The Role of Macrophages in Hepatocellular Carcinoma and Their Therapeutic Potential

Hepatocellular carcinoma (HCC) represents a significant clinical burden globally and is predicted to continue to increase in incidence for the foreseeable future. The treatment of HCC is complicated by the fact that, in the majority of cases, it develops on a background of advanced chronic inflammatory liver disease. Chronic inflammation can foster an immunosuppressive microenvironment that promotes tumour progression and metastasis. In this setting, macrophages make up a major immune component of the HCC tumour microenvironment, and in this review, we focus on their contribution to HCC development and progression. Tumour-associated macrophages (TAMs) are largely derived from infiltrating monocytes and their potent anti-inflammatory phenotype can be induced by factors that are found within the tumour microenvironment, such as growth factors, cytokines, hypoxia, and extracellular matrix (ECM) proteins. In general, experimental evidence suggest that TAMs can exhibit a variety of functions that aid HCC tumour progression, including the promotion of angiogenesis, resistance to drug therapy, and releasing factors that support tumour cell proliferation and metastasis. Despite their tumour-promoting profile, there is evidence that the underlying plasticity of these cells can be targeted to help reprogramme TAMs to drive tumour-specific immune responses. We discuss the potential for targeting TAMs therapeutically either by altering their phenotype within the HCC microenvironment or by cell therapy approaches by taking advantage of their infiltrative properties from the circulation into tumour tissue

Evaluation of {CirrhoCare}{\textregistered} - A digital-health solution for home management of patients with cirrhosis

Cirrhosis patients discharged from hospital following acute decompensation are at high-risk of new complications. This study aimed to assess the feasibility and potential clinical benefits of remote management of acutely decompensated cirrhosis patients using CirrhoCare®

Evaluation of CirrhoCare® - A digital-health solution for home management of patients with cirrhosis

BACKGROUND: Cirrhosis patients discharged from hospital following acute decompensation are at high-risk of new complications. This study aimed to assess the feasibility and potential clinical benefits of remote management of acutely decompensated cirrhosis patients using CirrhoCare®. METHODS: Cirrhosis patients with acute decompensation were followed with CirrhoCare® and compared with contemporaneous matched controls, managed with standard follow-up. Commercially available monitoring devices were linked to the smartphone CirrhoCare®-App, for daily recording of heart rate, blood pressure, weight, % body-water, cognitive function [CL-Animal Recognition Test (CL-ART) App], self-reported well-being and, intake of food, fluid and alcohol. The App had 2-way patient-physician communication. Independent external adjudicators assessed appropriateness of CirrhoCare-based decisions. RESULTS: Twenty-cirrhotic patients were recruited to CirrhoCare® (mean age 59±10 years, 14-male, alcoholic cirrhosis (80%), mean MELD-Na score 16.1±4.2) and were not statistically different to twenty contemporaneous controls. Follow up was 10.1±2.4 weeks. Fifteen-patients showed good engagement (≥4 readings/week), 2 moderate (2-3/week), and 3 poor (14 days. Sixteen other CirrhoCare-guided patient contacts were made, leading to clinical interventions that prevented further progression. Appropriateness was confirmed by adjudicators. Controls had 13-readmissions in 8-patients, lasting median 7 (IQR 3-15) days with 4-admissions of >14 days. They had 6 unplanned paracenteses compared to 1 in the CirrhoCare® group. CONCLUSIONS: This study demonstrates CirrhoCare® is feasible for community management of decompensated cirrhosis patients with good engagement and clinically-relevant alerts to new decompensating events. CirrhoCare® managed patients have fewer and shorter readmissions justifying confirmatory larger controlled clinical trials. LAY SUMMARY: This first study of digital, real-time, home management for multiple complications of advanced cirrhosis, with CirrhoCare®, showed positive patient engagement and feedback in patients with mainly alcohol-related cirrhosis, following a recent hospital discharge. CirrhoCare® allowed early diagnosis of new complications for patients at home, prompting their hepatologists to intervene over >10 weeks follow-up. CirrhoCare® managed patients had fewer and shorter hospital readmissions, as well as less unplanned abdominal fluid drains than in a control group. CirrhoCare® is a promising tool for specialist, community management of cirrhosis patients, at-risk of new cirrhosis complications

National study of NAFLD management identifies variation in delivery of care in the UK between 2019 to 2022

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is associated with liver and cardiovascular morbidity and mortality. Recently published NAFLD Quality Standards include 11 key performance indicators (KPIs) of good clinical care. This national study, endorsed by British Association for the Study of the Liver (BASL) and British Society of Gastroenterology (BSG), aimed to benchmark NAFLD care in UK hospitals against these KPIs. Methods: This study included all new patients with NAFLD reviewed in the outpatient clinic in the months of March 2019 and March 2022. Participating UK hospitals self-registered for the study through BASL/BSG. KPI outcomes were compared using Fisher's exact or Chi-square tests. Results: Data from 776 patients with NAFLD attending 34 hospitals (England [25], Scotland [four], Wales [three], Northern Ireland [two]) were collected. A total of 85.3% of hospitals reported established local liver disease assessment pathways, yet only 27.9% of patients with suspected NAFLD had non-invasive fibrosis assessment documented at the point of referral to secondary care. In secondary care, 79.1% of patients had fibrosis assessment. Assessment of cardiometabolic risk factors including obesity, type 2 diabetes, hypertension, and smoking were conducted in 73.2%, 33.0%, 19.3%, and 54.9% of all patients, respectively. There was limited documentation of diet (35.7%) and exercise advice (55.1%). Excluding those on statins, only 9.1% of patients with NAFLD at increased cardiovascular risk (T2DM and/or QRISK-3 >10%) had documented discussion of statin treatment. Significant KPI improvements from 2019 to 2022 were evident in use of non-invasive fibrosis assessment before secondary care referral, statin recommendations, and diet and exercise recommendations. Conclusions: This national study identified substantial variation in NAFLD management in the UK with clear areas for improvement, particularly fibrosis risk assessment before secondary care referral and management of associated cardiometabolic risk factors. Impact and implications: This study identified significant variation in the management of NAFLD in the UK. Only 27.9% of patients with suspected NAFLD had non-invasive fibrosis assessment performed to identify those at greater risk of advanced liver disease before specialist referral. Greater emphasis is needed on the management of associated cardiometabolic risk factors in individuals with NAFLD. Hospitals with multidisciplinary NAFLD service provision had higher rates of fibrosis evaluation and assessment and management of cardiometabolic risk than hospitals without multidisciplinary services. Further work is needed to align guideline recommendations and real-world practice in NAFLD care

The surgical safety checklist and patient outcomes after surgery: a prospective observational cohort study, systematic review and meta-analysis

© 2017 British Journal of Anaesthesia Background: The surgical safety checklist is widely used to improve the quality of perioperative care. However, clinicians continue to debate the clinical effectiveness of this tool. Methods: Prospective analysis of data from the International Surgical Outcomes Study (ISOS), an international observational study of elective in-patient surgery, accompanied by a systematic review and meta-analysis of published literature. The exposure was surgical safety checklist use. The primary outcome was in-hospital mortality and the secondary outcome was postoperative complications. In the ISOS cohort, a multivariable multi-level generalized linear model was used to test associations. To further contextualise these findings, we included the results from the ISOS cohort in a meta-analysis. Results are reported as odds ratios (OR) with 95% confidence intervals. Results: We included 44 814 patients from 497 hospitals in 27 countries in the ISOS analysis. There were 40 245 (89.8%) patients exposed to the checklist, whilst 7508 (16.8%) sustained ≥1 postoperative complications and 207 (0.5%) died before hospital discharge. Checklist exposure was associated with reduced mortality [odds ratio (OR) 0.49 (0.32–0.77); P\u3c0.01], but no difference in complication rates [OR 1.02 (0.88–1.19); P=0.75]. In a systematic review, we screened 3732 records and identified 11 eligible studies of 453 292 patients including the ISOS cohort. Checklist exposure was associated with both reduced postoperative mortality [OR 0.75 (0.62–0.92); P\u3c0.01; I2=87%] and reduced complication rates [OR 0.73 (0.61–0.88); P\u3c0.01; I2=89%). Conclusions: Patients exposed to a surgical safety checklist experience better postoperative outcomes, but this could simply reflect wider quality of care in hospitals where checklist use is routine

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally

Critical care admission following elective surgery was not associated with survival benefit:prospective analysis of data from 27 countries

Purpose: As global initiatives increase patient access to surgical treatments, there is a need to define optimal levels of perioperative care. Our aim was to describe the relationship between the provision and use of critical care resources and postoperative mortality. Methods: Planned analysis of data collected during an international 7-day cohort study of adults undergoing elective in-patient surgery. We used risk-adjusted mixed-effects logistic regression models to evaluate the association between admission to critical care immediately after surgery and in-hospital mortality. We evaluated hospital-level associations between mortality and critical care admission immediately after surgery, critical care admission to treat life-threatening complications, and hospital provision of critical care beds. We evaluated the effect of national income using interaction tests. Results: 44,814 patients from 474 hospitals in 27 countries were available for analysis. Death was more frequent amongst patients admitted directly to critical care after surgery (critical care: 103/4317 patients [2%], standard ward: 99/39,566 patients [0.3%]; adjusted OR 3.01 [2.10–5.21]; p < 0.001). This association may differ with national income (high income countries OR 2.50 vs. low and middle income countries OR 4.68; p = 0.07). At hospital level, there was no association between mortality and critical care admission directly after surgery (p = 0.26), critical care admission to treat complications (p = 0.33), or provision of critical care beds (p = 0.70). Findings of the hospital-level analyses were not affected by national income status. A sensitivity analysis including only high-risk patients yielded similar findings. Conclusions: We did not identify any survival benefit from critical care admission following surgery