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Background Quality of the nucleic acids extracted from Formalin Fixed Paraffin Embedded (FFPE) samples largely depends on pre-analytic, fixation and storage conditions. We assessed the differential sensitivity of viral and human double stranded DNA (dsDNA) to degradation with storage time. Methods We randomly selected forty-four HPV16-positive invasive cervical cancer (ICC) FFPE samples collected between 1930 and 1935 and between 2000 and 2004. We evaluated through qPCR the amplification within the same sample of two targets of the HPV16 L1 gene (69 bp, 134 bp) compared with two targets of the human tubulin-β gene (65 bp, 149 bp). Results Both viral and human, short and long targets were amplified from all samples stored for 15 years. In samples archived for 85 years, we observed a significant decrease in the ability to amplify longer targets and this difference was larger in human than in viral DNA: longer fragments were nine times (CI 95% 2.6–35.2) less likely to be recovered from human DNA compared with 1.6 times (CI 95% 1.1–2.2) for viral DNA. Conclusions We conclude that human and viral DNA show a differential decay kinetics in FFPE samples. The faster degradation of human DNA should be considered when assessing viral DNA prevalence in long stored samples, as HPV DNA detection remains a key biomarker of viral-associated transformation.

Aims Neuroendocrine tumors (NET) of the cervix are rare tumors with a very aggressive course. The human papillomavirus (HPV) has been linked to its etiology. The objective of this study is to describe HPV prevalence and genotype distribution of NET. Methods and Results Forty-nine tumors with histological neuroendocrine features were identified among 10,575 invasive cervical cancer (ICC) cases from an international study. HPV DNA detection was done using SPF10/DEIA /LiPA25 system. Immunohistochemical (IHC) staining for neuroendocrine markers (chromogranin A, synaptophysin, CD56) and for p16INK4a as a surrogate for HPV transforming infection was performed. In 13 samples with negative IHC for all 3 neuroendocrine markers studied, it was possible to conduct electron microscopy (EM). NET represented 0.5% of the total ICC series and HPV was detected in 42 out of 49 samples (85.7%, 95%CI:72.8%,94.1%). HPV16 was the predominant type (54.8%), followed by HPV18 (40.5%). p16INK4a overexpression was observed in 38/44 cases (86.4%). Neuroendocrine IHC markers could be demonstrated in 24/37 (64.9%) cases. EM identified neuroendocrine granules in 8 samples with negative IHC markers. Conclusions Our data confirms the association of cervical NET with HPV and p16INK4a overexpression. Specifically, HPV16 and 18 accounted together for over 95% of the HPV positive cases. Current HPV vaccines could largely prevent these aggressive tumors., Highlights • Neuroendocrine tumors of the cervix are rare tumors with aggressive course. • We identified HPV DNA in 85.7% of neuroendocrine tumors analyzed. • HPV16 and 18 accounted together for over 95% of the HPV DNA positive cases.

OBJECTIVES The aim of this study was to analyze whether scar characterization could improve the risk stratification for life-threatening ventricular arrhythmias and sudden cardiac death (SCD). BACKGROUND Among patients with a cardiac resynchronization therapy (CRT) indication, appropriate defibrillator (CRT-D) therapy rates are low. METHODS Primary prevention patients with a class I indication for CRT were prospectively enrolled and assigned to CRT-D or CRT pacemaker according to physician's criteria. Pre-procedure contrast-enhanced cardiac magnetic resonance was obtained and analyzed to identify scar presence or absence, quantify the amount of core and border zone (BZ), and depict BZ distribution. The presence, mass, and characteristics of BZ channels in the scar were recorded. The primary endpoint was appropriate defibrillator therapy or SCD. RESULTS 217 patients (39.6% ischemic) were included. During a median follow-up of 35.5 months (12 to 62 months), the primary endpoint occurred in 25 patients (11.5%) and did not occur in patients without myocardial scar. Among patients with scar (n = 125, 57.6%), those with implantable cardioverter-defibrillator (ICD) therapies or SCD exhibited greater scar mass (38.7 +/- 34.2 g vs. 17.9 +/- 17.2 g; p < 0.001), scar heterogeneity (BZ mass/scar mass ratio) (49.5 +/- 13.0 vs. 40.1 +/- 21.7; p = 0.044), and BZ channel mass (3.6 +/- 3.0 g vs. 1.8 +/- 3.4 g; p = 0.018). BZ mass (hazard ratio: 1.06 [95% confidence interval: 1.04 to 1.08]; p < 0.001) and BZ channel mass (hazard ratio: 1.21 [95% confidence interval: 1.10 to 1.32]; p < 0.001) were the strongest predictors of the primary endpoint. An algorithm based on scar mass and the absence of BZ channels identified 148 patients (68.2%) without ICD therapy/SCD during follow-up with a 100% negative predictive value. CONCLUSIONS The presence, extension, heterogeneity, and qualitative distribution of BZ tissue of myocardial scar independently predict appropriate ICD therapies and SCD in CRT patients. (c) 2018 by the American College of Cardiology Foundation.

Discurs de presentació del professor Victor Moreno Aguado, Discurs de la solemne investidura acadèmica de conferiment del grau de doctor honoris causa al senyor Francesc Xavier Bosch i José. El professor Víctor Moreno Aguado repassa la trajectòria del prestigiós oncòleg, posant èmfasi en les seves importants aportacions en la prevenció del càncer.

Discurs de presentació del professor Victor Moreno Aguado Discurs de la solemne investidura acadèmica de conferiment del grau de doctor honoris causa al senyor Francesc Xavier Bosch i José. El professor Víctor Moreno Aguado repassa la trajectòria del prestigiós oncòleg, posant èmfasi en les seves importants aportacions en la prevenció del càncer.

ResumenObjetivoEstimar el número de neoplasias incidentes en España para el período 1993-1996.MétodosSe han utilizado los datos disponibles de incidencia de los 9 registros poblacionales de cáncer de España publicados en la monografía Cancer Incidence in Five Continents, vols VI y VII (período 1983-1992) y los de mortalidad proporcionados por el Instituto Nacional de Estadística (período 1983- 1996). Para estimar el número de casos incidentes se han utilizado modelos lineales generalizados mixtos. Se ha modelado la razón incidencia/mortalidad. La provincia de residencia se ha considerado un efecto aleatorio para tener en cuenta la heterogeneidad. Otros factores considerados fueron el sexo, la edad y el período. Los parámetros de los modelos se han estimado por una aproximación bayesiana mediante el software BUGS. Para validar las estimaciones se ha comparado el número de casos observados con los estimados para aquellas provincias en las que se disponía de información.ResultadosEl promedio de casos incidentes anuales para la totalidad de tumores, excepto el de piel no melanoma, en el período 1993-1996 es de 78.440 en los varones y 55.480 en las mujeres. La neoplasia más frecuente en los varones es la de pulmón, con 15.480 casos, seguida de la de vejiga, con 9.445, y la colorrectal, con 8.876 casos. En las mujeres el cáncer más frecuente es el de mama, con 13.490 casos, seguido por el colorrectal, con 8.274 casos. Estas frecuencias absolutas indican una tendencia ascendente para el total de cáncer y para las localizaciones más frecuentes, con excepción del estómago y el cuello de útero. La validación interna de las estimaciones permite calcular que el error relativo es inferior al 10%.ImplicacionesSe presenta por primera vez una estimación del número de casos incidentes de cáncer en España cal-culado con una metodología que considera la heterogeneidad. Estos datos permiten situar al cáncer como uno de los principales problemas de salud en nuestro país.SummaryObjectiveTo estimate the number of incident cases of cancer in Spain between 1993 and 1996.MethodsWe used data on the incidence of cancer from nine Spanish population-based cancer registries published in the monograph Cancer incidence in Five Continents, vols. VI and VII (period 1983-92). The National Institute of Statistics provided mortality data (period 1983-96). Generalized linear mixed models were used to estimate the number of incident cases. The incidence/mortality ratio was modeled. To account for heterogeneity, the providence of residence was considered as a random effect. Other factors analyzed were sex, age and period. Model parameters were estimated using a Bayesian approach with BUGS software. Estimates were valdated by comparing the observed number of cases with those predicted by the model in the regions with cancer registry data.ResultsThe average number of incident cases per annum for all cancer sites except non-melanoma skin cancer was 78,440 for men and 55,480 for women. The most frequent neoplasm in men was lung with 15,480 cases followed by bladder with 9,445 cases and colorectal with 8,876 cases. In women the most frequent cancer was breast with 13,490 cases followed by colorectal with 8,274 cases. These absolute frequencies showed an increasing time trend for all cancers and for the most frequent sites, with the exception of stomach and uterine cervix. Internal validation of the estimates allowed calculation of a relative error smaller than 10%.ImplicationsThis is the first time that the number of incident cases of cancer in Spain has been estimated with methods that account for heterogeneity. These figures show the importance of cancer as a public health problem in our community.

Background Human papillomavirus (HPV) is a sexually transmitted infection that may lead to development of precancerous and cancerous lesions of the cervix. The aim of the current study was to investigate socio-demographic, lifestyle, and medical factors for potential associations with cervical HPV infection in women undergoing cervical cancer screening in Spain. Methods The CLEOPATRE Spain study enrolled 3 261 women aged 18–65 years attending cervical cancer screening across the 17 Autonomous Communities. Liquid-based cervical samples underwent cytological examination and HPV testing. HPV positivity was determined using the Hybrid Capture II assay, and HPV genotyping was conducted using the INNO-LiPA HPV Genotyping Extra assay. Multivariate logistic regression was used to identify putative risk factors for HPV infection. Results A lifetime number of two or more sexual partners, young age (18–25 years), a history of genital warts, and unmarried status were the strongest independent risk factors for HPV infection of any type. Living in an urban community, country of birth other than Spain, low level of education, and current smoking status were also independent risk factors for HPV infection. A weak inverse association between condom use and HPV infection was observed. Unlike monogamous women, women with two or more lifetime sexual partners showed a lower risk of infection if their current partner was circumcised (P for interaction, 0.005) and a higher risk of infection if they were current smokers (P for interaction, 0.01). Conclusion This is the first large-scale, country-wide study exploring risk factors for cervical HPV infection in Spain. The data strongly indicate that variables related to sexual behavior are the main risk factors for HPV infection. In addition, in non-monogamous women, circumcision of the partner is associated with a reduced risk and smoking with an increased risk of HPV infection.

Background: Infection with human papilloma virus (HPV) is the main cause of cervical cancer, but the risk associated with the various HPV types has not been adequately assessed. Methods: We pooled data from 11 case-control studies from nine countries involving 1918 women with histologically confirmed squamous-cell cervical cancer and 1928 control women. A common protocol and questionnaire were used. Information on risk factors was obtained by personal interviews, and cervical cells were collected for detection of HPV DNA and typing in a central laboratory by polymerase-chain-reaction-based assays (with MY09/MY11 and GP5+/6+ primers). Results: HPV DNA was detected in 1739 of the 1918 patients with cervical cancer (90.7 percent) and in 259 of the 1928 control women (13.4 percent). With the GP5+/6+ primer, HPV DNA was detected in 96.6 percent of the patients and 15.6 percent of the controls. The most common HPV types in patients, in descending order of frequency, were types 16, 18, 45, 31, 33, 52, 58, and 35. Among control women, types 16, 18, 45, 31, 6, 58, 35, and 33 were the most common. For studies using the GP5+/6+ primer, the pooled odds ratio for cervical cancer associated with the presence of any HPV was 158.2 (95 percent confidence interval, 113.4 to 220.6). The odds ratios were over 45 for the most common and least common HPV types. Fifteen HPV types were classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82); 3 were classified as probable high-risk types (26, 53, and 66); and 12 were classified as low-risk types (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108). There was good agreement between our epidemiologic classification and the classification based on phylogenetic grouping. Conclusions: In addition to HPV types 16 and 18, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should be considered carcinogenic, or high-risk, types, and types 26, 53, and 66 should be considered probably carcinogenic.

[eng] Low risk Human Papillomaviruses (LR-HPVs) 6 and 11 are the main causative agents of benign proliferative lesions such genital warts (GWs) and recurrent respiratory papillomatosis (RRP) (Aubin et al. 2008; Ball et al. 2011; Garland et al. 2009; Prétet et al. 2008). High Risk HPV (HR-HPV) 16 is the most oncogenic type and is responsible for invasive cancers (IC) of cervix (ICC), vulva (IVuC), vagina (IVaC), penis (IPeC) and anus (IAnC) (Alemany et al. 2014, 2015, 2016; Larsson et al. 2013; de Sanjose et al. 2010). The well-established connection between HPV16 infection and IC is observed for the most prevalent ICC histological presentations namely squamous cell carcinomas (SCC), adenocarcinomas (ADC) and adenosquamous cell carcinomas (ADSC) (de Sanjose et al. 2010). All these three HPVs (HPV6, HPV11 and HPV16) are the most prevalent in their associated pathological outcomes (Alemany et al. 2014, 2015, 2016; Aubin et al. 2008; Ball et al. 2011; Garland et al. 2009; Larsson et al. 2013; Prétet et al. 2008; de Sanjose et al. 2010). At level of HPV variants, previous studies have addressed differential HPV6 and HPV11 lineage distributions in GWs and RRP, but mainly at a national or regional level (Kocjan et al., 2009). Although without large sample size, some studies describe differential prevalence of HPV variants among distinct pathologies (Danielewski et al. 2013; Jelen et al. 2014). For HPV6, it has been observed a higher presence of HPV6_B1 variants in GWs compared to RRPs (Flores-Díaz et al. 2017b). HPV16 variant distribution has been mainly focused on the uterus cervix and less on other anatomical sites (Cornet et al. 2012; Yamada et al. 1997), what emphasizes the still wanting research of HPV16 viral lineages in other anogenital cancer location (non-cervical cancers). Some studies show that HPV16 variants in anogenital cancers are largely the same regardless of cancer anatomical locations (ICC, IVuC, IVaC, IAnC and IPeC) , showing increased prevalence of HPV16 A1-3 for all IC of squamous nature (de Koning, Quint, and Pirog 2008; Larsson et al. 2013; Ouhoummane et al. 2013; Tornesello et al. 2008; Zuna et al. 2011). HPV16 variants have been widely studied in SCC (Cornet et al. 2012; Zuna et al. 2011), as this histological type remains the most prevalent ICC (Vinh-Hung et al. 2007; Vizcaino et al. 2000). Nonetheless, data available is poorer for other cervical cancer histological presentations such ADC and ADSC. Although few studies had addressed other glandular histologies, they had been restricted to local geographic origin or small populations (Burk et al. 2003; Lizano 2006; Qmichou et al. 2013; Tornesello et al. 2011). Previously described background, shows an increased prevalence of HPV16_A1-3 variants in SCCs (Zuna et al. 2011) while an enhanced presence of HPV16_D in ADCs (Burk et al. 2003; Mirabello et al. 2016; Quint et al. 2010). Regarding HPV16 intratype variability, it has grown the interest of researchers on the T350G E6 polymorphism as data shows an increased oncogenic potential of those variants containing the 350G allele (Grodzki et al. 2006; Jackson et al. 2016; Zehbe et al. 1998, 2001). Finally, most of the data published do not show results regarding age at tumour diagnosis or use different age definitions such age at enrollment (Mirabello et al. 2016). According to the HPV variant context, the works presented in this thesis try to provide all together information about LR-HPV6 and 11 and HR-HPV16 variant diversity among different lesions, cancers and among different geographical regions with a worldwide spectrum, analyzing large number of HPV monoinfected samples, strategy that prevents possible added bias introduced by co-infections or multi-infections. Through these manuscripts we present for the first time the relative contributions of variant differential abundance, geographical origin, cancer anatomical locations and IC histological presentations to the observation of differential prevalence distribution of HPV16 variants. Through our cases data, we show concordant results with previous published works, observing an increased prevalence of HPV6 B1 variants in GWs, of HPV16 A1-3 variants in anogenital cancers of squamous nature and of HPV16 D variants in ADC. We further show determinate geographical structure of HPV16 variants largely based on the dominance of HPV16 A1-3 variants in Europe, the virtually exclusive presence of HPV16 B and C variants in Africa, the increased prevalence of HPV16 A4 variants in Asia and the enrichment of HPV16 D variants in the Americas. For the most oncogenic-related polymorphism, the E6- T350G, we further show different allelic frequencies according to geographical location independently of the anogenital cancer analyzed, revealing an enhanced 350G allele frequency in isolates from Central-South America compared with Europe. Additionally, we confirme the worldwide trend of cervical cancers to be diagnosed significantly earlier than other anogenital cancers and at histological level, we further present that ADC are diagnosed earlier (mid-forties) than SCC (mid-fifties). According to the previous context, our results complement and may expand those communicated. The current data suggests that the outcome of the virus-host interaction depends on the combination of phylogeny (i.e. the individual genetic background of both virus and patient) and ontogeny (i.e. the differential susceptibility of different tissues) and for HPV16, provide integrating knowledge of variant-specific differential risk that may impact the future screening algorithms, helping to ensure proper early detection of, for example, elusive ADCs. Furthermore, our data emphasizes the necessity of developing deep analyses in HPV variant field. Additionally, the monitoring of initial steps in viral colonization of anogenital mucosas and the follow-up of differential viral persistences according to patient genetic background, may be of remarkable importance. All these research might ultimately provide answers about the extent of the differential fitness of HPV viral lineages and will help to understand the virus-host interplay for the most oncogenic HPVs. Additionally, in vaccinated women follow-up, tracing HPV variants may need to keep more attention as, although not described any evidence, they may be indeed, a possible causative agent of not expected pathological outsiders., [spa] Descripción de la distribución diferencial de variantes de los virus del Papiloma humano 6 y 11 (VPH6 y VPH11) en sus patologías asociadas: verrugas genitales y papilomatosis respiratória recurrente. Descripción de la distribución diferencial de variantes del virus del Papiloma humano 16 (VPH16) en cánceres anogenitales humanos y en los distintos tipos hisológicos de cancer de cérvix (escamoso, adenoescamoso y adenocarcinoma). Para las variantes de VPH16, se decribe su distribución geográfica a nivel mundial y se cuantifica la contribución relativa de la distinta abundancia de las variantes de VPH16, localización anatómica del cáncer,histología y geografía respecto a la observación diferencial de las variantes de VPH16.

En esta tesis doctoral se han evaluado indicadores asociados a las principales estrategias propuestas de cribado vigentes en Catalunya desde el año 2006, incluyendo la evaluación de la participación en el cribado, intervalo entre visitas de cribado y el uso de la prueba de virus del papiloma humano (VPH) en el manejo de lesiones diagnosticadas con células escamosas atípicas de significado indeterminado (ASC-US), en la población atendida en el Sistema Nacional de Salud de Catalunya durante el periodo 2008-2015. En la presente tesis se destaca la importancia de mejorar la adherencia de la población a las actividades preventivas del cáncer de cuello uterino. El uso de VPH en estrategias de triaje da un excelente rendimiento y permite reforzar su utilidad como herramienta de cribado. El uso de bases de datos centralizados facilita la monitorización y evaluación de las actividades sanitarias en cribados poblacionales. Estas conclusiones están contempladas en el protocolo para un programa de prevención de cáncer de cuello uterino recientemente aprobado por el Departament de Salut de la Generalitat de Catalunya., Cervical cancer could be prevented by vaccination and screening. To assess the main strategies undertaken for the prevention of cervical cancer Catalonia since 2006 we estimated the major indicators associated to different recommendations. We evaluated the coverage, participation, interval between visits and the use of human papillomavirus test in cytological findings of atypical squamous cell of undetermined significance (ASC-US), in the National Health System from 2008 until 2015. In the present thesis, we highlight the importance of improvement adherence in cervical cancer screening activities. Furthermore, the introduction of the HPV test as a triage test proved to be in line with significant screening improvements. The use of centralized data bases is crucial for an adequate surveillance of the screening activities. These conclusions are covered by the protocol for a cervical cancer prevention program recently approved by Health Department of the Generalitat de Catalunya.

INTRODUCCIÓN:Diversos estudios epidemiológicos han mostrado la infección crónica por el virus de la hepatitis B (VHB) como factor etiológico del cáncer hepático (CH) y en las dos últimas décadas se ha constatado un incremento de la incidencia de éste en los países industrializados. Sin embargo, los factores de progresión a CH en portadores del VHB han sido estudiados mayoritariamente en países asiáticos, por lo que es importante determinar cuál es su incidencia en Catalunya. OBJETIVOSDeterminar: i) la tendencia de la incidencia y la mortalidad por cirrosis y cáncer hepático en Catalunya en el período 1980-1997; ii) la mortalidad por enfermedad hepática en una cohorte de 2.352 donantes de sangre infectados por el VHB; iii) los factores de riesgo de desarrollar enfermedad hepática en individuos infectados por el VHB.METODOLOGÍAi) los datos de incidencia y mortalidad por cirrosis y CH en Catalunya se recogieron a partir del Registro de Cáncer Poblacional de Tarragona y del Registro de Mortalidad de Catalunya. Las tendencias se evaluaron mediante el análisis joinpoint y el análisis edad-período-cohorte; ii) como grupo control se escogió a 15.504 donantes de sangre no infectados por el VHB. La cohorte y el grupo control se cruzaron con el Registro de Mortalidad de Catalunya para determinar el estado vital y la causa de defunción de los individuos fallecidos. El exceso de mortalidad de la cohorte respecto al grupo control se determinó mediante la Razón de la Mortalidad Estandarizada; iii) se invitó a la cohorte a una visita médica en el periodo 1994-1996, que incluyó una exploración médica, análisis de sangre (función hepática y marcadores serológicos de los virus hepatotrópicos) y un cuestionario epidemiológico. El cuestionario recogió la exposición a diversos factores de riesgo asociados a enfermedad hepática. Los sujetos diagnosticados de hepatopatía fueron los casos y los sujetos con función hepática normal los controles del estudio caso-control anidado en la cohorte. La asociación de cada factor de riesgo y la enfermedad hepática se determinó mediante la razón de las odds (OR). RESULTADOS i) En el período de estudio se constató una disminución de la mortalidad por cirrosis (- 3% anual) en ambos sexos, a excepción de los hombres de 25 a 35 años en que la mortalidad por esta causa aumentó (4.5% de incremento anual). La mortalidad y la incidencia del CH permanecieron estables en ambos sexos y en todos los grupos de edad. Se constató un incremento de la mortalidad por colangiocarcinoma en ambos sexos (10% de incremento anual). ii) Exceso de mortalidad por CH y cirrosis en los hombres infectados por el VHB respecto a los del grupo control (RME CH: 17.7; RME cirrosis: 10.5). En las mujeres, solo se evidenció un exceso de muertes por cirrosis respecto a las del grupo control (RME: 7.2). iii) Los factores de progresión a enfermedad hepática en individuos infectados por el VHB fueron: la replicación del VHB (OR: 20.5 IC95%: 7.9-53.0), historia de episodios de hepatitis agudas (OR: 2.3 IC 95%: 1.3-4.2), el consumo de alcohol (OR: 2.4 IC 95%: 1.5-4.1), la infección por el VHC (OR: 6.9 IC95%: 2.3-20.5). Se constató una interacción entre el consumo de alcohol y la historia de episodios de hepatitis agudas, y posiblemente, entre el consumo de alcohol y diabetes.CONCLUSIONESi) No se ha constatado en Catalunya un aumento de la incidencia y de la mortalidad por CH como en otros países industrializados. Si se ha constatado un incremento de la mortalidad por colangiocarcinoma; ii) Los individuos infectados por el VHB tienen un exceso de mortalidad por enfermedad hepática respecto a los individuos no infectados por el VHB; iii) La replicación del VHB, los antecedentes de episodios de hepatitis agudas, el consumo de alcohol y la coinfección por el VHC incrementan el riesgo de desarrollar enfermedad hepática en individuos infectados por el VHB., GOALS:To Determine: i) time trends on incidence and mortality by cirrhosis and liver cancer in Catalonia during the period 1980-1997; ii) the mortality by liver disease in a cohort of 2352 blood donors infected by the Hepatitis B Virus (HBV); iii) risk factors to develop liver disease in HBV infected individuals.METHODS: i) Liver cancer incidence and mortality and cirrhosis mortality data were extracted from the population-based cancer registry of Tarragona and from the Catalan Mortality Registry. Statistical analysis: joinpoint analysis and an age-period-cohort modeling. ii) Control Group: 15504 blood donors non-infected by HBV. Record Linkage of the cohort and the control group with the Catalan Mortality Registry. Statistical Analysis: Standardized Mortality Ratios for all causes of death in the cohort. iii) Nested case-control study in the cohort. Cases: ndividuals with liver disease. Controls: individuals without liver disease. Statistical analysis: logistic regression in order to estimate the odds ratios.RESULTS AND CONCLUSIONS:i) During the period of study it has been shown: stability of the incidence and mortality by liver cancer in Catalonia, and a decrease in the mortality by cirrhosis in both sexes excluding males aged 25-35 years old in which mortality by this cause of death increased, and an increase by death of cholangiocarcinoma in both sexes. ii) An excess of risk of death by liver cancer and cirrhosis in the cohort men when they were compared with the control group. It has been observed an excess mortality by cirrhosis in the cohort women. iii) Risk factors associated to de development of liver disease in individuals infected by HBV were replication of HBV, acute hepatitis history, alcohol consumption and Hepatitis C virus infection.