. The primary outcome measure was liver nodules detected in the MRI/CT scan. Predictors of liver nodules were identified by multivariate logistic regression. RESULTS: One hundred and fifty-two patients were enrolled (mean age 27.3 years). The mean time elapsed from surgery to inclusion was 18.3 years. Liver nodule prevalences were 29.6% (95% CI 23-37%) on US and 47.7% (95% CI 39-56%) on MRI/CT. Nodules were usually hyperechoic (76.5%), round-shaped (>80%), hyperenhancing in the arterial phase (92%) and located in the liver periphery (75%). The sensitivity and specificity of US were 50% (95% CI 38-62%) and 85.3% (95% CI 75-92%), respectively. Inter-imaging test agreement was low (adjusted kappa: 0.34). In the multivariate analysis, time since surgery >10 years was the single independent predictor of liver nodules (odds ratio 4.18; p = 0.040). Hepatocellular carcinoma was histologically diagnosed in 2 of the 8 patients with hypervascular liver nodules displaying washout. CONCLUSION: While liver nodules are frequent in Fontan patients, they may go unnoticed in US. Liver nodules are usually hyperechoic, hypervascular and predominantly peripheral. This population is at risk of hepatocellular carcinoma, the diagnosis of which requires confirmatory biopsy. LAY SUMMARY: Fontan surgery is the standard of care for many patients with univentricular congenital cardiopathies. Recent advances have improved the survival of Fontan patients, and nowadays most of them reach adulthood. In this setting, Fontan-associated liver disease (FALD) is increasingly recognised, and has become a significant prognostic factor. Liver nodules are considered a component of FALD yet their prevalence, imaging features and predictors have hardly been evaluated. In this study, we observed that liver nodules are frequent, typically hyperechoic, hypervascular and predominantly peripheral in patients with FALD. This population is at risk of hepatocellular carcinoma, the diagnosis of which must be confirmed by biopsy.


Assuntos
Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/etiologia , Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/cirurgia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Adulto , Carcinoma Hepatocelular/diagnóstico por imagem , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Masculino , Prevalência , Prognóstico , Estudos Prospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X/métodos , Ultrassonografia/métodos , Adulto Jovem
7.
J Hepatol ; 73(2): 315-327, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32173382

RESUMO

BACKGROUND & AIMS: Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies. METHODS: An integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC. RESULTS: KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFß signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors. CONCLUSION: An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches. LAY SUMMARY: Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Terapia de Alvo Molecular/métodos , Análise de Sequência de DNA/métodos , Transdução de Sinais/genética , Idoso , Antígeno B7-H1/genética , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Estudos de Coortes , Descoberta de Drogas , Europa (Continente)/epidemiologia , Feminino , Estudo de Associação Genômica Ampla/métodos , Fator 4 Nuclear de Hepatócito/genética , Humanos , Imuno-Histoquímica , Masculino , Prognóstico , Receptor de Morte Celular Programada 1/genética , Receptor ErbB-2/genética , Estados Unidos/epidemiologia
8.
Liver Int ; 40(8): 1906-1916, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32329119

RESUMO

BACKGROUND & AIMS: Check point inhibitors (CPI) have improved survival of oncology patients but adverse effects that mimic autoimmune disorders have been reported. Our aim was describe the characteristics of immune-related hepatitis (irH) and prognosis, and compared them to those of patients with autoimmune hepatitis (AIH). METHODS: This is a retrospective study including all grade ≥ 3 (severe) irH diagnosed among 414 patients treated with CPI from 2016 to 2018. RESULTS: Twenty-eight cases of severe irH were recorded: 10 on anti-CTLA-4 ± anti-PD1/PD-L1 and 18 on anti-PD1/PD-L1. Half were female, age 63 years, median time on CPI three cycles. Four (14.3%) presented acute liver injury or failure and one (3.6%) died as consequence. 94% presented normal immunoglobulin G (IgG). Six (21.4%) patients were retreated with CPI and none presented relapse or new immune-related adverse events after a median cycles of 11 (range 6-36). Subjects with irH were older and had lower IgG values than a cohort of AIH (N = 38). Presentation tended to be more severe in AIH. Twenty-five percent of irH and 84% AIH presented ANAs ≥ 1:80 (P = .001). In irH Initial dose of corticosteroids was higher (60 vs 30 mg, P < .001) but duration shorter (2.3 vs 7 months, P < .001) and frequently in monotherapy (41.7% vs 91.3%, P < .001). CONCLUSIONS: Immune-related hepatitis can lead to acute liver failure, with absence of increased values of IgG and ANAs. In contrast to autoimmune hepatitis, initial corticosteroids dose were higher, duration shorter with few requiring additional immunosuppression. Retreatment with CPI was not associated with recurrence.


Assuntos
Hepatite Autoimune , Inibidores de Checkpoint Imunológico , Feminino , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
9.
Liver Int ; 40(6): 1467-1476, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32170821

RESUMO

BACKGROUND & AIMS: Information on safety and efficacy of systemic treatment in patients with hepatocellular carcinoma (HCC) under dialysis are limited due to patient exclusion from clinical trials. Thus, we aimed to evaluate the rate, prevalence, tolerability, and outcome of sorafenib in this population. METHODS: We report a multicenter study comprising patients from Latin America and Europe. Patients treated with sorafenib were enrolled; demographics, dose modifications, adverse events (AEs), treatment duration, and outcome of patients undergoing dialysis were recorded. RESULTS: As of March 2018, 6156 HCC patients were treated in 44 centres and 22 patients were concomitantly under dialysis (0.36%). The median age was 65.5 years, 40.9% had hepatitis C, 75% had Child-Pugh A, and 85% were Barcelona Clinic Liver Cancer-C. The median time to first dose modification, treatment duration and overall survival rate were 2.4 months (interquartile ranges [IQR], 0.8-3.8), 10.8 months (IQR, 4.5-16.9), and 17.5 months (95% CI, 7.2-24.5), respectively. Seventeen patients required at least 1 dose modification. The main causes of first dose modification were asthenia/worsening of Eastern Cooperative Oncology Group-Performance Status and diarrhoea. At the time of death or last follow-up, four patients were still on treatment and 18 had discontinued sorafenib: 14 were due to tumour progression, 2 were sorafenib-related, and 2 were non-sorafenib-related AE. CONCLUSIONS: The outcomes observed in this cohort seem comparable to those in the non-dialysis population. Thus, to the best of our knowledge, this is the largest and most informative dataset regarding systemic treatment outcomes in HCC patients undergoing dialysis.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Europa (Continente) , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Diálise Renal , Sorafenibe/uso terapêutico , Resultado do Tratamento
10.
J Hepatol ; 70(5): 874-884, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30684506

RESUMO

BACKGROUND & AIMS: Despite direct-acting antivirals being highly effective at eradicating hepatitis C virus infection, their impact on the development of hepatocellular carcinoma (HCC) remains controversial. We analyzed the clinical and radiological outcome of cirrhotic patients treated with interferon-free regimens to estimate the risk of developing HCC. METHODS: This was a retrospective multicenter study focusing on cirrhotic patients treated with direct-acting antivirals until December 2016. Clinical and radiologic characteristics were collected before the start of antiviral therapy, at follow-up and at HCC development. Diagnosis of HCC was centrally validated and its incidence was expressed as HCC/100 person-years. RESULTS: A total of 1,123 patients were included (60.6% males, 83.8% Child-Pugh A) and 95.2% achieved a sustained virologic response. Median time of follow-up was 19.6 months. Seventy-two patients developed HCC within a median of 10.3 months after starting antiviral treatment. HCC incidence was 3.73 HCC/100 person-years (95% CI 2.96-4.70). Baseline liver function, alcohol intake and hepatic decompensation were associated with a higher risk of HCC. The relative risk was significantly increased in patients with non-characterized nodules at baseline 2.83 (95% CI 1.55-5.16) vs. absence of non-characterized nodules. When excluding these patients, the risk remained increased. CONCLUSION: These data expose a clear-cut time association between interferon-free treatment and HCC. The mechanisms involved in the increased risk of HCC emergence in the short term require further investigation. LAY SUMMARY: In this cohort of cirrhotic patients, interferon-free therapies achieved a high rate of sustained virologic response (>95%); however, we reported a risk of de novo hepatocellular carcinoma of 3.73 per 100 person-years and a clear-cut time association with antiviral therapy. The time association between starting direct-acting antivirals and developing hepatocellular carcinoma, together with the association with the presence of non-characterized nodules at baseline ultrasound, suggests that antiviral therapy elicits a mechanism (probably immune-related) that primes the growth and clinical recognition of hepatocellular carcinoma early during follow-up. As a result, short-term liver cancer risk is significantly increased.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/etiologia , Hepatite C/tratamento farmacológico , Cirrose Hepática/complicações , Neoplasias Hepáticas/etiologia , Idoso , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Feminino , Hepatite C/complicações , Humanos , Incidência , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resposta Viral Sustentada , Fatores de Tempo
11.
Hepatology ; 67(2): 612-622, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28898447

RESUMO

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. Conclusion: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib. (Hepatology 2018;67:612-622).


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pele/efeitos dos fármacos , Sorafenibe/uso terapêutico , Idoso , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sorafenibe/efeitos adversos , alfa-Fetoproteínas/análise
13.
J Hepatol ; 65(2): 289-95, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27085251

RESUMO

BACKGROUND & AIMS: Codrituzumab, a humanized monoclonal antibody against Glypican-3 (GPC3) that is expressed in hepatocellular carcinoma (HCC), interacts with CD16/FcγRIIIa and triggers antibody-dependent cytotoxicity. Codrituzumab was studied vs. placebo in a randomized phase II trial in advanced HCC patients who had failed prior systemic therapy. METHODS: Patients with advanced HCC who had failed prior systemic therapy, ⩾18years, Eastern cooperative oncology group (ECOG) 0-1, Child-Pugh A were randomized 2:1 to biweekly codrituzumab 1600mg vs. placebo. Patients were stratified based on GPC3 immunohistochemical expression: 2+/3+, 1+, and 0. Primary endpoint was progression free survival. Secondary endpoints include overall survival (OS), tolerability, pharmacokinetics, and an exploratory endpoint in biomarkers analysis. RESULTS: 185 patients were enrolled: 125 received codrituzumab and 60 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 84%/70% had prior sorafenib. Drug exposure was 98.4% of planned dose, with an identical adverse events profile between the 2 groups. The median progression free survival and overall survival in the codrituzumab vs. placebo groups in months were: 2.6 vs. 1.5 (hazard ratios 0.97, p=0.87), and 8.7 vs. 10 (hazard ratios 0.96, p=0.82). Projected Ctrough at cycle 3day 1 based exposure, high CD16/FcγRIIIa on peripheral immune cells, and GPC3 expression in the tumor, were all associated with prolonged progression free survival and overall survival. CONCLUSIONS: Codrituzumab did not show clinical benefit in this previously treated HCC population. Whether higher codrituzumab drug exposure or the use of CD16 and GPC3 as potential biomarkers would improve outcome remain unanswered questions. LAY SUMMARY: Codrituzumab is a manufactured antibody against a liver cancer protein called glypican-3. In this clinical trial, codrituzumab was not found be effective against liver cancer. It was suggested though that a higher dose of codrituzumab or selecting patients with high level of glypican-3 or its mediator CD16 might improve outcome. CLINICAL TRIAL REGISTRATION: This trial is registered at Clinicaltrials.gov (NCT01507168).


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticorpos Monoclonais Humanizados , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Glipicanas , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
16.
Gastroenterology ; 148(4): 806-18.e10, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25557953

RESUMO

BACKGROUND & AIMS: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. METHODS: By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. RESULTS: Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine enriched production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. CONCLUSIONS: In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time.


Assuntos
Carcinoma Hepatocelular/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Adolescente , Adulto , Idoso , Proliferação de Células/genética , Criança , Aberrações Cromossômicas , Análise por Conglomerados , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Variações do Número de Cópias de DNA , Feminino , Genoma , Proteínas de Choque Térmico HSP40/genética , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Adulto Jovem
17.
J Clin Gastroenterol ; 49(2): 165-8, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24637729

RESUMO

Hepatitis E virus (HEV) is responsible for a small number of acute hepatitis in developed countries. In this setting, HEV infection seems to be a zoonosis, although this has not been completely demonstrated. High morbidity and mortality associated with severe acute infections have been described, as well as the possible role of ribavirin therapy in those cases. We describe a case of acute hepatitis after pork meat ingestion in a patient with Waldeström macroglobulinemia with immunoglobulin A deficiency. Acute hepatitis E was diagnosed based on positive IgM anti-HEV antibodies and HEV RNA detected by real-time PCR. Because of clinical and analytical worsening, ribavirin was initiated, achieving sustained virologic response after 12 weeks of treatment. The phylogenetic analysis revealed the same HEV strain genotype 3 in both plasma and consumed meat samples, proving the zoonotic transmission. Regarding immunocompromised patients, acute hepatitis E can be associated to high morbidity and mortality rate, so dietetic recommendations may be needed to avoid the virus transmission.


Assuntos
Microbiologia de Alimentos , Vírus da Hepatite E/genética , Hepatite E/transmissão , Carne/virologia , Filogenia , RNA Viral/genética , Suínos , Zoonoses , Doença Aguda , Idoso , Animais , Antivirais/uso terapêutico , Biomarcadores/sangue , Genótipo , Anticorpos Anti-Hepatite/sangue , Hepatite E/diagnóstico , Hepatite E/tratamento farmacológico , Vírus da Hepatite E/efeitos dos fármacos , Vírus da Hepatite E/imunologia , Humanos , Hospedeiro Imunocomprometido , Masculino , RNA Viral/sangue , Ribavirina/uso terapêutico , Fatores de Risco , Resultado do Tratamento
18.
Gastroenterology ; 144(5): 1024-30, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23333348

RESUMO

BACKGROUND & AIMS: Cirrhosis affects 1% to 2% of the world population and is the major risk factor for hepatocellular carcinoma (HCC). Hepatitis C cirrhosis-related HCC is the most rapidly increasing cause of cancer death in the United States. Noninvasive methods have been developed to identify patients with asymptomatic early-stage cirrhosis, increasing the burden of HCC surveillance, but biomarkers are needed to identify patients with cirrhosis who are most in need of surveillance. We investigated whether a liver-derived 186-gene signature previously associated with outcomes of patients with HCC is prognostic for patients with newly diagnosed cirrhosis but without HCC. METHODS: We performed gene expression profile analysis of formalin-fixed needle biopsy specimens from the livers of 216 patients with hepatitis C-related early-stage (Child-Pugh class A) cirrhosis who were prospectively followed up for a median of 10 years at an Italian center. We evaluated whether the 186-gene signature was associated with death, progression of cirrhosis, and development of HCC. RESULTS: Fifty-five (25%), 101 (47%), and 60 (28%) patients were classified as having poor-, intermediate-, and good-prognosis signatures, respectively. In multivariable Cox regression modeling, the poor-prognosis signature was significantly associated with death (P = .004), progression to advanced cirrhosis (P < .001), and development of HCC (P = .009). The 10-year rates of survival were 63%, 74%, and 85% and the annual incidence of HCC was 5.8%, 2.2%, and 1.5% for patients with poor-, intermediate-, and good-prognosis signatures, respectively. CONCLUSIONS: A 186-gene signature used to predict outcomes of patients with HCC is also associated with outcomes of patients with hepatitis C-related early-stage cirrhosis. This signature might be used to identify patients with cirrhosis in most need of surveillance and strategies to prevent the development of HCC.


Assuntos
DNA/genética , Diagnóstico Precoce , Regulação da Expressão Gênica , Hepatite C Crônica/complicações , Cirrose Hepática/diagnóstico , Fígado/patologia , Transcriptoma/genética , Biópsia por Agulha , Progressão da Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/genética , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Tempo
19.
Cancers (Basel) ; 16(8)2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38672603

RESUMO

BACKGROUND: In the past decades, global changes, including hepatitis B vaccination, hepatitis B and C antiviral therapies, and the increasing prevalence of steatotic liver disease, have influenced the landscape of liver cancer etiologies. METHODS: We performed a retrospective study focused on the etiological factors of de novo hepatocellular carcinoma (HCC) diagnoses in an academic center between 2019 and 2022. RESULTS: Among 352 consecutive patients with HCC, alcohol-related liver disease was the predominant etiology (33.3%), followed by hepatitis C (HCV) infection (30.7%). Significant associations were found between HCC etiology and patient demographics, BCLC stage at diagnosis, and cirrhosis prevalence. CONCLUSIONS: Whereas accessibility to antiviral therapy is granted, HCV infection remains as one of the main HCC etiologies. MASLD-related HCC, although growing globally, is not as relevant in our area. Strong public policies need to be implemented to prevent alcohol consumption, the main etiology of liver disease and liver cancer.

20.
Antioxidants (Basel) ; 13(8)2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39199213

RESUMO

Coenzyme Q10 (CoQ) is a ubiquitous lipid with different biological functions. In blood, there is a close relationship between CoQ status and cholesterol, which strongly supports the study of both molecules simultaneously. The objective of this study was to evaluate plasma CoQ, lipoprotein concentrations and CoQ/Chol ratio in a cohort of paediatric patients with different types of dyslipidaemias. A total of 60 paediatric patients were recruited (age range: 7 months-18 years), including 52 with different types of hypercholesterolemia, 2 with isolated hypertriglyceridemia and 6 with hypobetalipoproteinemia. Plasma CoQ was analysed by HPLC with electrochemical detection, and lipoprotein and cholesterol concentrations by standard automated methods. The lowest CoQ values were detected in patients with hypobetalipoproteinemia and in two cases of liver cirrhosis. Mean CoQ values were significantly higher in hypercholesterolemic patients compared to controls (average values 1.07 µmol/L and 0.63 µmol/L) while the CoQ/cholesterol ratio did not show differences (170 vs. 163, respectively). Mean CoQ values were significantly lower in the group of patients with hypobetalipoproteinemia compared to controls (mean CoQ values of 0.22 µmol/L vs. 0.63 µmol/L, respectively), while those of CoQ/cholesterol did not show differences. Pearson's correlation test showed a positive correlation between the CoQ and cholesterol values (r = 0.565, p < 0.001) and between the CoQ and the LDL cholesterol values (r = 0.610, p < 0.001). Our results suggest that it is advisable to analyse plasma CoQ and cholesterol concentrations in patients with hypobetalipoproteinemia and hypercholesterolemia associated with liver damage.

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