Unrecognized liver cirrhosis is common and associated with worse survival in hepatocellular carcinoma: A nationwide cohort study of 3473 patients.

BACKGROUND: Data on unrecognized liver cirrhosis in patients with hepatocellular carcinoma (HCC) are derived mainly from cohorts with a risk of selection bias. OBJECTIVES: In a population-based cohort study we aimed to determine the proportion, characteristics, and prognosis of HCC in patients with unrecognized cirrhosis. METHODS: Using the Swedish quality register for liver cancer and other nationwide registers, we identified all adults with HCC in Sweden between 2012 and 2018 (n = 3,473). RESULTS: The final study cohort comprised 2670 patients with established cirrhosis, of which 1033 (39%) had unrecognized cirrhosis at HCC diagnosis. These patients were more often male, older, and had larger tumors, multinodular cancer, portal vein thrombosis, and extrahepatic metastasis compared to patients with known cirrhosis with HCC and under surveillance (34%). Compared to surveilled patients, those with unrecognized cirrhosis had worse median survival (0.89 years, 95% confidence interval [CI] = 0.78-1.01 vs. 3.79 years, 95%CI = 3.19-4.39), and an adjusted hazard ratio of 2.36 (95%CI = 2.09-2.66). Patients with cirrhosis but not under surveillance (27%) and patients with unrecognized cirrhosis had similar characteristics, such as equal proportions diagnosed at late stage (79%). CONCLUSIONS: Cirrhosis is often not recognized in patients with HCC. Unrecognized cirrhosis is associated with more advanced HCC at diagnosis and a worse prognosis. More efforts are needed to diagnose cirrhosis at an earlier stage.

Targeting population groups with heavier burden of hepatocellular carcinoma incidence: A nationwide descriptive epidemiological study in Sweden.

Contemporary European studies examining associations between socioeconomic status and hepatocellular carcinoma (HCC) incidence are scarce. We aimed to target population groups with a heavier burden of HCC by assessing associations of individual-level sociodemographic variables and neighbourhood deprivation with all-stage and stage-specific HCC incidence rates (IR). Patient and population data stratified by calendar year (2012-2018), sex, age (5-year groups), household income (low, medium and high), country of birth (Nordic, non-Nordic) and neighbourhood deprivation (national quintiles Q1-Q5) were retrieved from Swedish registers. HCC stages were defined by Barcelona Clinic Liver Cancer stages 0 to A (early-stage) and B to D (late-stage). IR (per 100 000 person-years) were estimated by Poisson regression models. Men had four times higher IR than women. IRs increased markedly with lower household income as well as with neighbourhood deprivation. Seven times higher IR was observed among people with a low household income living in the most deprived neighbourhoods (IR 3.90, 95% confidence interval [CI] 3.28-4.64) compared to people with a high household income living in the least deprived neighbourhoods (IR 0.58, 95% CI 0.46-0.74). The gradient across income categories was more pronounced for late-stage than early-stage HCC. IR reached 30 (per 100 000 person-years) for people in the age span 60 to 79 years with low income and 20 for 60 to 79 year old people living in the most deprived neighbourhoods (regardless of income). Men with low household income and/or living in the most deprived neighbourhoods might be considered as primary targets in studies evaluating the cost-effectiveness of screening for early-stage HCC detection.

Incidence, aetiology and related comorbidities of cirrhosis: a Swedish population-based cohort study.

BACKGROUND: The incidence of cirrhosis for individuals in Sweden has previously been reported as stable/low among European countries. However, Swedish population-based studies are scarce and none of them included data from the most recent decade (2010-2019). We aimed to describe the incidence and aetiology of cirrhosis in the Halland region from 2011 to 2018, and to describe the severity and prevalence of liver-related complications and other primary comorbidities at the time of cirrhosis diagnosis. METHODS: We conducted a retrospective cohort study of all patients with cirrhosis in Halland, which has a population of 310,000 inhabitants. Medical records and histopathology registries were reviewed. RESULTS: A total of 598 patients with cirrhosis were identified. The age-standardised incidence was estimated at 23.2 per 100,000 person-years (95% CI 21.3-25.1), 30.5 (95% CI 27.5-33.8) for men and 16.4 (95% CI 14.3-18.7) for women. When stratified by age, the highest incidence rates were registered at age 60-69 years. Men had a higher incidence rate for most age groups when compared to women. The most common aetiology was alcohol (50.5%), followed by cryptogenic cirrhosis (14.5%), hepatitis C (13.4%), and non-alcoholic fatty liver disease (5.7%). Most patients had at least one liver-related complication at diagnosis (68%). The most common comorbidities at diagnosis were arterial hypertension (33%), type 2 diabetes (29%) and obesity (24%). CONCLUSIONS: Based on previous Swedish studies, our results indicate that the incidence of cirrhosis in Sweden might be considerably higher than previously reported. It is uncertain if the incidence of cirrhosis has previously been underestimated or if an actual increment has occurred during the course of the most recent decade. The increased incidence rates of cirrhosis reported in Halland are multifactorial and most likely related to higher incidence rates among the elderly. Pre-obesity and obesity are common in cirrhosis and non-alcoholic fatty liver disease has become an important cause of cirrhosis in Halland.

Socioeconomic and marital status among liver cirrhosis patients and associations with mortality: a population-based cohort study in Sweden.

BACKGROUND: The importance of socioeconomic status for survival in cirrhosis patients is more or less pronounced within different populations, most likely due to cultural and regional differences combined with dissimilarities in healthcare system organisation and accessibility. Our aim was to study the survival of patients with cirrhosis in a population-based Swedish cohort, using available data on marital status, employment status, and occupational skill level. METHODS: We conducted a retrospective cohort study of 582 patients diagnosed with cirrhosis in the Region of Halland (total population 310,000) between 2011 and 2018. Medical and histopathologic data, obtained from registries, were reviewed. Cox regression models were used to estimate associations between survival and marital status (married, never married, previously married), employment status (employed, pensioner, disability retired, unemployed), and occupational skill level (low-skilled: level I; medium-skilled: level II; medium-high skilled: level III; professionals: level IV); adjusting for sex, age, aetiology, Model for End-stage Liver Disease (MELD) score, Child-Pugh class, and comorbidities. RESULTS: Alcohol was the most common aetiology (51%). Most patients were male (63%) and the median age was 66 years. Occupational skill level was associated with the severity of cirrhosis at diagnosis and the prevalence of Child-Pugh C gradually increased from professionals through low-skilled. The mean survival for professionals (6.39 years, 95% CI 5.54-7.23) was higher than for low-skilled (3.00 years, 95% CI 2.33-3.67) and medium-skilled (4.04 years, 95% CI 3.64-4.45). The calculated hazard ratios in the multivariate analysis were higher for low-skilled (3.43, 95% CI 1.89-6.23) and medium-skilled (2.48, 95% CI 1.48-4.12), compared to professionals. When aggregated, low- and medium-skilled groups also had poorer mean survival (3.79 years, 95% CI 3.44-4.14; vs 5.64 years, 95% CI 5.00-6.28) and higher hazard ratios (1.85, 95% CI 1.32-2.61) compared to the aggregated medium-high skilled and professional groups. Marital and employment status were not statistically significant predictors of mortality in the multivariate analysis. CONCLUSIONS: Occupational skill level was strongly associated with mean survival and mortality risk. Poorer prognosis among patients with low and medium occupational skill level could not be explained by differences in sex, age, marital status, employment status, MELD score, Child-Pugh class, or comorbidity.

Frequently Recurrent Takotsubo Syndrome in COPD.

Cardiovascular disease is common among patients with chronic obstructive pulmonary disease (COPD). Takotsubo syndrome (TTS) is a transient cardiac disorder that, in its typical form, involves left ventricular dysfunction with apical ballooning and mimics acute coronary syndrome (ACS). "Bronchogenic TTS" has been proposed as a specific form of TTS (during severe acute dyspnea in asthma or COPD) with atypical presentation. Recurrent TTS in COPD seems to be exceptionally rare since only a handful of clinical cases have previously been reported in the literature. Here, we present a unique case of a frequently recurrent TTS during COPD exacerbation in a 70-year-old woman, with at least 4 different episodes of TTS within 5 years. This case report exemplifies the difficulties of the diagnosis of TTS at the onset of acute COPD exacerbation. Potential pathophysiological mechanisms and therapeutic strategies are also briefly discussed.

SPARC: A Potential Prognostic and Therapeutic Target in Pancreatic Cancer.

Pancreatic cancer is a complex and heterogeneous disease that often lacks disease-specific symptoms in early stages. The malignancy is currently the fourth leading cause of cancer-related death in Western countries. In advanced stages, the overall 5-year survival is less than 1% to 2%. Most available treatments lack convincing cost-efficiency determinations and are generally not associated with relevant success rates. Targeting stromal components and stromal depletion is currently becoming an area of extensive research in pancreatic cancer. In this context, a glycoprotein, SPARC (secreted protein acidic and rich in cysteine) appears to play a central role. Still, the role of SPARC in carcinogenesis is controversial because conflicting results have been reported, and the pathways involved in SPARC signaling are not well established. Nonetheless, SPARC is highly expressed in the tumor stroma, principally in peritumoral fibroblasts, and the overexpression of SPARC in this compartment is associated with poorer prognosis. Interestingly, it has been suggested that SPARC present in the tumor stroma could sequester albumin-bound paclitaxel, enhancing the delivery of paclitaxel into the tumor microenvironment. In the present review, we summarize the known associations between SPARC and pancreatic cancer. Moreover, present and future therapies comprising SPARC-targeting are discussed.

Intervention on toll-like receptors in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with pronounced morbidity and a high mortality rate. Currently available treatments lack convincing cost-efficiency determinations and are in most cases not associated with relevant success rate. Experimental stimulation of the immune system in murine PDA models has revealed some promising results. Toll-like receptors (TLRs) are pillars of the immune system that have been linked to several forms of malignancy, including lung, breast and colon cancer. In humans, TLRs are expressed in the pancreatic cancer tissue and in several cancer cell lines, whereas they are not expressed in the normal pancreas. In the present review, we explore the current knowledge concerning the role of different TLRs associated to PDA. Even if almost all known TLRs are expressed in the pancreatic cancer microenvironment, there are only five TLRs suggested as possible therapeutic targets. Most data points at TLR2 and TLR9 as effective tumor markers and agonists could potentially be used as e.g. future adjuvant therapies. The elucidation of the role of TLR3 in PDA is only in its initial phase. The inhibition/blockage of TLR4-related pathways has shown some promising effects, but there are still many steps left before TLR4 inhibitors can be considered as possible therapeutic agents. Finally, TLR7 antagonists seem to be potential candidates for therapy. Independent of their potential in immunotherapies, all existing data indicate that TLRs are strongly involved in the pathophysiology and development of PDA.

Controversial role of toll-like receptors in acute pancreatitis.

Acute pancreatitis (AP) is a common clinical condition with an incidence of about 300 or more patients per million annually. About 10%-15% of patients will develop severe acute pancreatitis (SAP) and of those, 10%-30% may die due to SAP-associated complications. Despite the improvements done in the diagnosis and management of AP, the mortality rate has not significantly declined during the last decades. Toll-like receptors (TLRs) are pattern-recognition receptors that seem to play a major role in the development of numerous diseases, which make these molecules attractive as potential therapeutic targets. TLRs are involved in the development of the systemic inflammatory response syndrome, a potentially lethal complication in SAP. In the present review, we explore the current knowledge about the role of different TLRs that have been described associated with AP. The main candidate for targeting seems to be TLR4, which recognizes numerous damage-associated molecular patterns related to AP. TLR2 has also been linked with AP, but there are only limited studies that exclusively studied its role in AP. There is also data suggesting that TLR9 may play a role in AP.

Estudio preliminar de las grietas internas en anillos de madera inicial y su relación con características de la estructura anatómica y densidad en Eucalyptus nitens / Preliminary study of internal checks within growth-rings and their relationship with anatomical features and density in Eucalyptus nitens / preliminar das fissuras internas em anéis de madeira inicial e sua relação com características da estrutura anatômica e densidade em Eucalyptus nitens

La presencia de grietas internas dentro de los anillos de crecimiento fue relacionada con la densidad y las características anatómicas de un árbol de Eucalyptus nitens. El diseño experimental incluyó como variables la posición radial y apical. Las grietas internas fueron evaluadas después del secado al aire y a 60ºC. Las características anatómicas y la densidad fueron determinadas mediante métodos normalizados y apoyo de rayos X. La intensidad de las grietas internas fue condicionada por la posición radial y apical en el árbol. Las grietas internas fueron más intensas entre los anillos 4 a 9, y se relacionaron inversamente con la densidad de la madera y directamente con la proporción y diámetro de vasos.

Internal checks within growth rings were correlated with density and anatomical characteristics of Eucalyptus nitens. The radial and longitudinal positions in the tree were the experimental variables. Internal checks were characterized after air drying and after conventional drying at 60°C. The anatomical characteristics and density were determined using standardized methods and the X-ray technique. The size of internal checks was influenced by their radial and longitudinal positions in the tree. Internal checks were larger in growth rings 4 to 9, and were inversely related to wood density and directly related to the proportion and diameter of the vessels.

A presença de fissuras internas dentro dos anéis de crescimento foi relacionada com a densidade e as características anatômicas de uma árvore de Eucaliptus nitens. O desenho experimental incluiu como variáveis a posição radial e apical. As fissuras internas foram avaliadas depois da secagem ao ar e a 60ºC. As características anatômicas e a densidade foram determinadas mediante métodos normalizados e apoio de raios X. A intensidade das fissuras internas foi condicionada pela posição radial e apical na árvore. As fissuras internas foram mais intensas entre os anéis 4 a 9, e se relacionaram inversamente com a densidade da madeira e diretamente com a proporção e diâmetro de vasos.