Inflammation-scores as prognostic markers of overall survival in lung cancer: a register-based study of 6,210 Danish lung cancer patients

Background Inflammation-scores based on general inflammation markers are suggested as prognostic markers of overall survival (OS) in lung cancer. However, whether these inflammation-scores improves the prognostication performed by well-established prognostic markers is unsettled. In a large register-based lung cancer patient cohort, nine different inflammation-scores were compared, and their ability to optimize the prognostication of OS was evaluated. Methods Lung cancer patients diagnosed from 2009–2018 in The Central Denmark Region were identified in the Danish Lung Cancer Registry. Pre-treatment inflammation markers were extracted from the clinical laboratory information system. Prognostication of OS was evaluated by Cox proportional hazard models. Comparison of the inflammation-scores and their added value to established prognostic markers were assessed by Akaike's information criteria and Harrel's C-index. Results In total, 5,320 patients with non-small cell lung cancer (NSCLC) and 890 patients with small cell lung cancer (SCLC) were identified. In NSCLC, the Aarhus composite biomarker score (ACBS), including albumin, C-reactive protein, neutrophil count, lymphocyte count and haemoglobin, and the neutrophil-lymphocyte-ratio (NLR) were superior. Furthermore, they improved the prognostication of OS significantly (p <0.0001) (ACBS: HR: 2.24 (95%CI: 1.97–2.54); NLR: HR: 1.58 (95%CI: 1.47 – 1.69)). In SCLC, three scores were equally superior and improved the prognostication of OS p < 0.0001): neutrophil–lymphocyte-ratio (HR:1.62 (95%CI: 1.38–1.90)), modified Glasgow Prognostic Score (mGPS) (HR:1.70 (95%CI: 1.55–1.86) and the Combined NLR and GPS (CNG) (HR:2.10 (95%CI: 1.77–2.49). Conclusions The ACBS was the optimal score in NSCLC, whereas neutrophil–lymphocyte-ratio, mGPS and CNG were equally superior in SCLC. Additionally, these inflammation-scores all optimised the prognostication of OS and added value to well-established prognostic markers.

Results of the non-interventional observational program: Influence of Novel COroNavirus on the condition of patients with liver and gastrointestinal Tract diseases and the effect of Ursodeoxycholic acid drugs and Rebamipide on the course of COVID-19 infection (CONTUR)

Intriduction. The course and outcome of COVID-19 infection in patients with liver and gastrointestinal tract diseases remain poorly understood. The article presents a multicenter non-interventional observational program conducted by the Russian Society for the Study of the Liver.Aim. To study the relationship between COVID-19 and injuries of gastrointestinal tract and liver, to assess the effect of therapy with UDCA and Rebamipide on the course and outcome of COVID-19 infection. Materials and methods. 460 patients were enrolled in the study, of which 46% were patients with gastrointestinal and liver diseases. Some patients received Rebamipide and UDCA at a dose of 15 mg/kg body weight, followed by assessment of the clinical and laboratory parameters.Results. In the study group, more severe lung injury and the course of infection were observed. The investigators detected three phenotypes of gastrointestinal tract injury: dyspeptic, diarrheal and painful. The latter was more common in patients with gastrointestinal diseases. Liver injury occurred in 87% of patients with COVID-19 (of which 44% had a history of liver disease). Increased ALT and AST were more often recorded in patients with obesity and diabetes mellitus and correlated with the severity of the infection. An inverse relationship was found between the albumin level and death and transfer to mechanical ventilation. At least 5-day Rebamipide therapy leads to reduction of diarrhea and abdominal pain (p < 0.00001 and p = 0.002), decrease in the levels of systemic inflammatory markers (CRP and ferritin, p<0.00001). The use of UDCA leads to a decrease of the systemic inflammation markers: ferritin and is associated with a significant decrease/normalization of ALT levels (p < 0.00001).Conclusions. In patients with diseases of the gastrointestinal tract and liver, COVID-19 develops in a more severe form and symptoms of gastrointestinal tract injury may prevail in the clinical picture. The severity of liver injury correlates with the severity of COVID-19 and a poor prognosis. Rebamipide reduces diarrhea and abdominal pain. UDCA prevents or reduces liver injury in COVID-19 infection. Both drugs reduce the level of systemic inflammation markers.

The Effects of ATIR Blocker on the Severity of COVID-19 in Hypertensive Inpatients and Virulence of SARS-CoV-2 in Hypertensive hACE2 Transgenic Mice

Angiotensin-converting enzyme 2 (ACE2) is required for the cellular entry of the severe acute respiratory syndrome coronavirus 2. ACE2, via the Ang-(1-7)-Mas-R axis, is part of the antihypertensive and cardioprotective effects of the renin-angiotensin system. We studied hospitalized COVID-19 patients with hypertension and hypertensive human(h) ACE2 transgenic mice to determine the outcome of COVID-19 with or without AT1 receptor (AT1R) blocker treatment. The severity of the illness and the levels of serum cardiac biomarkers (CK, CK-BM, cTnI), as well as the inflammation markers (IL-1, IL-6, CRP), were lesser in hypertensive COVID-19 patients treated with AT1R blockers than those treated with other antihypertensive drugs. Hypertensive hACE2 transgenic mice, pretreated with AT1R blocker, had increased ACE2 expression and SARS-CoV-2 in the kidney and heart, 1 day post-infection. We conclude that those hypertensive patients treated with AT1R blocker may be at higher risk for SARS-CoV-2 infection. However, AT1R blockers had no effect on the severity of the illness but instead may have protected COVID-19 patients from heart injury, via the ACE2-angiotensin1-7-Mas receptor axis.

Nonalcoholic Fatty Liver Disease-Associated Liver Fibrosis Is Linked with the Severity of Coronary Artery Disease Mediated by Systemic Inflammation

Background and Aim. Nonalcoholic fatty liver disease (NAFLD) is an independent risk factor for cardiovascular disease. Hepatic fibrosis is the most significant determinant of all-cause- and liver -related mortality in NAFLD. However, the relationship between NAFLD fibrosis and severe coronary artery disease (CAD) remains unclear. Methods and Results. We conducted a retrospective study of 531 patients with ultrasonogram-confirmed NAFLD who underwent percutaneous coronary intervention (PCI). Then, all patients were separated into four categories by Gensini score (0, 0-9, 9-48, and ≥48) for use in ordinal logistic regression analysis to determine whether NAFLD fibrosis was associated with increased Gensini scores. Mediation analysis was used to investigate whether systemic inflammation is a mediating factor in the association between NAFLD fibrosis and CAD severity. FIB − 4 > 2.67 ( OR = 5.67 , 95% CI 2.59-12.38) and APRI > 1.5 ( OR = 14.8 , 95% CI 3.24-67.60) remained to be independent risk factors for the severity of CAD after adjusting for conventional risk factors, whereas among the inflammation markers, only neutrophils and neutrophil-to-lymphocyte ratio (NLR) were independently associated with CAD. Multivariable ordinal regression analysis suggested that increasing Gensini score (0, 0-9, 9-48, and ≥48) was associated with advanced NAFLD fibrosis. ROC curve showed that either fibrosis markers or inflammation markers, integrating with traditional risk factors, could increase the predictive capacity for determining CAD. Inflammation markers, especially neutrophils and NLR, were mediators of the relationship between NAFLD fibrosis and CAD severity. Conclusions. NAFLD patients with advanced fibrosis are at a high risk of severe coronary artery stenosis, and inflammation might mediate the association between NAFLD fibrosis and CAD severity.

Longitudinal Relationship of Liver Injury with Inflammation Biomarkers in Covid-19 Hospitalized Patients Using a Joint Modeling Approach

Background: The mechanisms underlying liver disease in patients with COVID-19 are not entirely known.Aim: To investigate, by means of novel statistical techniques, the changes over time in the relationship between inflammation markers and liver damage markers in relation to survival in COVID-19.Methods: The study included 221 consecutive patients admitted to the hospital during the first COVID-19 wave in Spain. Generalized additive mixed models were used to investigate the influence of time and inflammation markers on liver damage markers in relation to survival. Joint modeling regression was used to evaluate the temporal correlations between inflammation markers (serum C-reactive protein [CRP], interleukin-6, plasma D-dimer, and blood lymphocyte count) and liver damage markers, after adjusting for age, sex, and therapy.Results: The patients who died showed a significant elevation in serum aspartate transaminase (AST) and alkaline phosphatase levels over time. Conversely, a decrease in serum AST levels was observed in the survivors, who showed a negative correlation between inflammation markers and liver damage markers (CRP with serum AST, alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]; and D-dimer with AST and ALT) after a week of hospitalization. Conversely, most correlations were positive in the patients who died, except lymphocyte count, which was negatively correlated with AST, GGT, and alkaline phosphatase. These correlations were attenuated with age. Conclusion: The patients who died during COVID-19 infection displayed a significant elevation of liver damage markers, which is correlated with inflammation markers over time. These results are consistent with the role of systemic inflammation in liver damage during COVID-19.

Elevated Plasma Level of the Glycolysis Byproduct Methylglyoxal on Admission Is an Independent Biomarker of Mortality in ICU COVID-19 Patients

Biomarkers to identify ICU COVID-19 patients at high risk for mortality are urgently needed for therapeutic care and management. In this study we found that plasma levels of the glycolysis byproduct methylglyoxal (MG) were 4.4-fold and 1.7-fold higher (P<0.0001) upon ICU admission in patients that later died (n=34) compared to uninfected controls (n=30) and those survived (n=31), respectively. The increase in MG was inversely correlated with glutathione (r2=-0.63) and the MG-glutathione degrading glyoxalase-1 (r2=-0.50), and positively correlated with the inflammation markers, SSAO (r2 =0.52), TNF-a (r2 =0.41), IL-1b (r2 =0.25), CRP (r2 =0.26) and age (r2 =0.20). Logistic regression analysis provides evidence of a significant relationship between the elevated MG upon admission into ICU and death (P<0.0001), with 42% of the death variability explained. From these data we conclude that elevated plasma MG on admission is a novel independent biomarker that predicts ICU COVID-19 patients at high risk of mortality.

Gut-derived Lipopolysaccharide Promotes Alcoholic Hepatosteatosis and Subsequent Hepatocellular Carcinoma by Stimulating Neutrophil Extracellular Traps Through TLR4

BackgroundBinge drinking leads to many disorders, including alcoholic hepatosteatosis, which is characterized by intrahepatic neutrophil infiltration and which increases the risk of hepatocellular carcinoma (HCC). Molecular mechanisms may involve the migration of bacterial metabolites from the gut to the liver and activation of neutrophil extracellular traps (NETs). MethodsSerum from both binge drinking and alcohol-avoiding patients was analyzed. Mouse models of chronical plus binge alcohol indued steatosis and HCC models were used. ResultsA marker of NETs formation, lipopolysaccharide, was significantly higher in alcoholic steatosis and HCC patients and mice than in controls. Intrahepatic inflammation markers and HCC-related cytokines were decreased in mice with reduced NET formation due to neutrophil elastase (NE) deletion, and liver-related symptoms of alcohol were also alleviated in NE KO mice. Removal of intestinal bacteria with antibiotics led to decreases in markers of NETs formation and inflammatory cytokines upon chronic alcohol consumption, and genesis of alcoholic hepatosteatosis and HCC was also attenuated. These functions were restored upon supplementation with the bacterial product lipopolysaccharide (LPS). When mice lacking TLR4 received chronic alcohol feeding, intrahepatic markers of NETs formation decreased, and hepatosteatosis and HCC were alleviated. ConclusionFormation of NETs following LPS stimulation of TLR4 upon chronic alcohol usage leads to increased alcoholic steatosis and subsequent HCC.

Exercise reduces systemic immune inflammation index (SII) in childhood cancer patients

While exercise and physical activity have been suggested to reduce mortality and symptoms in cancer, knowledge on these associations in patients with childhood cancer (CCPs) is sparse. Anti-inflammatory properties of exercise might mediate these beneficial effects. We investigated the influence of exercise on the inflammation markers neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and systemic-immune-inflammation index (SII) and associations to patient-reported-outcomes in CCPs in a randomized-controlled trial. Results show associations between inflammation markers and patient-reported outcomes. Compared to the control group, SII was significantly reduced following exercise (p=0.036). Anti-inflammatory effects of exercise are also present in CCPs and may underlie exercise-induced benefits on symptoms. Clinical Trial Registration Number: NCT02612025