Patrick R. Varley

Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high‐fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte‐derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4 −/− ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro . Conclusion: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (H epatology 2018).

Importance: Patients with frailty have higher risk for postoperative mortality and complications; however, most research has focused on small groups of high-risk procedures. The associations among frailty, operative stress, and mortality are poorly understood. Objective: To assess the association between frailty and mortality at varying levels of operative stress as measured by the Operative Stress Score, a novel measure created for this study. Design, Setting, and Participants: This retrospective cohort study included veterans in the Veterans Administration Surgical Quality Improvement Program from April 1, 2010, through March 31, 2014, who underwent a noncardiac surgical procedure at Veterans Health Administration Hospitals and had information available on vital status (whether the patient was alive or deceased) at 1 year postoperatively. A Delphi consensus method was used to stratify surgical procedures into 5 categories of physiologic stress. Exposures: Frailty as measured by the Risk Analysis Index and operative stress as measured by the Operative Stress Score. Main Outcomes and Measures: Postoperative mortality at 30, 90, and 180 days. Results: Of 432 828 unique patients (401 453 males [92.8%]; mean (SD) age, 61.0 [12.9] years), 36 579 (8.5%) were frail and 9113 (2.1%) were very frail. The 30-day mortality rate among patients who were frail and underwent the lowest-stress surgical procedures (eg, cystoscopy) was 1.55% (95% CI, 1.20%-1.97%) and among patients with frailty who underwent the moderate-stress surgical procedures (eg, laparoscopic cholecystectomy) was 5.13% (95% CI, 4.79%-5.48%); these rates exceeded the 1% mortality rate often used to define high-risk surgery. Among patients who were very frail, 30-day mortality rates were higher after the lowest-stress surgical procedures (10.34%; 95% CI, 7.73%-13.48%) and after the moderate-stress surgical procedures (18.74%; 95% CI, 17.72%-19.80%). For patients who were frail and very frail, mortality continued to increase at 90 and 180 days, reaching 43.00% (95% CI, 41.69%-44.32%) for very frail patients at 180 days after moderate-stress surgical procedures. Conclusions and Relevance: We developed a novel operative stress score to quantify physiologic stress for surgical procedures. Patients who were frail and very frail had high rates of postoperative mortality across all levels of the Operative Stress Score. These findings suggest that frailty screening should be applied universally because low- and moderate-stress procedures may be high risk among patients who are frail.

OBJECTIVE AND BACKGROUND: The Risk Analysis Index (RAI) predicts 30-, 180-, and 365-day mortality based on variables constitutive of frailty. Initially validated, in a single-center Veteran hospital, we sought to improve model performance by recalibrating the RAI in a large, veteran surgical registry, and to externally validate it in both a national surgical registry and a cohort of surgical patients for whom RAI was measured prospectively before surgery. METHODS: The RAI was recalibrated among development and confirmation samples within the Veterans Affairs Surgical Quality Improvement Program (VASQIP; 2010-2014; N = 480,731) including major, elective noncardiac surgery patients to create the revised RAI (RAI-rev), comparing discrimination and calibration. The model was tested externally in the American College of Surgeons National Surgical Quality Improvement Program dataset (NSQIP; 2005-2014; N = 1,391,785), and in a prospectively collected cohort from the Nebraska Western Iowa Health Care System VA (NWIHCS; N = 6,856). RESULTS: Recalibrating the RAI significantly improved discrimination for 30-day [c = 0.84-0.86], 180-day [c = 0.81-0.84], and 365-day mortality [c = 0.78-0.82] (P < 0.001 for all) in VASQIP. The RAI-rev also had markedly better calibration (median absolute difference between observed and predicted 180-day mortality: decreased from 8.45% to 1.23%). RAI-rev was highly predictive of 30-day mortality (c = 0.87) in external validation with excellent calibration (median absolute difference between observed and predicted 30-day mortality: 0.6%). The discrimination was highly robust in men (c = 0.85) and women (c = 0.89). Discrimination also improved in the prospectively measured cohort from NWIHCS for 180-day mortality [c = 0.77 to 0.80] (P < 0.001). CONCLUSIONS: The RAI-rev has improved discrimination and calibration as a frailty-screening tool in surgical patients. It has robust external validity in men and women across a wide range of surgical settings and available for immediate implementation for risk assessment and counseling in preoperative patients.

Importance: Frailty is an important risk factor for postoperative mortality. Whether the association between frailty and mortality is consistent across all surgical specialties, especially those predominantly performing lower stress procedures, remains unknown. Objective: To examine the association between frailty and postoperative mortality across surgical specialties. Design, Setting, and Participants: A cohort study was conducted across 9 noncardiac specialties in hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) and Veterans Affairs Surgical Quality Improvement Program (VASQIP) from January 1, 2010, through December 31, 2014, using multivariable logistic regression to evaluate the association between frailty and postoperative mortality. Data analysis was conducted from September 15, 2019, to April 30, 2020. Patients 18 years or older undergoing noncardiac procedures were included. Exposures: Risk Analysis Index measuring preoperative frailty categorized patients as robust (Risk Analysis Index ≤20), normal (21-29), frail (30-39), or very frail (≥40). Operative Stress Score (OSS) categorized procedures as low (1-2), moderate (3), and high (4-5) stress. Specialties were categorized by case-mix as predominantly low intensity (>75% OSS 1-2), moderate intensity (50%-75%), or high intensity (<50%). Main Outcomes and Measures: Thirty-day (both measures) and 180-day (VASQIP only) postoperative mortality. Results: Of the patients evaluated in NSQIP (n = 2 339 031), 1 309 795 were women (56.0%) and mean (SD) age was 56.49 (16.4) years. Of the patients evaluated in VASQIP (n = 426 578), 395 761 (92.78%) were men and mean (SD) age was 61.1 (12.9) years. Overall, 30-day mortality was 1.2% in NSQIP and 1.0% in VASQIP, and 180-day mortality in VASQIP was 3.4%. Frailty and OSS distributions differed substantially across the 9 specialties. Patterns of 30-day mortality for frail and very frail patients were similar in NSQIP and VASQIP for low-, moderate-, and high-intensity specialties. Frailty was a consistent, independent risk factor for 30- and 180-day mortality across all specialties. For example, in NSQIP, for plastic surgery, a low-intensity specialty, the odds of 30-day mortality in very frail (adjusted odds ratio [aOR], 27.99; 95% CI, 14.67-53.39) and frail (aOR, 5.1; 95% CI, 3.03-8.58) patients were statistically significantly higher than for normal patients. This was also true in neurosurgery, a moderate-intensity specialty, for very frail (aOR, 9.8; 95% CI, 7.68-12.50) and frail (aOR, 4.18; 95% CI, 3.58-4.89) patients and in vascular surgery, a high-intensity specialty, for very frail (aOR, 10.85; 95% CI, 9.83-11.96) and frail (aOR, 3.42; 95% CI, 3.19-3.67) patients. Conclusions and Relevance: In this study, frailty was associated with postoperative mortality across all noncardiac surgical specialties regardless of case-mix. Preoperative frailty assessment could be implemented across all specialties to facilitate risk stratification and shared decision-making.

UNLABELLED: Despite the high prevalence of fatty liver disease, the safety of liver resection in settings of steatohepatitis (SH) or hepatic steatosis is poorly understood. The aim of this study was to determine whether underlying SH or simple hepatic steatosis increases morbidity after liver resection. We compared patients undergoing liver resection with underlying SH or greater than 33% simple hepatic steatosis to controls selected for similar demographics, diagnoses, comorbidities, preoperative chemotherapy treatments, and extent of partial hepatectomy. Primary endpoints included postoperative overall and hepatic-related morbidity. One hundred and two patients with SH and 72 with greater than 33% simple hepatic steatosis who underwent liver resection from 2000 to 2011 were compared to corresponding controls. There were no differences in extent or approach of liver resection, malignant indications, preoperative chemotherapy treatment, elements of metabolic syndrome, alcohol use history, American Society of Anesthesiologists score, age, or gender between patients with SH or simple steatosis and corresponding controls. Ninety-day postoperative overall morbidity (56.9% versus 37.3%; P = 0.008), any hepatic-related morbidity (28.4% versus 15.7%; P = 0.043), surgical hepatic complications (19.6% versus 8.8%; P = 0.046), and hepatic decompensation (16.7% versus 6.9%; P = 0.049) were greater among SH patients, compared to corresponding controls. In contrast, there were no differences in postoperative overall morbidity (34.7% versus 44.4%; P = 0.310), any hepatic-related morbidity (19.4% versus 19.4%; P = 1.000), surgical hepatic complications (13.9% versus 9.7%; P = 0.606), or hepatic decompensation (8.3% versus 9.7%; P = 0.778) between simple hepatic steatosis patients and corresponding controls. Using multivariable logistic regression, SH was independently associated with postoperative overall (odds ratio [OR], 2.316; 95% confidence interval [95% CI]: 1.267-4.241; P = 0.007) and any hepatic-related (OR, 2.722; 95% CI: 1.201-6.168; P = 0.016) morbidity. CONCLUSION: Underlying SH, but not simple hepatic steatosis, increases overall and hepatic-related morbidity after liver resection.