Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a high mortality neoplasm which usually appears on a cirrhotic liver. The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis. Notwithstanding the current deployment of treatments with curative intent (liver resection/local ablation and liver transplantation) in early and intermediate stages, a high rate of HCC recurrence persists, underscoring a pivotal clinical challenge. Emergent systemic therapies (ST), particularly immunotherapy, have demonstrate promising outcomes in terms of increase overall survival, but they are currently bound to the advanced stage of HCC. This review provides a comprehensive analysis of the literature, encompassing studies up to March 10, 2024, evaluating the impact of novel ST in the early and intermediate HCC stages, specially focusing on the findings of neoadjuvant and adjuvant regimens, aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent. We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent. Finally, we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Current characteristics of patients with hepatitis C virus: results from an automated alert system.

Alert systems are proving to be useful to increase hepatitis C virus (HCV) diagnoses and facilitating access to antiviral treatment. Since 2020, our health department has had a fully automated alert system set up at the Microbiology Department. In this study, we present the results of the 2022-2023 period to assess the current characteristics of HCV diagnosed patients. In addition, we analyzed, through a comparison, whether a limitation that we noticed during the 2020-2021 period (whose results were published) is still present. This limitation consists of that 24.2% (34/134) of those candidates for antiviral treatment were not treated because they could not be located or refused treatment. During the 2022-2023 period, 188 new cases were diagnosed, and 75% (141/188) were treated. The comparison of both periods showed that in 2022-2023, the rate of treatment rejection by the patient was significantly lower (1.4% vs 14.5%, p < 0.05) and, therefore, the rate of antiviral treatment increased (75% vs 58.9%, p < 0.05). These results suggest that our alert system is useful and efficient for the diagnosis and treatment of HCV.

Hepatitis B virus reactivation after ibrutinib treatment.

New immunosuppressive and antineoplastic drugs are becoming both more numerous and more widely used, even during several years. Most of them present a low-moderate risk of hepatitis B virus (HBV) reactivation in HBsAg-negative and anti-HBc-positive patients. However, their reactivation capacity has not been clearly studied. We present the clinical case of a patient with these serological characteristics who, after 5 years of treatment with ibrutinib for chronic lymphocytic leukaemia, developed VHB reactivation, which was controlled with tenofovir. The occurrence of this event with drugs such as ibrutinib may lead to changes in HBV reactivation prophylaxis.

Outcomes of an automated alert system from Microbiology to link diagnosis to treatment in patients with hepatitis C virus.

INTRODUCTION: simplification strategies for the care circuit of patients with hepatitis C virus (HCV) are key to achieve eradication. An electronic identification system was set up for HCV serology to link diagnosis to specialist management, aimed to reduce patient loss. MATERIAL AND METHODS: a retrospective, single-center study was performed in patients with HCV identified from 15/3/2020 to 15/12/2021, using an alert system from Microbiology that notified specialists of positive cases. The patient was contacted and appointed a Fibroscan® and viral load measurement, with antiviral therapy prescribed on the same day. Origin, public health data, patient location rate and antiviral therapy prescription were recorded. RESULTS: of 174 patients identified, 171 had positive viremia, with a mean age of 59.6 ± 15.9 years, 61.5 % were males and 81.2 % were Spanish nationals. Origin in the outpatient setting predominated (57.9 %, 99/171), particularly Primary Care (51/171), penitentiaries (21/171) and addiction units (14/171). Overall, 43.3 % (74/171) were aware of their diagnosis; 19.4 % (20/103) of patients had F3 fibrosis and 25.2 % (26/103) had F4 fibrosis. Also, 78.4 % (134/171) were deemed candidates for treatment. Of these, 74.6 % (100/134) were located and treatment was initiated, and all those who completed their treatment achieved a sustained viral response (96/96). This system managed 58.5 % (100/171) of the patients identified. The only association found between antiviral therapy and patient variables was comorbidities with being untreated (OR, 7.14; p ˂ 0.001). CONCLUSIONS: this alert system allows to minimize patient loss in the care circuit and provides high rates of treated patients.

Resultados de un sistema de alertas automático desde Microbiología para ligar diagnóstico y tratamiento en pacientes con virus de la hepatitis C / Outcomes of an automated alert system from Microbiology to link diagnosis to treatment in patients with hepatitis C virus

Introducción: las estrategias de simplificación del circuitoasistencial para pacientes con virus de la hepatitis C (VHC)son fundamentales para lograr su erradicación. Para ello,introdujimos un sistema electrónico de detección de serología VHC con el objetivo de ligar diagnóstico y asistenciaespecializada para disminuir la pérdida de pacientes.Material y métodos: estudio retrospectivo unicéntrico depacientes VHC detectados del 15/3/2020 al 15/12/2021 mediante un sistema de alertas desde Microbiología que notificaba los casos positivos a facultativos especialistas. Se contactaba con el paciente concertando una cita donderealizaban Fibroscan® y determinación de carga viral y sepautaba tratamiento antiviral el mismo día. Registramosprocedencia, datos sociosanitarios, tasa de localización delpaciente y prescripción de tratamiento antiviral.Resultados: de 174 pacientes detectados, 171 presentaronviremia positiva, con edad media de 59,6 ± 15,9 años, un61,5 % varones y el 81,2 % españoles. Predominó la procedencia del ámbito extrahospitalario (57,9 %, 99/171), destacando Atención Primaria (51/171), centro penitenciario(21/171) y unidades de adicción (14/171). El 43,3 % (74/171)conocía el diagnóstico. Registramos un 19,4 % (20/103) depacientes con fibrosis F3 y un 25,2 % (26/103) con F4. Consideramos candidatos a tratamiento al 78,4 % (134/171). Deestos, fueron localizados e iniciaron tratamiento el 74,6 %(100/134) y lograron respuesta viral sostenida todos los quelo completaron (96/96). Con este sistema hemos tratado al58,5 % (100/171) de los pacientes detectados. La única asociación detectada entre tratamiento antiviral y variablesdel paciente fue que presentar comorbilidades se asociócon no ser tratado (OR 7,14, p < 0,001).Conclusiones: este sistema de alerta permite minimizar lapérdida de pacientes en el circuito asistencial y presentatasas elevadas de pacientes tratados. (AU)

Abnormal liver chemistry constitutes an independent prognostic factor of less favorable clinical course in patients with COVID-19.

INTRODUCTION: abnormal liver biochemistry (ALB) is correlated with increased clinical involvement or severity in COVID-19, but its prognostic implications have not been studied extensively. The aim of this study was to determine whether ALB is a risk factor for unfavorable clinical outcome and involvement. MATERIALS AND METHODS: a retrospective, single-center study in confirmed COVID-19 cases. Patients with pharmacological hepatotoxicity or liver diseases were excluded. ALB was defined as any elevation of total bilirubin, AST, ALT, alkaline phosphatase, and/or GGT above the upper limit of normal. First, an assessment was made of the correlation between ALB and need for hospitalization. This was followed by an assessment of the correlation of ALB in hospitalized patients with demographic variables, comorbidities, and treatment for COVID-19, and with clinical involvement and outcome. The statistical analysis was performed using an age-adjusted multiple logistic regression with a p-value < 0.05. RESULTS: of 1,277 confirmed cases, 346 required hospitalization and 302 were included. The prevalence of ALB was higher in hospitalized patients compared to non-hospitalized patients (60.9 % vs. 10.3 %, p ˂ 0.001). Among hospitalized patients, there was no correlation between ALB and demographic variables, comorbidities, or treatment for COVID-19, except for low molecular weight heparin. There was a significant correlation between ALB and moderate/severe COVID-19 involvement and between unfavorable clinical outcomes and elevated total bilirubin. The period of greatest clinical worsening and deterioration of liver biochemistry parameters occurred during the first seven days. There was a significant correlation of ALB with longer hospital stay and admission to the intensive care unit, but this did not imply increased mortality. CONCLUSIONS: ALB correlates with greater clinical involvement and worse clinical outcomes in hospitalized patients with COVID-19.

[Gastrointestinal bleeding and acute hepatic failure by leptospirosis: an entity that should not be forgotten]. / Hemorragia digestiva e insuficiencia hepática aguda por leptospirosis: una entidad que no debemos olvidar.

Leptospirosis disease is caused by the spirochete Leptospira. It is a worldwide distribution zoonosis, with predominance in the tropics. In Spain, it is not frequent but some cases have been noticed especially in humid areas surrounded by rivers, lakes or ponds, such as Catalonia, Andalucia or the Valencian Community. It is transmitted by a variety of animals such as cows or rats, that are infected either by direct contact with these animals or their urine, or indirectly by consuming or being in contact with water contaminated by their urine. The clinical manifestations are very variable, being asymptomatic or not very symptomatic in most of the patients. Unusually, leptospirosis presents with a first phase with fever, myalgias, liver injury or different organs hemorrhage, followed by a second phase with the presence of jaundice due to hepatic failure. Weil's disease is a kind of severe leptospirosis characterized by hepatic failure with jaundice and acute renal failure, associated with high mortality rates.The diagnosis is based on serological techniques and DNA detection by PCR. The treatment consists of life support measures and antibiotic therapy. A patient with Weil's disease and leptospirosis digestive bleeding is presented, with a fulminant clinical course. In order to achieve an early diagnosis, the need to keep this entity in mind must be emphasized, especially in favorable epidemiological environments as the one of this patient.

Hemorragia digestiva e insuficiencia hepática aguda por leptospirosis: una entidad que no debemos olvidar / Gastrointestinal bleeding and acute hepatic failure by leptospirosis: an entity that should not be forgotten

La leptospirosis es una enfermedad causada por la espiroqueta Leptospira. Se trata de una zoonosis de distribución mundial, con predominio en los trópicos. En España no es frecuente pero sí se observan casos en zonas más húmedas o con presencia de ríos, lagos o estanques, como son Cataluña, Andalucía o la Comunidad Valenciana, donde se relaciona con los arrozales. Los transmisores son múltiples animales como vacas o ratas, contagiándose el ser humano mediante contacto directo con estos animales o su orina, o bien de forma indirecta al consumir o estar en contacto con agua contaminada por la orina de éstos. Las manifestaciones clínicas son muy variables, siendo asintomática o poco sintomática en la mayoría de los pacientes. Aunque no ocurre siempre, la leptospirosis cursa con una primera fase con fiebre, mialgias, afectación renal o hemorragia de distintos órganos, seguida de una segunda fase con presencia de ictericia por afectación hepática. La enfermedad de Weil es una forma de leptospirosis grave caracterizada por afectación hepática con ictericia e insuficiencia renal aguda, asociada a una considerable mortalidad. El diagnóstico se basa en técnicas serológicas y detección de DNA mediante PCR. El tratamiento consta de medidas de soporte y antibioticoterapia. Presentamos un paciente con enfermedad de Weil y hemorragia digestiva por leptospirosis, con una evolución clínica fulminante, y hacemos hincapié en la necesidad de tener presente esta entidad, especialmente en ambientes epidemiológicos favorables como el de este paciente, con el fin de lograr un diagnóstico precoz.

Leptospirosis disease is caused by the spirochete Leptospira. It is a worldwide distribution zoonosis, with predominance in the tropics. In Spain, it is not frequent but some cases have been noticed especially in humid areas surrounded by rivers, lakes or ponds, such as Catalonia, Andalucia or the Valencian Community. It is transmitted by a variety of animals such as cows or rats, that are infected either by direct contact with these animals or their urine, or indirectly by consuming or being in contact with water contaminated by their urine. The clinical manifestations are very variable, being asymptomatic or not very symptomatic in most of the patients. Unusually, leptospirosis presents with a first phase with fever, myalgias, liver injury or different organs hemorrhage, followed by a second phase with the presence of jaundice due to hepatic failure. Weil's disease is a kind of severe leptospirosis characterized by hepatic failure with jaundice and acute renal failure, associated with high mortality rates. The diagnosis is based on serological techniques and DNA detection by PCR. The treatment consists of life support measures and antibiotic therapy. A patient with Weil's disease and leptospirosis digestive bleeding is presented, with a fulminant clinical course. In order to achieve an early diagnosis, the need to keep this entity in mind must be emphasized, especially in favorable epidemiological environments as the one of this patient.

[Effectiveness of maintenance azathioprine therapy without oral cyclosporine after severe attacks of ulcerative colitis refractory to endovenous steroids]. / Eficacia del mantenimiento con azatioprina sin ciclosporina oral tras un brote grave de colitis ulcerosa refractario a esteroides intravenosos.

INTRODUCTION: Intravenous (i.v.) cyclosporine (CsA) has proved effective in controlling acute attacks of ulcerative colitis unresponsive to IV steroids. After the initial response to i.v. CsA, two alternatives for maintaining remission have been proposed: either double or triple association with immunosuppressors. The aim of this study was to evaluate the effectiveness of i.v. CsA, its adverse effects, and the subsequent long-term effectiveness of azathioprine/6-mercaptopurine without oral CsA. MATERIAL AND METHODS: Intravenous CsA was administered for 10 days, at a dose of 4 mg/kg per day, to 20 patients diagnosed with a severe attack of ulcerative colitis who did not respond to IV steroid treatment. Patients who responded to CsA and could be discharged were administered azathioprine or 6-mercaptopurine associated with a decreasing dose of oral steroids, without oral CsA. RESULTS: Sixty per cent (12/20) of the patients showed clinical-biological improvement after CsA administration, thus avoiding colectomy, and were discharged from hospital. Nine of the 12 responders (three withdrew from the study) were followed-up long term. Of these nine patients, four (44.4%) underwent colectomy, all before the sixth month of discharge. All adverse effects were mild, except for one death. CONCLUSIONS: Intravenous CsA is effective in inducing remission of ulcerative colitis in severe attacks resistant to i.v. steroids. When treatment with azathioprine is administered without oral CsA, patients requiring colectomy need this procedure within the first 6 months of discharge.

Eficacia del mantenimiento con azatioprina sin ciclosporina oral tras un brote grave de colitis ulcerosa refractario a esteroides intravenosos / Effectiveness of maintenance azathioprine therapy without oral cyclosporine after severe attacks of ulcerative colitis refractory to endovenous steroids

INTRODUCCIÓN: La ciclosporina (CyA) intravenosa (i.v.) hademostrado ser eficaz en el control de los brotes agudos gravesde colitis ulcerosa que no responden a esteroides i.v.Tras la respuesta inicial a la CyA i.v., se han propuesto dosalternativas para mantener la remisión, la doble o triple asociaciónde inmunosupresores. Los objetivos de nuestro estudiohan sido valorar la eficacia de CyA i.v., sus efectos secundariosy la efectividad posterior a largo plazo de laazatioprina/6-mercaptopurina sin CyA oral.MATERIAL Y MÉTODOS: Se administró CyA i.v. durante 10días, en dosis de 4 mg/kg/día a 20 pacientes diagnosticadosde colitis ulcerosa en brote grave y que no respondieron atratamiento con esteroides i.v. A los que respondieron y pudieronser dados de alta se les administró azatioprina o 6-mercaptopurina asociadas a esteroides orales en pauta descendentey sin CyA oral.RESULTADOS: El 60% (12/20) de los pacientes presentó unamejoría clínico-biológica tras la administración de CyA, loque permitió evitar la colectomía y que fueran dados de altahospitalaria. Se siguieron a largo plazo 9 de los 12 pacientesque respondieron (3 se excluyeron del estudio), y de ellos 4(44,4%) tuvieron que ser colectomizados, todos antes delsexto mes del alta. Los efectos secundarios fueron todos leves,excepto un fallecimiento.CONCLUSIONES: La CyA i.v. es eficaz para inducir la remisiónde la colitis ulcerosa en los brotes graves resistentes aesteroides i.v. Con la estrategia de administrar azatioprinasin CyA oral, los pacientes que requieren colectomía la precisanen los primeros 6 meses tras el alta (AU)

INTRODUCTION: Intravenous (i.v.) cyclosporine (CsA) hasproved effective in controlling acute attacks of ulcerative colitisunresponsive to IV steroids. After the initial response toi.v. CsA, two alternatives for maintaining remission havebeen proposed: either double or triple association with immunosuppressors.The aim of this study was to evaluate theeffectiveness of i.v. CsA, its adverse effects, and the subsequentlong-term effectiveness of azathioprine/6-mercaptopurinewithout oral CsA.MATERIAL AND METHODS: Intravenous CsA was administeredfor 10 days, at a dose of 4 mg/kg per day, to 20 patientsdiagnosed with a severe attack of ulcerative colitis who didnot respond to IV steroid treatment. Patients who respondedto CsA and could be discharged were administeredazathioprine or 6-mercaptopurine associated with a decreasingdose of oral steroids, without oral CsA.RESULTS: Sixty per cent (12/20) of the patients showed clinical-biological improvement after CsA administration, thusavoiding colectomy, and were discharged from hospital. Nineof the 12 responders (three withdrew from the study) werefollowed-up long term. Of these nine patients, four (44.4%)underwent colectomy, all before the sixth month of discharge.All adverse effects were mild, except for one death.CONCLUSIONS: Intravenous CsA is effective in inducing remissionof ulcerative colitis in severe attacks resistant to i.v.steroids. When treatment with azathioprine is administeredwithout oral CsA, patients requiring colectomy need thisprocedure within the first 6 months of discharge (AU)