Resumen Introducción : El carcinoma hepatocelular (HCC) es el cáncer primario más común del hígado y la tercera causa principal de muerte por cáncer en todo el mun do. La resección hepática es el tratamiento de elección para pacientes no cirróticos, mientras que, en cirróticos, la elección depende del estadio tumoral y la función hepática. Métodos : En este estudio retrospectivo realizado en el Hospital El Cruce entre 2015 y 2022, se evaluaron pa cientes con HCC sometidos a resección hepática, tanto cirróticos como no cirróticos. Se analizó la morbimorta lidad, la tasa de recurrencia y la sobrevida. Resultados : Se realizaron 262 hepatectomías, 44 fue ron para tratamiento del HCC, de las cuales 35 fueron hepatectomías menores, y 9 hepatectomías mayores (no cirróticos). La mayoría eran hombres (77%) con una edad promedio de 58.5 años. Hubo 29 pacientes con cirrosis, siendo la hepatitis C (HCV) la causa principal en un 48%, HCV con alcohol como cofactor (21%) y alcohol (17%). La morbilidad fue del 47.7%, con complicaciones menores predominantes. La recurrencia de enfermedad ocurrió en el 59% de los pacientes, y los factores asociados incluyeron tamaño tumoral y niveles elevados de Alfa-fetoproteína. La supervivencia fue mejor en pacientes cirróticos en comparación con no cirróticos. Conclusión : La resección hepática es una opción efectiva para el tratamiento del HCC en pacientes bien seleccionados cirróticos y no cirróticos, con resultados alentadores en términos de supervivencia y control de la enfermedad. Además, se sugiere una vigilancia cercana para detectar recurrencias tempranas y proporcionar tratamientos oportunos.

Abstract Introduction : Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third lead ing cause of cancer-related deaths worldwide. Hepatic resection is the treatment of choice for non-cirrhotic patients, while in cirrhotic individuals, the choice de pends on tumor stage and liver function. Methods : In this retrospective study conducted at Hospital El Cruce between 2015 and 2022, patients with HCC undergoing hepatic resection, both cirrhotic and non-cirrhotic, were evaluated. Morbidity, mortality, re currence rate, and survival were analyzed. Results : A total of 262 hepatectomies were performed, with 44 for HCC treatment. Among them, 35 were minor hepatectomies, and 9 were major hepatectomies (non-cirrhotic patients). The majority were males (77%) with an average age of 58.5 years. Twenty-nine patients had cirrhosis, with hepatitis C (HCV) being the main cause in 48%, HCV with alcohol as a cofactor (21%), and alcohol alone (17%). Morbidity was 47.7%, with predominance of minor complications. Disease recurrence occurred in 59% of patients, and associated factors included tumor size and elevated AFP levels. Survival was better in cir rhotic patients compared to non-cirrhotic ones. Discussion : Results tion 5837Hepatic resection is an effective option for treating HCC in well-selected cirrho tic and non-cirrhotic patients, with encouraging results in terms of survival and disease control. Additionally, close surveillance for early recurrence detection and timely interventions is suggested.

Modified flavonoids of the sub-group of pterocarpans, 5-carba-pterocarpans, 5-carbapterocarpens, 1-carba-isoflavanones, coumestans, and aurones were synthesized and evaluated as antiproliferative, antileishmanial and antiviral. A new scaffold, called pterocarpanquinone, was discovered and LQB-118, the prototypical scaffold of its series, showed consistent antileishmanial (mice and hamster in vivo) and antineoplastic (respectively, human and mice tumors ex vivo and in vivo) activity. 5-Carpa-pterocarpan LQB-485 is potent towards SF-295 cancer cells (CNS). LQB-262 and LQB-34 are new inhibitors of NB5S RdRp polymerase of hepatitis C virus (HCV) while LQB-314 and LQB-360 demonstrated potent activity and selectivity against HCV replicon reporter cells. LQB-454 and LQB-501 were evaluated for their in vitro anti-proliferative effects against human breast cancer and leukemia cell lines with diverse profiles of drug resistance. In breast cancer they present higher toxicity on multidrug resistant cells (collateral sensitivity). Aurone LQB-814, featuring a “lipophilic phenol” at A-ring”, was a very potent and selective inhibitor of SARS-CoV-2 in Calu-3 cells. Other four aurones bearing EC50 (concentration required to inhibit 50% of cell growth) < 1 were also discovered. subgroup sub group pterocarpans 5carbapterocarpans, 5carbapterocarpans carbapterocarpans 5 carba 5-carba-pterocarpans 5carbapterocarpens, 5carbapterocarpens carbapterocarpens carbapterocarpens, 5-carbapterocarpens 1carbaisoflavanones, 1carbaisoflavanones carbaisoflavanones isoflavanones, isoflavanones 1-carba-isoflavanones coumestans antiproliferative antiviral pterocarpanquinone LQB118, LQB118 LQB 118, 118 LQB-118 series respectively, respectively (respectively 5Carpapterocarpan Carpapterocarpan Carpa pterocarpan LQB485 485 LQB-48 SF295 SF 295 SF-29 CNS. CNS . (CNS) LQB262 262 LQB-26 LQB34 34 LQB-3 NBS NB S (HCV LQB314 314 LQB-31 LQB360 360 LQB-36 LQB454 454 LQB-45 LQB501 501 LQB-50 anti proliferative resistance collateral sensitivity. sensitivity sensitivity) LQB814, LQB814 814, 814 LQB-814 lipophilic phenol Aring, Aring ring , A-ring” SARSCoV2 SARSCoV SARS CoV 2 SARS-CoV- Calu3 Calu 3 Calu- EC EC5 concentration 50 growth LQB11 11 LQB-11 LQB48 48 LQB-4 SF29 29 SF-2 (CNS LQB26 26 LQB-2 LQB3 LQB- LQB31 31 LQB36 36 LQB45 45 LQB50 LQB-5 LQB81 81 LQB-81 A-ring SARS-CoV LQB1 LQB-1 LQB4 4 SF2 SF- LQB2 LQB5 LQB8 8 LQB-8

ABSTRACT Background: Spontaneous regression (SR) is defined as the partial or complete disappearance of a tumor, in the absence of a specific treatment. Evidence of the SR in hepatocellular carcinoma (HCC) is rare. Objective: The authors aimed to review all the cases of SR of HCC in two reference centers of Southern Brazil, highlighting the main characteristics. Methods: Data of all patients with HCC were retrospectively reviewed looking for the occurrence of SR in patients from two tertiary centers in Southern Brazil, in the last five years. The diagnosis of cirrhosis was established according to clinical, laboratory and imaging data, as well as upper endoscopy or histopathological examination when necessary. The diagnosis of HCC was based on typical findings according to radiologic criteria (LIRADS) or histopathological examination. Spontaneous regression was defined as a partial or complete involution of a HCC in the absence of a specific therapy. Results: From all cases of HCC in the last 5 years (n=433), there were five cases of SR. Three (60%) were men, the mean age was 62.6 (50.0-76.0) years, and the etiology was HCV in 3 (60%). Complete regression was observed in three patients (60%), one patient (20%) presented partial regression, and one (20%) relapesed and died. The time of follow-up varied between 12 and 21 months. In this presentation, it was highlighted one case of SR observed after COVID-19 infection in a patient with cirrhosis. The possible mechanisms involved in this situation were reviewed, emphasizing the most common like hypoxia and immunological. There were also one patient submitted to a surgical procedure as a possible fator involved and three patients without obvious risk factors. Conclusion: This phenomenon will possibly contribute to a better understanding of the pathophysiological mechanisms of HCC. Background (SR tumor treatment (HCC rare Objective Brazil characteristics Methods clinical data necessary LIRADS (LIRADS therapy Results n=433, n433 n n=433 , 433 (n=433) 60% 60 (60% men 626 62 6 62. 50.076.0 500760 50.0 76.0 50 0 76 (50.0-76.0 60%. . 60%, 20% 20 (20% died followup follow up 1 2 months presentation COVID19 COVID 19 COVID-1 immunological factors Conclusion n43 n=43 43 (n=433 (60 076 50.076. 50076 500 50. 760 76. 7 (50.0-76. (20 COVID1 COVID- n4 n=4 4 (n=43 (6 07 50.076 5007 (50.0-76 (2 n= (n=4 ( 50.07 (50.0-7 (n= (50.0- (n (50.0 (50. (50 (5

RESUMO Contexto: A evidência da regressão espontânea (RE) no carcinoma hepatocelular (CHC) é rara. Objetivo: Revisar todos os casos de RE de CHC em dois centros de referência do Sul do Brasil, destacando as principais características. Métodos: Os dados de todos os pacientes com CHC foram revisados retrospectivamente buscando a ocorrência de RE em pacientes de dois centros terciários do Sul do Brasil, nos últimos 5 anos. O diagnóstico de cirrose foi estabelecido de acordo com dados clínicos, laboratoriais e de imagem, além de endoscopia digestiva alta ou exame histopatológico quando necessário. O diagnóstico de CHC foi baseado em achados típicos de acordo com critérios radiológicos (LIRADS) ou exame histopatológico. A RE foi definida como uma involução parcial ou completa de um CHC na ausência de terapia específica. Resultados: Do total de casos de CHC nos últimos 5 anos (n=433), houve cinco casos de RE. Três (60%) eram homens, a média de idade foi de 62,6 (50,0-76,0) anos, a etiologia foi virus da hepatite C em 3 (60%). A regressão completa foi observada em três pacientes (60%), um paciente (20%) apresentou regressão parcial e um (20%) apresentou recidiva e evoluiu a óbito. O tempo de seguimento variou entre 12 e 21 meses. Nesta apresentação foi destacado um caso (20%) de RE observado após infecção por COVID-19 em paciente com cirrose. Foram revisados os possíveis mecanismos envolvidos nesta situação, enfatizando os mais comuns como hipóxia e imunológicos. Houve também um paciente submetido a procedimento cirúrgico como possível fator envolvido e três pacientes sem fatores de risco evidentes. Conclusão: Este fenômeno possivelmente contribuirá para uma melhor compreensão dos mecanismos fisiopatológicos do CHC. Contexto (RE (CHC rara Objetivo Brasil características Métodos clínicos imagem necessário LIRADS (LIRADS específica Resultados n=433, n433 n n=433 , 433 (n=433) 60% 60 (60% homens 626 62 6 62, 50,076,0 500760 50,0 76,0 50 0 76 (50,0-76,0 60%. . 60%, 20% 20 (20% óbito 1 2 meses COVID19 COVID 19 COVID-1 situação imunológicos evidentes Conclusão n43 n=43 43 (n=433 (60 076 50,076, 50076 500 50, 760 76, 7 (50,0-76, (20 COVID1 COVID- n4 n=4 4 (n=43 (6 07 50,076 5007 (50,0-76 (2 n= (n=4 ( 50,07 (50,0-7 (n= (50,0- (n (50,0 (50, (50 (5

Introduction: Colonoscopy is a basic tool in the study of pathology of the colorectal area, as well as one of the pillars of colon and rectal cancer screening. However, it is not a risk-free procedure, some of them with high morbimortality. Case Report: 55-year-old male with chronic alcoholism and hepatopathy due to HCV, COPD. During a study for diarrhea, an ultrasound of the abdomen revealed a 7 mm pancreas tumor, and a diagnostic colonoscopy showed no significant alterations. With the suspicion that the pancreatic lesion could be the cause of the diarrhea, an abdominal scan was performed showing a subcapsular collection at the splenic level of 11 × 3 cm compatible with hematoma without signs of active bleeding. Due to the hemodynamic stability, conservative management was decided, with worsening abdominal pain and hypotension in the following 12 hours. A new imaging test showed an enlarged splenic hematoma and free abdominal fluid suggestive of hemoperitoneum. Urgent surgery found hemoperitoneum secondary to splenic lesion and splenectomy was required. Conclusion: The presence of a possible iatrogenic splenic lesion should be considered in the differential diagnosis in a patient with acute onset abdominal pain and anemia or hemodynamic status alteration within the first 24-48 hours after colonoscopy.

Resumen Introducción: La colonoscopia es una herramienta básica en el estudio de patologías del área colorrectal, así como uno de los pilares del screening del cáncer de colon y recto. Sin embargo, no es un procedimiento exento de riesgos, algunos de ellos con elevada morbimortalidad. Caso Clínico: Varón de 55 años con enolismo crónico y hepatopatía por Virus Hepatitis C y Enfermedad Pulmonar Obstructiva Crónica. En estudio por diarrea se solicita una ecografía de abdomen donde, como único hallazgo, se muestra una lesión de 7 mm a nivel de páncreas y una colonoscopia con intención diagnóstica que no muestra alteraciones significativas. Con la sospecha de que la lesión pancreática pudiese ser la causa del cuadro diarreico, se realiza un escáner abdominal donde se muestra una colección subcapsular a nivel esplénico de 11 × 3 cm compatible con hematoma sin signos de sangrado activo. Dada la estabilidad hemodinámica, se inicia manejo conservador, con empeoramiento del dolor abdominal e hipotensión en las siguientes 12 h. Se repite prueba de imagen objetivando aumento de hematoma esplénico y líquido libre intraabdominal. Se indica cirugía urgente donde se evidencia hemoperitoneo secundario a lesión esplénica que obliga a realizar esplenectomía. Conclusión: La presencia de una posible lesión esplénica yatrogénica se debe tener en cuenta en el diagnóstico diferencial en un paciente con dolor abdominal de inicio agudo y anemización o alteración del estado hemodinámico dentro de las primeras 24-48 h tras la realización de una colonoscopia.

Abstract Background: Arsenic trioxide is a chemical compound that has been used as a treatment for various diseases. Despite being potentially toxic, this compound has been used as a therapy to treat Acute Myeloid Leukemia and is being investigated as a possible treatment for different types of cancer. Objectives: The present review aims to describe the use and studies reported in the literature of Arsenic Trioxide as a possible therapeutic agent for Acute Myeloid Leukemia, Acute Promyelocytic Leukemia, Chronic Myeloid Leukemia, Multiple Myeloma, Myelodysplastic Syndrome, Hepatocellular Carcinoma, Lung Cancer, Neuroblastoma, Breast Cancer, Aplastic Hepatitis C, and HIV-1. Methods: A systematic review was conducted using databases (Elsevier, Google Scholar, PubMed) to compile documents published before December 2023. Results: Multiple pharmacological applications of arsenic trioxide have been reported to treat acute and chronic myeloid leukemia. Arsenic trioxide has been shown to inhibit angiogenesis, which helps treat multiple myeloma. Several studies have shown and suggested the effectiveness of arsenic trioxide as a treatment of hepatocellular carcinoma, lung cancer, neuroblastoma, prostate cancer, breast cancer, aplastic anemia, hepatitis C, and HIV-1. Conclusion: Despite potentially toxic effects, Arsenic compounds are therapeutic agents for multiple diseases, from syphilis to cancer. In recent years, more efficient ways have been investigated to deliver and find the specific dose to treat the disease, causing the fewest possible adverse effects.

Resumen Antecedentes: El trióxido de arsénico es un compuesto químico que se ha utilizado como tratamiento de diversas enfermedades. A pesar de ser potencialmente tóxico, este compuesto se ha utilizado como terapia para tratar la leucemia mieloide aguda y se está investigando como posible tratamiento para diferentes tipos de cáncer. Objetivos: La presente revisión pretende describir el uso del trióxido de arsénico como posible agente terapéutico para la leucemia mieloide aguda, la leucemia promielocítica aguda, la leucemia mieloide crónica, el mieloma múltiple, el síndrome mielodisplásico, el carcinoma hepatocelular, el cáncer de pulmón, el neuroblastoma, el cáncer de mama, la hepatitis C aplásica y el VIH-1. Métodos: Se realizó una revisión sistemática utilizando bases de datos (Elsevier, Google Scholar, PubMed) para recopilar documentos publicados antes de diciembre de 2023. Resultados: Se ha informado de múltiples aplicaciones farmacológicas del trióxido de arsénico para tratar la leucemia mieloide aguda y la leucemia mieloide crónica. Se ha demostrado que el trióxido de arsénico inhibe la angiogénesis, lo que resulta útil para el tratamiento del mieloma múltiple. Varios estudios han demostrado y sugerido la eficacia del trióxido de arsénico como tratamiento del carcinoma hepatocelular, el cáncer de pulmón, el neuroblastoma, el cáncer de próstata, el cáncer de mama, la anemia aplásica, la hepatitis C y el VIH-1. Conclusión: A pesar de tener un efecto potencialmente tóxico, los compuestos de arsénico destacan como agentes terapéuticos para múltiples enfermedades, desde la sífilis hasta el cáncer. En los últimos años, se han investigado formas más eficientes de administrar y encontrar la dosis específica para poder tratar la enfermedad, causando los menores efectos adversos posibles.

ABSTRACT Among individuals coinfected with HCV and HIV, studies of mortality from non-hepatic causes have shown inconsistent results. The aim of this study was to investigate the contribution of HCV and HIV co-infection to mortality from hepatic and non-hepatic causes in Brazil. This retrospective cohort study included blood donors from Fundação Pró-Sangue de São Paulo (FPS) who were followed from 1994 to 2016 to compare mortality and its causes between HIV-HCV coinfected individuals versus those seronegative for all tested infections. Records from the FPS database and the Mortality Information System were linked through a probabilistic record Relationship (RL). The Hazard Ratio (HR) was estimated using Cox multiple regression models. HCV-HIV coinfected individuals compared to seronegative individuals had a higher risk of death from all causes (HR = 14.54), non-liver neoplasms (HR = 2.55), infections (HR = 10.37) and liver disease (HR = 7.0). In addition, HCV mono-infected individuals compared to seronegative individuals had a higher risk of death from all causes (HR = 2.23), liver cancer (HR = 32.21), liver disease (HR = 14.92), infection (HR = 3.22), and trauma (HR = 1.68). Individuals coinfected with HCV and HIV have increased overall mortality and death due to infections, liver diseases and non-liver neoplasms as compared to those uninfected with HCV and HIV. nonhepatic non results coinfection co Brazil PróSangue Pró Sangue (FPS 199 201 HIVHCV RL. RL . (RL) HR models HCVHIV 14.54, 1454 14.54 , 14 54 14.54) nonliver 2.55, 255 2.55 2 55 2.55) 10.37 1037 10 37 7.0. 70 7.0 7 0 7.0) addition monoinfected mono infected 2.23, 223 2.23 23 2.23) 32.21, 3221 32.21 32 21 32.21) 14.92, 1492 14.92 92 14.92) 3.22, 322 3.22 3 22 3.22) 1.68. 168 1.68 1 68 1.68) 19 20 (RL 145 14.5 5 25 2.5 10.3 103 7. 2.2 32.2 149 14.9 9 3.2 16 1.6 6 14. 2. 10. 32. 3. 1.

Resumen El carcinoma hepatocelular (HCC) es el tumor primario más frecuente del hígado, con 905 677 casos diagnosticados en 2020, en todo el mundo, y 830 180 muertes. Es responsable de la novena causa de muerte por cáncer en los hombres y la décima en mujeres en Argentina. A diferencia de otros tumo res de alta prevalencia, la evidencia científica acerca del HCC se limita principalmente a pequeñas cohortes y estudios retrospectivos. El objetivo de este estudio fue describir epidemiológicamente a aquellos pacientes con diagnóstico de HCC en el Hospital Italiano de Buenos Aires en un periodo de 12 años. La supervivencia global para nuestra cohorte fue de 58, 46 y 36% a 1, 3 y 5 años respectivamente. El promedio de supervivencia en pacientes con tratamiento paliativo fue de 5 meses, 23 para aquellos que recibieron tratamientos no curativos y 75 meses para los que recibieron tratamientos curativos. El porcentaje de pacientes libres de enfermedad a 1, 3 y 5 años fue de 89%, 76% y 61% respectivamente. Se realizó un estudio minucioso de la etiología, factores de riesgo, incidencia, mortalidad y tratamientos realizados. Su importancia yace en su tamaño muestral, calidad y cantidad de información disponible.

Abstract Hepatocellular carcinoma is the most common primary liver tumor, with 905 677 diagnosed cases and 830 180 deaths, in 2020 worldwide. In Argentina, it accounts for the 9th cause of death for cancer in men and the 10th in women. Unlike other highly-prevalent tumors, scientific evidence for most therapeutic options is limited mainly to small cohorts and retrospective studies. The aim of this study is to characterize and describe epidemiologically patients with diagnosis of hepatocellular carcinoma in the Italian Hospital of Buenos Aires during a 12-year period. Overall survival for our cohort was 58%, 46%, and 36% at 1, 3 and 5 years respectively. Average survival for patients receiving palliative treatment was 5 months, while for those who received either non-curative or curative treatment was 23 and 75 months respectively. Recurrence-free survival for those patients who under went a curative treatment was 89%, 76% y 61% at 1, 3 and 5 years. A thorough analysis of etiology, risk factors, incidence, mortality and treatment was made. The study’s importance lies in its large sample size, quantity and quality of data, and will most certainly stimulate the development of local studies in hepatocellular carcinoma.

RESUMO Contexto: Carcinoma hepatocelular (CHC) é o tipo mais comum de câncer de fígado. Os fatores de risco para CHC incluem infecção pelo vírus da hepatite C (VHC) e B (VHB), cirrose alcoólica e alterações genéticas que podem afetar diversas vias celulares. Objetivo: Este estudo teve como objetivo analisar a expressão gênica e proteica sérica de VEGF, AFP, CSTB, β-catenina e GPC3 em grupos com CHC, cirrose ou VHC e controles, e sua relação com o estadiamento clínico nos grupos CHC e cirrose, bem como sua valores de sensibilidade e especificidade. Métodos: Duzentos e trinta indivíduos foram distribuídos no Grupo 1 (G1) - 80 pacientes com CHC; Grupo 2 (G2) - 76 pacientes com cirrose de qualquer etiologia; Grupo 3 (G3) - 33 pacientes com VHC; Grupo 4 (G4 - Controles) - 41 indivíduos sem sinais clínicos ou bioquímicos de qualquer doença hepática. A expressão gênica foi analisada por qRT-PCR e as proteínas séricas foram realizadas pelo método ELISA. Resultados: Aumento da expressão de VEGF e AFP pode ser observado em pacientes BCLC estágio D em comparação com pacientes estágio B, e pacientes estágio C apresentaram maior expressão de CTNNB1, em comparação com pacientes estágio B (P<0,05). Para VEGF e GPC3, foi observado poder discriminatório entre pacientes com CHC e controles (AUC = 0,71; 0,82, respectivamente). O CSTB mostrou poder discriminatório na comparação entre pacientes com VHC e controles (AUC =0,74). Conclusão: O presente estudo confirma a sensibilidade do CSTB sérico no diagnóstico da hepatite C, e a expressão gênica de VEGF e GPC3 sérica conferem sensibilidade e especificidade para o diagnóstico de CHC.

ABSTRACT Background: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Risk factors for HCC include hepatitis C (HCV) and B (HBV) virus infection, alcoholic cirrhosis and genetic alterations that can affect several cellular pathways. Objective: This study purposed to analyze the gene and serum protein expression of vascular endothelial growth factor (VEGF), angiogenesis, alpha fetoprotein, cystatin B (CSTB), β-catenin and glypican-3 (GPC3) in groups with HCC, cirrhosis or HCV and controls, and their relation with clinical staging in the HCC and cirrhosis groups, as well its sensitivity and specificity values. Methods: A total of 230 individuals were distributed in Group 1 (G1) - 80 patients with HCC; Group 2 (G2) - 76 patients with cirrhosis due to any etiology; Group 3 (G3) - 33 patients with HCV; Group 4 (G4 - controls) - 41 individuals without clinical or biochemical signs of any liver disease. Gene expression was analyzed by qRT-PCR and serum proteins were performed using the ELISA method. Results: Increased VEGF and angiogenesis, alpha fetoprotein expression could be observed in BCLC stage-D patients compared to stage-B patients, and stage-C patients showed higher expression of β-catenin, compared to stage-B patients (P<0.05). For VEGF and GPC3, discriminatory power was observed between HCC patients and controls (AUC =0.71; 0.82, respectively). CSTB showed discriminatory power in the comparison between patients with HCV and controls (AUC =0.74). Conclusion The present study confirms the sensitivity of serum CSTB in the diagnosis of hepatitis C, and gene expression of VEGF and serum GPC3, confer both sensitivity and specificity for the diagnosis of HCC.

Abstract Mediation analysis has been receiving much attention from the scientific community in the last years, mainly due to its ability to disentangle causal pathways from exposures to outcomes. Particularly, causal mediation analysis for time-to-event outcomes has been widely discussed using accelerated failures times, Cox and Aalen models, with continuous or binary mediator. We derive general expressions for the Natural Direct Effect and Natural Indirect Effect for the time-to-event outcome when the mediator is modeled using generalized linear models, which includes existing procedures as particular cases. We also define a responsiveness measure to assess the variations in continuous exposures in the presence of mediation. We consider a community-based prospective cohort study that investigates the mediation of hepatitis B in the relationship between hepatitis C and liver cancer. We fit different models as well as distinct distributions and link functions associated to the mediator. We also notice that estimation of NDE and NIE using different models leads to non-contradictory conclusions despite their effect scales. The survival models provide a compelling framework that is appropriate to answer many research questions involving causal mediation analysis. The extensions through GLMs for the mediator may encompass a broad field of medical research, allowing the often necessary control for confounding.

Resumen El análisis de mediación ha recibido mucha atención en los últimos años, principalmente debido a su capacidad para desenredar las vías causales. Particularmente, mediación causal para el tiempo hasta el evento se ha discutido ampliamente utilizando tiempos de falla acelerados, modelos de Cox y Aalen, con mediador continuo o binario. Derivamos expresiones generales para el efecto directo natural y el efecto indirecto natural para el el tiempo hasta el evento cuando el mediador se modela utilizando modelos lineales generalizados, que incluyen procedimientos existentes como casos particulares. Definimos una medida para evaluar variaciones en exposiciones continuas en presencia de mediación. Consideramos un estudio de cohorte prospectivo que investiga la mediación de la hepatitis B en la relación entre la hepatitis C y el cáncer de hígado. Encajamos diferentes modelos, así como distintas distribuciones y funciones de enlace. Todos los enfoques dan como resultado evaluaciones consistentes de los effectos considerando sus correspondientes escalas. Los modelos de supervivencia proporcionan un marco convincente apropiado para responder a muchas preguntas de investigación que involucran mediación causal. Las extensiones a través de GLM para el mediador pueden abarcar un amplio campo de investigación médica, lo que permite el control necesario para los factores de confusión.

Resumen Se reporta el caso de una paciente con reciente diagnóstico de hepatocarcinoma y cirrosis hepática asociada a hepatitis C hace 11 años, la cual fue sometida a hepatectomía derecha. La implicancia de pacientes con enfermedad hepática crónica como cirrosis es el aumento en la morbimortalidad tras la resección. La resección hepática en la mayoría de las ocasiones suele ser el tratamiento más efectivo para el aclaramiento oncológico. El manejo anestésico quirúrgico ha ido evolucionando y en la actualidad se pueden realizar resecciones extensas en pacientes complejos.

Abstract We report the case of a patient with a recent diagnosis of hepatocarcinoma and liver cirrhosis associated with Hepatitis C reported 11 years ago, who underwent right hepatectomy. The implication of patients with chronic liver disease such as cirrhosis is the increase in post-resection morbidity and mortality. Liver resection in most cases is the most effective treatment for cancer clearance. Surgical and anesthetic management has evolved and extensive resections can now be performed in complex patients.

Abstract Hepatitis C virus (HCV) infection is currently the main blood-borne viral infection. One of the main obstacles to achieving its control in Argentina is related to difficulties in accessing the diagnosis and timely treatment of infected people. We carried out this study with the aim of characterizing the HCV-infected patients who started treatment with direct-acting antivirals (DAAs) and to describe the experience related to treatment. The medical records of 82 patients, 44 (53.7%) male, 37 (45.1%) female, and one (1.2%) transgender, were selected. The mean age was 49 years. We report a frequency of cirrhosis, 39%, in 32 patients, coinfection with HIV in 48 (58.5%) and with HBV in 27 (32.9%). In 52 patients (63.4%), no risk factor clearly associated with infection was observed. All completed the therapy, of them 72 (87.8%) carried out the control to confirm sustained viral response (SVR), that attained 98.6%. We conclude that universal testing should be implemented over testing based on a risk approach, and that a simplified and decentralized care criterion should be promoted, reserving specialized care for patients with decompensated cirrhosis and liver cancer.

Resumen La principal infección viral transmisible por sangre es actualmente la debida al virus de hepatitis C (VHC). Uno de los mayores obstáculos para el logro de su control en la Argentina se relaciona con las dificultades de acceso al diagnóstico y tratamiento oportuno de las personas infectadas. Este estudio se realizó con el objetivo de caracterizar a los pacientes infectados con VHC que iniciaron tratamiento con antivirales de acción directa (AAD) y describir la experiencia vinculada al tratamiento. Se seleccionaron las historias clínicas de 82 pacientes, 44 (53.7%) de sexo masculino, 37 (45.1%) de sexo femenino, y uno (1.2%) transgénero. La media de edad fue de 49 años. Se halló una frecuencia de cirrosis de 39%, 32 pacientes, coinfección con HIV en 48 (58.5%) y con VHB en 27 (32.9%). En 52 (63.4%) no se observó ningún factor de riesgo claramente asociado a infección. Todos completaron la terapia, de ellos 72 (87.8%) efectuaron el control para confirmar respuesta viral sostenida (RVS), que fue de 98.6%. Concluimos que el testeo universal debe implementarse por sobre el testeo con enfoque de riesgo, y que debe promoverse un criterio de atención simplificado y descentralizado, reservando la atención especializada para pacientes con cirrosis descompensada y cáncer de hígado.

RESUMO Tumores malignos do fígado são a quarta maior causa de morte por câncer, sendo que o carcinoma hepatocelular (CHC) corresponde a 85-90% desses casos. A maioria dos doentes apresenta-se, ao diagnóstico, sem possibilidade de tratamento curativo, restando apenas as opções paliativas (quimioembolização e sorafenibe). Há poucos estudos nacionais acerca do sorafenibe. OBJETIVO Avaliar fatores preditivos de sobrevida em pacientes com CHC que tiveram indicação de tratamento com sorafenibe na Irmandade da Santa Casa de Misericórdia de São Paulo (ISCMSP) e avaliação da conformidade da indicação da medicação em relação às recomendações do BCLC. MÉTODOS Foram analisados retrospectivamente os dados de 88 pacientes que tiveram indicação de tratamento com sorafenibe no período de 2010 a 2017 na ISCMSP. Análises univariada e multivariada foram realizadas na busca de preditores de sobrevida global nos pacientes que receberam a medicação. RESULTADOS Idade média de 61,2 anos, sendo 70,5% homens. A maioria (69,3%) foi classificada como Child Pugh A e BCLC C (94,3%). A cirrose esteve presente em 84,6% e a hipertensão portal em 55,7% desses. O vírus da hepatite C foi a etiologia mais comum (40,9%) do CHC. Sessenta e nove (78,4%) pacientes receberam a medicação, sendo o tempo médio de duração do tratamento 9,7 meses e a sobrevida global média, 16,8 meses. Diferenças significativas foram observadas na análise multivariada: Ecog PS (p=0,024), CP (p=0,013), tempo de uso de medicação (p<0,001), suspensão por piora clínica (p=0,031) e trombose portal (p=0,010). CONCLUSÃO Ausência de trombose portal, Child Pugh A, Ecog PS 0, tempo maior de uso de medicação e ausência de suspensão por piora clínica foram fatores preditores de melhor sobrevida global e a indicação da medicação esteve em conformidade com as orientações do BCLC em 94% dos pacientes.

SUMMARY Malignant liver tumors are the fourth leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) accounts for 75-85% of these. Most patients are diagnosed at incurable stages. Palliative care is the appropriate treatment course in these circumstances (chemoembolization and sorafenib). There are few national studies on sorafenib. The objective is to evaluate survival predictors of HCC patients treated with sorafenib and evaluate the compliance of its indication in relation to BCLC recommendations. METHODS A total of 88 patients with an indication of sorafenib from 2010 to 2017 at the ISCMSP were retrospectively analyzed. Univariate and multivariate analyzes were performed in the search for predictors of survival. RESULTS The mean age was 61.2 years, 70.5% were men, most were classified as Child-Pugh A (69.3%), and BCLC C (94.3%). Cirrhosis was present in 84.6% and portal hypertension in 55.7%. Hepatitis C virus was the most common etiology (40.9%). Sixty-nine (78.4%) patients received the medication, with the average duration of treatment being 9.7 months. The mean overall survival was 16.8 months. Significant differences were observed in the multivariate analysis: ECOG PS (p = 0.024): Child-Pugh (p = 0.013), time of medication use (p <0.001), clinical worsening (p = 0.031) and portal thrombosis (p = 0.010). CONCLUSION Absence of portal thrombosis, Child-Pugh A, longer time of medication use, ECOG PS 0, and absence of suspension due to clinical worsening were predictors of better overall survival in the study. The drug’s indication complies with BCLC guidelines in 94% of patients.

Chronic viral hepatitis types B and C may eventually lead to the development of hepatocellular carcinoma. Although hepatitis B is readily preventable by vaccination, there is growing evidence that antiviral therapy directed against hepatitis B may reduce the risk of liver cancer among those already infected. There is no vaccine against hepatitis C, but the evidence is now strong that antiviral therapy with sustained virological response (viral cure) reduces, but does not eliminate, the risk of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) originates from hepatocytes usually secondary to chronic inflammation and cirrhosis. It is an important disease of global significance with a high incidence and mortality. It is the fifth and eighth most common cancer in males and females, respectively. HCC is also extremely lethal; in 2015 it was the second and sixth most common cause of death from cancer in males and females, respectively. Chronic viral hepatitis B and C are the most frequent risk factors for the development of HCC, and the global distribution of HCC largely mirrors that of chronic viral hepatitis. More recently, there has been a notable increase in the incidence of HCC as a result of obesity-related fatty liver disease. Here, we review the epidemiology of HCC, examine recent advances in our understanding of the pathogenesis of HCC, discuss the implications for identification of potential therapeutic targets, and provide the most updated recommendations on surveillance for HCC, with particular attention to the unique challenges and potential opportunities to reduce the burden of illness and death from HCC in sub-Saharan Africa.

ABSTRACT The increase of incidences of Hepatocellular Carcinoma (HCC) will continue in the next decades. The therapies about hepatitis C infection has been questioned as a risk factor. Some authors emphasized that sustained virologic response (SVR) with interferon- based therapy reduced the risk of developing HCC. In contrast, some publications that to suggest an increasing risk of HCC in patients treated with Direct-Acting Antivirals (DAA). Whether these therapies are associated with an increased risk of HCC remains to be studied and continued long-term observational studies will be needed. The goal in HCV care needs to go beyond merely achieving an SVR.