RESUMO
BACKGROUND AND AIMS: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis. APPROACH AND RESULTS: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12). CONCLUSIONS: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis.
Assuntos
Antivirais , Hepatite D Crônica , Vírus Delta da Hepatite , Cirrose Hepática , Uso Off-Label , Humanos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Cirrose Hepática/tratamento farmacológico , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Hepatite D Crônica/tratamento farmacológico , Hepatite D Crônica/complicações , Adulto , Idoso , Resultado do TratamentoRESUMO
Immunotherapy has become the standard of care in advanced HCC but is only approved in first- or second-line treatment. We report a patient with HCC refractory to several lines of tyrosine kinase inhibitors, who was treated with Ipilimumab and Nivolumab (Ipi/Nivo) as the fourth line. The tumor responded profoundly to Ipi/Nivo. Established biomarker-predicting responses to immunotherapy, such as a high PD-L1 staining, a high combined-positive score, microsatellite instability or a high tumor mutational burden, were not detected. Potential negative predictive markers for response to immunotherapy such as CTNNB1 and TERT were present. This constellation puts the spotlight on two mutations observed here in the SET domain-containing 2 (SETD2) and low-density lipoprotein receptor-related protein 1b (LRP1B) genes, which may explain the outstanding response. Our case demonstrates that immunotherapy can be efficient in a late-line scenario, resulting in long-term survival. Further studies should prospectively evaluate the value of SETD2 and LRP1B alterations as predictors for the success of immunotherapy in HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Antígeno CTLA-4/genética , Ipilimumab , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Mutação , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1 , Receptores de LDLRESUMO
BACKGROUND: Due to the number of emerging new treatment options, the systemic treatment of hepatocellular carcinoma (HCC) is rapidly changing. We provide here an overview of the current landscape of systemic treatment of HCC and discuss its potential future development. SUMMARY: HCC is a leading cause of tumor-related death worldwide. Despite the efforts aimed at reducing the prevalence of HCC through vaccination and antiviral treatment, and the implementation of screening programs for early tumor detection, most patients are diagnosed with or progress to advanced HCC. For approximately 10 years, sorafenib has been the only effective systemic treatment available for these patients. Recently, however, a number of new systemic compounds, comprising several multi-kinase inhibitors and immune-checkpoint inhibitors, have been approved for treatment of HCC. These new agents are opening a plethora of therapeutic options for the future therapy of HCC. KEY MESSAGES: The rapid progress in the treatment of HCC raises the question of the optimal combination and sequence of these agents in the treatment of patients with advanced disease. The substantial improvements in terms of objective response and survival indicate that the use of immune-checkpoint inhibitors-based treatment combinations may be extended to patients with intermediate-stage HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/patologia , Humanos , Inibidores de Checkpoint Imunológico , Imunoterapia , Neoplasias Hepáticas/patologia , Sorafenibe/uso terapêuticoRESUMO
The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab + bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase II study is the first trial to evaluate the safety and efficacy of atezolizumab + bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov).
Assuntos
Anticorpos Monoclonais Humanizados , Bevacizumab , Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/métodos , Ensaios Clínicos Fase II como Assunto , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Estudos Multicêntricos como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Recurrent attacks of acute intermittent porphyria (AIP) result in poor quality of life and significant risks of morbidity and mortality. Liver transplantation (LT) offers a cure, but published data on outcomes after LT are limited. We assessed the pretransplant characteristics, complications, and outcomes for patients with AIP who received a transplant. Data were collected retrospectively from the European Liver Transplant Registry and from questionnaires sent to identified transplant and porphyria centers. We studied 38 patients who received transplants in 12 countries from 2002 to 2019. Median age at LT was 37 years (range, 18-58), and 34 (89%) of the patients were women. A total of 9 patients died during follow-up, and 2 patients were retransplanted. The 1-year and 5-year overall survival rates were 92% and 82%, which are comparable with other metabolic diseases transplanted during the same period. Advanced pretransplant neurological impairment was associated with increased mortality. The 5-year survival rate was 94% among 19 patients with moderate or no neuropathy at LT and 83% among 10 patients with severe neuropathy (P = 0.04). Pretransplant renal impairment was common. A total of 19 (51%) patients had a GFR < 60 mL/minute. Although few patients improved their renal function after LT, neurological impairments improved, and no worsening of neurological symptoms was recorded. No patient had AIP attacks after LT, except for a patient who received an auxiliary graft. LT is a curative treatment option for patients with recurrent attacks of AIP. Severe neuropathy and impaired renal function are common and increase the risk for poor outcomes. If other treatment options fail, an evaluation for LT should be performed early.
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Transplante de Fígado , Porfiria Aguda Intermitente , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Masculino , Porfiria Aguda Intermitente/complicações , Qualidade de Vida , Sistema de Registros , Estudos RetrospectivosRESUMO
INTRODUCTION AND OBJECTIVE: Acute cholangitis is a life-threatening condition. The early initiation of antibiotic therapy significantly impacts the course of disease. Only few data are available on distribution and resistance profiles of bile pathogens. Here, we report on an analysis of routinely acquired bile specimens and provide an overview of the prevalence, resistance rates, and risk factors for the presence of pathogens in bile. METHODS: Bile cultures obtained from 388 endoscopic retrograde cholangiographies (ERCs) with corresponding clinical data were analysed in 208 patients. RESULTS: The majority (84.8%) of cultures yielded positive for at least 1 organism. Abundance was highest for Enterococcus faecalis, Enterococcus faecium, and Escherichia coli. Multiresistant organisms were present in 14.9%. The initial antibiotic regimen was changed in 44.1%, which increased the length of hospital stay significantly (***p < 0.001). Pre-existing papillotomy (EPT) or biliary drainage was associated with higher frequency of bile pathogens (**p < 0.01) in a univariate analysis. Multivariate analysis confirmed these results for EPT and revealed significantly more positive results for pathogens, gram-negative bacteria, and fungi in patients with biliary drainage. Significant differences in the prevalence of pathogens were observed between relevant subgroups of ERC indications. The highest susceptibility rates were observed for linezolid and tigecycline in gram-positive bacteria and for meropenem and gentamicin in gram-negative bacteria. CONCLUSIONS: Our study provides a comprehensive analysis of the distribution, resistance profiles, and risk factors for the detection of bile pathogens. The frequent change in initial antibiotic treatment highlights the importance of routine bile culture and indicates that current schemas of empirical treatment might not cover the contemporary spectrum of pathogens in bile.
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Bile/microbiologia , Colangiopancreatografia Retrógrada Endoscópica , Resistência Microbiana a Medicamentos , Antibacterianos/uso terapêutico , Bactérias/isolamento & purificação , Ductos Biliares/cirurgia , Drenagem , Feminino , Fungos/isolamento & purificação , Humanos , Tempo de Internação , Testes de Sensibilidade Microbiana , Prevalência , Fatores de RiscoRESUMO
Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life "American lifestyle-induced obesity syndrome" (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r-/-- but not Il-1r-/- mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
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Interleucina-18/metabolismo , Interleucina-1/metabolismo , Fígado/lesões , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais , Animais , Interleucina-1/genética , Interleucina-18/genética , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-18/genética , Receptores de Interleucina-18/metabolismoRESUMO
Liver cirrhosis is a life-threatening consequence of liver fibrosis. The aim of this study was to investigate the antifibrotic potential of clinically available vitamin D analogs compared to that of calcitriol in vitro and in vivo. Murine hepatic stellate cells, Kupffer cells, and human LX-2 cells were treated with vitamin D analogs, and the profibrotic behavior of these cells was studied. In vivo liver fibrosis was induced using CCl4 until measurable fibrosis was established. Animals were then treated with calcitriol and paricalcitol. Vitamin D and its analogs showed antifibrotic effects in vitro. Treatment with active vitamin D (calcitriol, CAL) and its analogs reduced the protein expression of α-smooth muscle actin (α-SMA) in mHSC. In human LX-2 cells alfacalcidol reduced transforming growth factor-ß (TGF-ß) induced platelet-derived growth factor receptor-ß protein expression and contractility while paricalcitol (PCT), in its equipotent dose to CAL, reduced TGF-ß induced α-SMA protein expression, and ACTA2 and TGF-ß mRNA expression. No effects of a treatment with vitamin D and its analogs were observed in Kupffer cells. In vivo, PCT-treated mice had significantly lower calcium levels than CAL-treated mice. CAL and PCT reduced the hepatic infiltration of CD11b-positive cells and alanine transaminase levels, while PCT but not CAL significantly inhibited fibrosis progression, with a favorable side effect profile in the CCl4 model. We conclude that hypocalcemic vitamin D analogs should be considered in future studies investigating vitamin D for the treatment of liver fibrosis.
Assuntos
Ergocalciferóis/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Animais , Calcitriol/farmacologia , Calcitriol/uso terapêutico , Cálcio/sangue , Tetracloreto de Carbono , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Ergocalciferóis/farmacologia , Humanos , Células de Kupffer/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Masculino , Camundongos Endogâmicos C57BL , Cultura Primária de Células , Fator de Crescimento Transformador beta , Vitamina D/análogos & derivadosRESUMO
BACKGROUND: Distant metastases frequently occur in gastroenteropancreatic neuroendocrine tumors. If hepatic surgery is not feasible, patients are treated with somatostatin analogs. However, the underlying mechanisms of action of this treatment remain to be defined. The aim of the present study was to analyze the micro-RNA expression profile inter-individually before and after the treatment with somatostatin analogs. MATERIAL AND METHODS: Tumor specimens of all included patients (n = 8) before and after the onset of a therapy with somatostatin analogs were analyzed and a micro-RNA expression profile (754 micro-RNAs) of each probe was generated. This analysis in an intra-individual setting was selected to avoid bias from inter-individual differences. The micro-RNA expression profiles were validated by qPCR. Patients with any other systemic treatment were excluded from the present study. RESULTS: Eight patients were included in the present study of which all had neuroendocrine tumors of the small intestine with diffuse hepatic metastases. Grouped analyses revealed that 15 micro-RNAs were differentially expressed (3 up- and 12 downregulated) after the exposure to somatostatin analogs. Additionally, let-7c-5p and mir-3137 are concordantly regulated in the inter-individually analysis. CONCLUSIONS: This is the first study analyzing the individual micro-RNA expression profile before and after a therapy with somatostatin analogs. Data from this study reveal that somatostatin analogs may in part exert their beneficial effects through an alteration in the micro-RNA expression profile.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Intestino Delgado/patologia , MicroRNAs/genética , Tumores Neuroendócrinos/tratamento farmacológico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Idoso , Variação Biológica da População , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND/AIMS: The recently proposed Munich-transarterial chemoembolisation-score (M-TACE) was tailored to suit hepatocellular Carcinoma (HCC) patients evaluated for TACE. M-TACE outperformed the established HCC-staging-systems and successfully passed external validation. Modifications of staging-systems through the rearrangement of stages or by adding prognostic factors are methods of improving prognostic power. M-TACEs performance compared to scores modified this way should be tested. METHODS: Seven well-known HCC staging-systems (including Cancer of the Liver Italian Program-score [CLIP] and Barcelona Clinic liver cancer [BCLC]) and 2 TACE-specific scores (Selection for Transarterial Chemoembolisation Treatment [STATE] and Hepatoma Arterial embolisation Prognostic [HAP]) were rearranged in a cohort of 186 TACE-patients through score-point-analysis and subsequent linking of non-significant adjacent score-points. Additionally, a new score was constructed by combining the top established staging-system in TACE patients (CLIP-TACE) and the prognostic parameter with the highest hazard ratio for death in the TACE-cohort [C-reactive protein (CRP)]. Additionally, the TACE-tailored-scores were applied to an external TACE-cohort (n = 71). -Results: Rearrangement resulted in optimal stratification and monotonicity. CLIP-TACE demonstrated the best prognostic capability of all rearranged scores (c-index 0.668, AIC 1294) and the addition of CRP yielded further prognostic improvement (c-index 0.680, AIC 1289). However, superiority over M-TACE could not be achieved by any of the new scores in the internal and external cohort. CONCLUSION: M-TACE outperforms TACE-tailored modifications of all relevant HCC-staging-systems. Prospective validation of M-TACE to promote its role as the preferred staging-system for TACE-patients is therefore justified.
Assuntos
Carcinoma Hepatocelular/diagnóstico , Quimioembolização Terapêutica , Neoplasias Hepáticas/diagnóstico , Idoso , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/terapia , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Prognóstico , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND & AIM: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. METHODS: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. RESULTS: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. CONCLUSIONS: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.
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Colangite Esclerosante/tratamento farmacológico , Colestase/tratamento farmacológico , Ácido Ursodesoxicólico/análogos & derivados , Adulto , Fosfatase Alcalina/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Ursodesoxicólico/efeitos adversos , Ácido Ursodesoxicólico/uso terapêuticoAssuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Anticorpos Monoclonais Humanizados , Bevacizumab/efeitos adversos , Biologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Doadores Vivos , Recidiva Local de Neoplasia , Seleção de Pacientes , Sistema de RegistrosRESUMO
Liver transplantation (LT) is the only definitive treatment for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow-up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow-up for 98.8 months. The 1-, 5-, and 10-year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient-donor constellation.
Assuntos
Doenças Biliares/epidemiologia , Colangite Esclerosante/cirurgia , Transplante de Fígado/mortalidade , Complicações Pós-Operatórias/epidemiologia , Adulto , Constrição Patológica/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Recidiva , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND/PURPOSE OF THE STUDY: Vitamin D3-deficiency is common in patients with chronic liver-disease and may promote disease progression. Vitamin D3-administration has thus been proposed as a therapeutic approach. Vitamin D3 has immunomodulatory effects and may modulate autoimmune liver-disease such as primary sclerosing cholangitis. Although various mechanisms of action have been proposed, experimental evidence is limited. Here we test the hypothesis that active 1,25-(OH)2-vitamin D3 inhibits activation of hepatic stellate cells (HSC) in vitro and modulates liver-injury in vivo. METHODS: Proliferation and activation of primary murine HSC were assessed by BrdU- and PicoGreen(®)-assays, immunoblotting, immunofluorescence-microscopy, quantitative-PCR, and zymography following calcitriol-treatment. Wild-type and ATP-binding cassette transporter b4(-/-) (Abcb4(-/-))-mice received calcitriol for 4 weeks. Liver-damage, inflammation, and fibrosis were assessed by serum liver-tests, Sirius-red staining, quantitative-PCR, immunoblotting, immunohistochemistry and hydroxyproline quantification. RESULTS: In vitro, calcitriol inhibited activation and proliferation of murine HSC as shown by reduced α-smooth muscle actin and platelet-derived growth factor-receptor-ß-protein-levels, BrdU and PicoGreen®-assays. Furthermore, mRNA-levels and activity of matrix metalloproteinase 13 were profoundly increased. In vivo, calcitriol ameliorated inflammatory liver-injury reflected by reduced levels of alanine aminotransferase in Abcb4(-/-)-mice. In accordance, their livers had lower mRNA-levels of F4/80, tumor necrosis factor-receptor 1 and a lower count of portal CD11b positive cells. In contrast, no effect on overall fibrosis was observed. CONCLUSION: Calcitriol inhibits activation and proliferation of HSCs in vitro. In Abcb4(-/-)-mice, administration of calcitriol ameliorates inflammatory liver-damage but has no effect on biliary fibrosis after 4 weeks of treatment.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Calcitriol/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Hepatite Animal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Estreladas do Fígado/imunologia , Células Estreladas do Fígado/patologia , Hepatite Animal/imunologia , Hepatite Animal/patologia , Fatores Imunológicos/farmacologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPAssuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias Encefálicas/terapia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Nivolumabe/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/secundário , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/radioterapia , Masculino , Pessoa de Meia-Idade , Indução de RemissãoRESUMO
ABSTRACT: We report on a 70-year-old man affected with prostate carcinoma (PC) scheduled for prostate-specific membrane antigen (PSMA) PET/CT using 18 F-PSMA1007. Because of uptake in the liver and corresponding findings on magnetic resonance, diagnosis of hepatocellular carcinoma (HCC, G1) was established. The patient was then scheduled for antihormonal treatment for PC and locoregional therapy due to HCC. On follow-up PSMA-targeted PET/CT, we observed durable response to PC-associated therapy, whereas hepatic lesions showed progressive disease. As such, we herein report on a dual-cancer targeting molecular imaging strategy to determine disease extent in a patient affected with both PC and HCC, along with potential of monitoring both systemic and locoregional treatment.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias da Próstata , Masculino , Humanos , Idoso , Próstata/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Carcinoma Hepatocelular/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias da Próstata/patologia , Radioisótopos de GálioRESUMO
Background: Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation. Summary: Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies. Key Messages: In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.
RESUMO
Primary sclerosing cholangitis (PSC) represents a chronic liver disease characterized by poor prognosis and lacking causal treatment options. Yes-associated protein (YAP) functions as a critical mediator of fibrogenesis; however, its therapeutic potential in chronic biliary diseases such as PSC remains unestablished. The objective of this study is to elucidate the possible significance of YAP inhibition in biliary fibrosis by examining the pathophysiology of hepatic stellate cells (HSC) and biliary epithelial cells (BEC). Human liver tissue samples from PSC patients were analyzed to assess the expression of YAP/connective tissue growth factor (CTGF) relative to non-fibrotic control samples. The pathophysiological relevance of YAP/CTGF in HSC and BEC was investigated in primary human HSC (phHSC), LX-2, H69, and TFK-1 cell lines through siRNA or pharmacological inhibition utilizing verteporfin (VP) and metformin (MF). The Abcb4-/- mouse model was employed to evaluate the protective effects of pharmacological YAP inhibition. Hanging droplet and 3D matrigel culture techniques were utilized to investigate YAP expression and activation status of phHSC under various physical conditions. YAP/CTGF upregulation was observed in PSC patients. Silencing YAP/CTGF led to inhibition of phHSC activation and reduced contractility of LX-2 cells, as well as suppression of epithelial-mesenchymal transition (EMT) in H69 cells and proliferation of TFK-1 cells. Pharmacological inhibition of YAP mitigated chronic liver fibrosis in vivo and diminished ductular reaction and EMT. YAP expression in phHSC was effectively modulated by altering extracellular stiffness, highlighting YAP's role as a mechanotransducer. In conclusion, YAP regulates the activation of HSC and EMT in BEC, thereby functioning as a checkpoint of fibrogenesis in chronic cholestasis. Both VP and MF demonstrate effectiveness as YAP inhibitors, capable of inhibiting biliary fibrosis. These findings suggest that VP and MF warrant further investigation as potential therapeutic options for the treatment of PSC.
Assuntos
Colestase , Células Estreladas do Fígado , Camundongos , Animais , Humanos , Cirrose Hepática/tratamento farmacológico , Fibrose , Colestase/metabolismo , Ductos Biliares , Epitélio/metabolismoRESUMO
Background and Aims: Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort. Methods: A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively. Results: Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure. Conclusions: In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed. Impact and implications: Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.