Down-regulation of miR-150 was recently linked to inflammation and bacterial infection. Furthermore, reduced serum levels of miR-150 were reported from a small cohort of patients with sepsis. We thus ...aimed at evaluating the diagnostic and prognostic value of miR-150 serum levels in patients with critically illness and sepsis.
miR-150 serum levels were analyzed in a cohort of 223 critically ill patients of which 138 fulfilled sepsis criteria and compared to 76 healthy controls. Results were correlated with clinical data and extensive sets of routine and experimental biomarkers.
Measurements of miR-150 serum concentrations revealed only slightly reduced miR-150 serum levels in critically ill patients compared to healthy controls. Furthermore miR-150 levels did not significantly differ in critically ill patients with our without sepsis, indicating that miR-150 serum levels are not suitable for diagnostic establishment of sepsis. However, serum levels of miR-150 correlated with hepatic or renal dysfunction. Low miR-150 serum levels were associated with an unfavorable prognosis of patients, since low miR-150 serum levels predicted mortality with high diagnostic accuracy compared with established clinical scores and biomarkers.
Reduced miR-150 serum concentrations are associated with an unfavorable outcome in patients with critical illness, independent of the presence of sepsis. Besides a possible pathogenic role of miR-150 in critical illness, our study indicates a potential use of circulating miRNAs as a prognostic rather than diagnostic marker in critically ill patients.
Abdominal infections including cholangitis represent a major problem in patients with perihilar cholangiocarcinoma (pCCA). Thus, we investigated bacterial colonization of the bile ducts and ...determined its impact on postoperative outcome focusing on abdominal infections. A cohort of 95 pCCA patients who underwent surgery between 2010 and 2019 with available intraoperative microbial bile cultures were analyzed regarding bile duct colonization and postoperative abdominal infection by group comparisons and logistic regressions. 84.2% (80/95) showed bacterial colonization of the bile ducts and 54.7% (52/95) developed postoperative abdominal infections. Enterococcus faecalis (38.8%, 31/80), Enterococcus faecium (32.5%, 26/80), Enterobacter cloacae (16.3%, 13/80) and Escherichia coli (11.3%, 9/80) were the most common bacteria colonizing the bile ducts and Enterococcus faecium (71.2%, 37/52), Enterococcus faecalis (30.8%, 16/52), Enterobacter cloacae (25.0%, 13/52) and Escherichia coli (19.2%, 10/52) the most common causes of postoperative abdominal infection. Further, reduced susceptibility to perioperative antibiotic prophylaxis (OR = 10.10, p = .007) was identified as independent predictor of postoperative abdominal infection. Bacterial colonization is common in pCCA patients and reduced susceptibility of the bacteria to the intraoperative antibiotic prophylaxis is an independent predictor of postoperative abdominal infections. Adapting antibiotic prophylaxis might therefore have the potential to improve surgical outcome pCCA patients.
Background
Diabetes mellitus (DM) has recently been associated with an increased incidence of such digestive tract malignancies as gastric or colorectal cancer. However, systematic data on the ...prevalence of DM among digestive tract cancer entities, especially in terms of geographic distributions, are lacking.
Methods
We used the Oncology Dynamics database (IQVIA) to identify a total of 80,193 patients with gastrointestinal (GI) cancer (5845 esophagus, 20,806 stomach, 38,138 colon, and 15,414 rectum cancer patients) from eight European and Asian countries.
Results
The overall prevalence of DM among all digestive tract cancer patients was 14.8% (11,866/80,193). In terms of cancer site, DM prevalence was highest in patients with colon (15.5%) or rectal (15.3%) cancer and lowest in patients with esophageal cancer (12.0%). Interestingly, we observed significant differences in DM prevalence between countries. Spain (27.8%, 31.3%) and South Korea (21.0%, 27.9%) had the highest prevalence of DM among gastric and colon cancer patients, while DM prevalence in esophageal (18.8%) and rectal (38.0%) cancer patients was highest in Germany.
Conclusion
Our data revealed a high prevalence of DM among digestive tract cancer patients in Europe and Asia, and showed that DM prevalence varies among digestive tract cancer sites as well as countries.
A hallmark of acute hepatic injury is the recruitment of neutrophils, monocytes and lymphocytes, including natural killer (NK) or T cells, towards areas of inflammation. The recruitment of leukocytes ...from their reservoirs bone marrow or spleen into the liver is directed by chemokines such as CCL2 (for monocytes) and CCL5 (for lymphocytes). We herein elucidated the impact of chemokine receptor inhibition by the dual CCR2 and CCR5 inhibitor cenicriviroc (CVC) on the composition of myeloid and lymphoid immune cell populations in acute liver injury. CVC treatment effectively inhibited the migration of bone marrow monocytes and splenic lymphocytes (NK, CD4 T-cells) towards CCL2 or CCL5 in vitro. When liver injury was induced by an intraperitoneal injection of carbon tetrachloride (CCl4) in mice, followed by repetitive oral application of CVC, flow cytometric and unbiased t-SNE analysis of intrahepatic leukocytes demonstrated that dual CCR2/CCR5 inhibition in vivo significantly decreased numbers of monocyte derived macrophages in acutely injured livers. CVC also reduced numbers of Kupffer cells (KC) or monocyte derived macrophages with a KC-like phenotype, respectively, after injury. In contrast to the inhibitory effects in vitro, CVC had no impact on the composition of hepatic lymphoid cell populations in vivo. Effective inhibition of monocyte recruitment was associated with reduced inflammatory macrophage markers and moderately ameliorated hepatic necroses at 36h after CCl4. In conclusion, dual CCR2/CCR5 inhibition primarily translates into reduced monocyte recruitment in acute liver injury in vivo, suggesting that this strategy will be effective in reducing inflammatory macrophages in conditions of liver disease.
Liver cirrhosis and hepatocellular carcinoma (HCC) represent the endstage of most chronic liver diseases and are a major global health burden. It has been consistently shown that both liver cirrhosis ...and HCC are triggered by inflammatory processes, but the molecular mechanisms linking chronic hepatitis with cirrhosis and HCC are only poorly understood. Recent studies suggested that the intestinal microflora as a main source of portal-vein LPS might play a critical role in this process. Here we summarize the available literature on the role of the gut microbiome in hepatofibrogenesis and -carcinogenesis. Such knowledge might help to develop novel, innovative strategies for the prevention and therapy of liver disease.
The prognosis of heart failure (HF) patients is determined to a decisive extent by comorbidities. The present study investigates the association between a broad spectrum of diseases and the ...occurrence of HF in a large collective of outpatients. This retrospective case control study assessed the prevalence of 37 cardiac and extracardiac diseases in patients with an initial diagnosis of heart failure (ICD-10: I50) in 1,274 general practices in Germany between January 2005 and December 2019. The study is based on the Disease Analyzer database (IQVIA), which contains drug prescriptions, diagnoses, and basic medical and demographic data. Patients with and without heart failure were matched by sex, age, and index year. Hazard regression models were conducted to evaluate the association between different disease entities and heart failure. The present study included 162,246 patients with heart failure and 162,246 patients without heart failure. Mean age SD was 73.7 12.1 years; 52.6% were women. Out of 37 predefined diagnoses, 36 were more prevalent in HF patients. The highest prevalence was primary hypertension (63.4% in HF patients vs. 53.3% in controls, p < 0.001) followed by lipid metabolism disorders (34.6% in HF patients vs. 29.1% in HF patients p < 0.001) and diabetes mellitus type II (32.2% in HF patients vs. 25.2% in controls, p < 0.001). In the regression analysis, 19 diseases were significantly associated with heart failure. Non-cardiovascular diagnoses strongly associated with HF were obesity (HR = 1.46), chronic bronchitis and COPD (HR = 1.41), gout (HR: 1.41), and chronic kidney disease (HR = 1.27). In the present study, we identified a variety of cardiac and extracardiac diseases associated with heart failure. Our data underscore the immense importance of comorbidities, even as early as at the stage of initial diagnosis of heart failure.
Interleukin-8 (IL-8, CXCL8) is a potent chemoattractant for neutrophils and contributes to acute liver inflammation. Much less is known about IL-8 in chronic liver diseases (CLD), but elevated levels ...were reported from alcoholic and hepatitis C-related CLD. We investigated the regulation of IL-8, its receptors CXCR1 and CXCR2 and possible IL-8 responding cells in CLD patients.
Serum IL-8 levels were measured in CLD patients (n = 200) and healthy controls (n = 141). Intrahepatic IL-8, CXCR1 and CXCR2 gene expression was quantified from liver samples (n = 41), alongside immunohistochemical neutrophil (MPO) and macrophage (CD68) stainings. CXCR1 and CXCR2 expression was analyzed on purified monocytes from patients (n = 111) and controls (n = 31). In vitro analyses explored IL-8 secretion by different leukocyte subsets.
IL-8 serum levels were significantly increased in CLD patients, especially in end-stage cirrhosis. Interestingly, patients with cholestatic diseases exhibited highest IL-8 serum concentrations. IL-8 correlated with liver function, inflammatory cytokines and non-invasive fibrosis markers. Intrahepatically, IL-8 and CXCR1 expression were strongly up-regulated. However, intrahepatic IL-8 could only be associated to neutrophil infiltration in patients with primary biliary cirrhosis (PBC). In non-cholestatic cirrhosis, increased IL-8 and CXCR1 levels were associated with hepatic macrophage accumulation. In line, CXCR1, but not CXCR2 or CXCR3, expression was increased on circulating monocytes from cirrhotic patients. Moreover, monocyte-derived macrophages from CLD patients, especially the non-classical CD16⁺ subtype, displayed enhanced IL-8 secretion in vitro.
IL-8 is strongly activated in CLD, thus likely contributing to hepatic inflammation. Our study suggests a novel role of IL-8 for recruitment and activation of hepatic macrophages via CXCR1 in human liver cirrhosis.
Macrophages constitute a major proinflammatory component during chronic liver diseases and are considered a key factor in promoting hepatic fibrosis. However, there is increasing evidence that ...distinct monocyte and macrophage subsets exert critical functions in regression from organ fibrosis as well. Experimental mouse models of fibrosis regression have identified “restorative” macrophages as Ly‐6C (Ly6C, Gr1) low‐expressing, monocyte‐derived cells. We investigated molecular pathways balancing proinflammatory and restorative macrophages during fibrosis regression as well as pharmacologically augmenting beneficial macrophage functionality in fibrosis resolution. Therefore, we employed a Spiegelmer‐based inhibitor of the chemokine, C‐C motif chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1), termed mNOX‐E36, in the regression phase of two murine models of toxic (CCl4) and metabolic (methionine‐choline–deficient diet) liver fibrosis. Although inflammation rapidly declined after cessation of injury, we observed a transient influx of Ly‐6C+ infiltrating monocytes (iMΦ), which are characterized by typical macrophage morphology, up‐regulated expression of CCR2, and the pro‐inflammatory cytokine, tumor necrosis factor (TNF), in injured liver. By inhibiting the early influx of Ly‐6C+ iMΦ by the CCL2 inhibitor, mNOX‐E36, the intrahepatic macrophage equilibration shifted toward the “restorative” Ly‐6C‐ subset of iMΦ. Consequently, fibrosis resolution was significantly accelerated upon mNOX‐E36 administration in both models. Blocking transient recruitment of infiltrating Ly‐6C+ monocytes, but not direct effects of the inhibitor on the remaining macrophages, resulted in reduced intrahepatic levels of proinflammatory cytokines. Conclusion: Transient CCL2‐dependent recruitment of infiltrating Ly‐6C+ monocytes during fibrosis regression counteracts scar resolution by perpetuating inflammatory reactions through release of proinflammatory cytokines such as TNF. Pharmacological inhibition of Ly‐6C+ monocyte recruitment using the CCL2‐inhibitor, mNOX‐E36, accelerates regression from toxic and metabolic liver fibrosis in two independent experimental models. (Hepatology 2014;59:1060–1072)
Summary
Background and Aims
Phase III trials have established atezolizumab plus bevacizumab as the novel standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, these ...trials raised concerns regarding treatment efficacy in non‐viral HCC, and it remains unclear whether combination immunotherapy is safe and effective in patients with advanced cirrhosis.
Methods
One hundred patients with unresectable HCC initiated therapy with atezolizumab plus bevacizumab at our centre between January 2020 and March 2022. The control cohort consisted of 80 patients with advanced HCC who received either sorafenib (n = 43) or lenvatinib (n = 37) as systemic treatment.
Results
Overall survival (OS) and progression‐free survival (PFS) were significantly longer within the atezolizumab/bevacizumab group and comparable to phase III data. The benefits in terms of increased objective response rate (ORR), OS and PFS were consistent across subgroups, including non‐viral HCC (58%). The ROC‐optimised neutrophil‐to‐lymphocyte ratio (NLR) cut‐off of 3.20 was the strongest independent predictor of ORR and PFS. In patients with advanced cirrhosis Child–Pugh B, liver function was significantly better preserved with immunotherapy. Patients with Child–Pugh B cirrhosis showed similar ORR but shorter OS and PFS compared to patients with preserved liver function.
Conclusions
Atezolizumab plus bevacizumab showed good efficacy and safety in patients with unresectable HCC and partially advanced liver cirrhosis in a real‐world setting. Moreover, the NLR was able to predict response to atezolizumab/bevacizumab treatment and may guide patient selection.
Safety and clinical effectiveness of atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma, partially advanced and predominantly non‐viral liver cirrhosis.
Cholangiocarcinoma (CCA) is the second most common primary liver cancer and associated with a dismal prognosis due to the lack of an efficient systemic therapy. In contrast to other cancers, new ...immunotherapies have demonstrated unsatisfactory results in clinical trials, underlining the importance of a deeper understanding of the special tumor microenvironment of CCA and the role of immune cells interacting with the tumor. Tumor-infiltrating lymphocytes (TILs) are an important component of the adaptive immune system and the foundation of current immunotherapy. Therefore, the aim of this systemic review is to summarize the current literature focusing on the proportions and distribution, molecular pathogenesis, prognostic significance of TILs and their role in immunotherapy for CCA patients.In CCA, CD8+ and CD4+ T lymphocytes represent the majority of TILs and are mostly sequestered around the cancer cells. CD20+ B lymphocytes and Natural Killer (NK) cells are less frequent. In contrast, Foxp3+ cells (regulatory T cells, Tregs) are observed to infiltrate into the tumor. In the immune microenvironment of CCA, cancer cells and stromal cells such as TAMs, TANs, MSDCs and CAFs inhibit the immune protection function of TILs by secreting factors like IL-10 and TGF-β. With respect to molecular pathogenesis, the Wnt/-catenin, TGF-signaling routes, aPKC-i/P-Sp1/Snail Signaling, B7-H1/PD-1Pathway and Fas/FasL signaling pathways are connected to the malignant potential and contributed to tumor immune evasion by increasing TIL apoptosis. Distinct subtypes of TILs show different prognostic implications for the long-term outcome in CCA. Although there are occasionally conflicting results, CD8+ and CD4+ T cells, and CD20+ B cells are positively correlated with the oncological prognosis of CCA, while a high number of Tregs is very likely associated with worse overall survival. TILs also play a major role in immunotherapy for CCA.In summary, the presence of TILs may represent an important marker for the prognosis and a potential target for novel therapy, but more clinical and translationaldata is needed to fully unravel the importance of TILs in the treatment of CCA.
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