Gregory C. Wilson

A novel mouse model of depletion of stellate cells clarifies their role in ischemia/reperfusion- and endotoxin-induced acute liver injury

BACKGROUND & AIMS Hepatic stellate cells (HSCs) that express glial fibrillary acidic protein (GFAP) are located between the sinusoidal endothelial cells and hepatocytes. HSCs are activated during liver injury and cause hepatic fibrosis by producing excessive extracellular matrix. HSCs also produce many growth factors, chemokines and cytokines, and thus may play an important role in acute liver injury. However, this function has not been clarified due to unavailability of a model, in which HSCs are depleted from the normal liver. METHODS We treated mice expressing HSV-thymidine kinase under the GFAP promoter (GFAP-Tg) with 3 consecutive (3 days apart) CCl4 (0.16 μl/g; ip) injections to stimulate HSCs to enter the cell cycle and proliferate. This was followed by 10-day ganciclovir (40 μg/g/day; ip) treatment, which is expected to eliminate actively proliferating HSCs. Mice were then subjected to hepatic ischemia/reperfusion (I/R) or endotoxin treatment. RESULTS CCl4/ganciclovir treatment caused depletion of the majority of HSCs (about 64-72%), while the liver recovered from the initial CCl4-induced injury (confirmed by histology, serum ALT and neutrophil infiltration). The magnitude of hepatic injury due to I/R or endotoxemia (determined by histopathology and serum ALT) was lower in HSC-depleted mice. Their hepatic expression of TNF-α, neutrophil chemoattractant CXCL1 and endothelin-A receptor also was significantly lower than the control mice. CONCLUSIONS HSCs play an important role both in I/R- and endotoxin-induced acute hepatocyte injury, with TNF-α and endothelin-1 as important mediators of these effects.

Long-term outcomes after total pancreatectomy and islet cell autotransplantation: is it a durable operation?

Objective:Total pancreatectomy and islet cell autotransplantation (TPIAT) has been increasingly utilized for the management of chronic pancreatitis (CP) with early success. However, the long-term durability of this operation remains unclear. Methods:All patients undergoing TPIAT for the treatment of CP with 5-year or greater follow-up were identified for inclusion in this single-center observational study. End points included narcotic requirements, glycemic control, islet function, quality of life (QOL), and survival. Results:Between 2000 and 2013, 166 patients underwent TPIAT; 112 of these patients had 5-year follow-up data to analyze. All patients underwent successful IAT with a mean of 6027 ± 595 islet equivalents per body weight. There was no perioperative mortality and actuarial survival at 5 years was 94.6%. The narcotic independence rate at 1 year was 55% and continued to improve to 73% at 5-year follow-up (P < 0.05). The insulin independence rate declined over time (38% at 1 year vs 27% at more than 5 years), but insulin requirements remained similar (21.4 vs 24.3 units per day, P = 0.6). All patients achieved stable glycemic control with a median hemoglobin A1C (HgA1C) of 6.9% (range: 5.85%–8.3%). The short form 36-item QOL assessment of a subset of patients available for contact demonstrated continued improvements in all tested modules in patients with at least 5-year follow-up. Two patients developed diabetic complications requiring whole organ pancreas transplant for salvage. Conclusions:This represents one of the largest series examining long-term outcomes after TPIAT. This operation produces durable pain relief and improvement in QOL parameters. Insulin independence rates decline over time, but most patients maintain stable glycemic control.

Impact of recipient morbid obesity on outcomes after liver transplantation

The aim of this study was to analyze the impact of morbid obesity in recipients on peritransplant resource utilization and survival outcomes. Using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 12 445 patients who underwent liver transplantation (LT) between 2007 and 2011 and divided them into two cohorts based on recipient body mass index (BMI; <40 vs. ≥40 kg/m²). Recipients with BMI ≥40 comprised 3.3% (n = 416) of all LTs in the studied population. There were no significant differences in donor characteristics between two groups. Recipients with BMI ≥40 were significant for being female, diabetic, and with NASH cirrhosis. Patients with a BMI ≥40 had a higher median MELD score, limited physical capacity, and were more likely to be hospitalized at LT. BMI ≥40 recipients had higher post‐LT length of stay and were less often discharged to home. With a median follow‐up of 2 years, patient and graft survival were equivalent between the two groups. In conclusion, morbidly obese LT recipients appear sicker at time of LT with an increase in resource utilization but have similar short‐term outcomes.

Neighborhood level effects of socioeconomic status on liver transplant selection and recipient survival.

BACKGROUND & AIMS Previous studies have reported that patients of higher socioeconomic status (SES) have increased access to liver transplantation and reduced waitlist mortality than patients of lower SES. However, little is known about the association between SES and outcomes after liver transplantation. METHODS By using a link between the University HealthSystem Consortium and the Scientific Registry of Transplant Recipients databases, we identified 12,445 patients who underwent liver transplantation from 2007 through 2011. We used a proportional hazards model to assess the effect of SES on patient survival, controlling for characteristics of recipients, donors, geography, and center. RESULTS Compared with liver recipients in the lowest SES quintile, those in the highest quintile were more likely to be male, Caucasian, have private insurance, and undergo transplantation when they had lower Model for End-Stage Liver Disease scores. In proportional hazards model analysis, liver recipients of the lowest SES were at an increased risk for death within a median of 2 years after transplantation (hazard ratio, 1.17; 95% confidence interval, 1.02-1.35). CONCLUSIONS Patients of lower SES appear to face barriers to liver transplantation, but perioperative outcomes (length of stay, in-hospital mortality, or 30-day readmission) do not differ significantly from those of patients of higher SES. However, fewer patients of low SES survive for 2 years after transplantation, independent of features of the recipient, donor, surgery center, or location.

A Novel Subcutaneous Counterpulsation Device: Acute Hemodynamic Efficacy During Pharmacologically Induced Hypertension, Hypotension, and Heart Failure

The miniaturization of mechanical assist devices and less invasive implantation techniques may lead to earlier intervention in patients with heart failure. As such, we evaluated the effectiveness of a novel, minimally invasive, implantable counterpulsation device (CPD) in augmenting cardiac function during impaired hemodynamics. We compared the efficacy of a 32-mL stroke volume CPD with a standard 40-mL intra-aortic balloon pump (IABP) over a range of clinically relevant pathophysiological conditions. Male calves were instrumented via thoracotomy, the CPD was anastomosed to the left carotid artery, and the IABP was positioned in the descending aorta. Hemodynamic conditions of hypertension, hypotension, and heart failure were pharmacologically simulated and data were recorded during CPD and IABP support (off, 1:2, 1:1 modes) for each condition. In all three pathophysiological conditions, the CPD and IABP produced similar and statistically significant (P < 0.05) increases in coronary artery blood flow normalized to the left ventricular (LV) workload. During hypotension and heart failure conditions, however, the CPD produced significantly greater reductions in LV workload and myocardial oxygen consumption as compared with the IABP. A novel 32-mL CPD connected to a peripheral artery produced equivalent or greater hemodynamic benefits than a standard 40-mL IABP during pharmacologically induced hypertension, hypotension, and heart failure conditions.

Variation by center and economic burden of readmissions after liver transplantation

The rate and causes of hospital readmissions after liver transplantation (LT) remain largely unknown in the United States. Adult patients (n = 11,937; 43.1% of all LT cases) undergoing LT from 2007 to 2011 were examined with a linkage of the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases to determine the incidence and risk factors for 30‐day readmissions and utilization metrics 90 days after LT. The overall 30‐day hospital readmission rate after LT was 37.9%, with half of patients admitted within 7 days after discharge. Readmitted patients had worse overall graft and patient survival with a 2‐year follow‐up. Multivariate analysis identified risk factors associated with 30‐day hospital readmission, including a higher Model for End‐Stage Liver Disease score, diabetes at LT, dialysis dependence, a high donor risk index allograft, and discharge to a rehabilitation facility. After adjustments for donor, recipient, and geographic factors in a hierarchical model, we found significant variation in readmission rates among hospitals ranging from 26.3% to 50.8% (odds ratio, 0.53‐1.90). In the 90‐day analysis after LT, readmissions accounted for

Is liver transplantation safe and effective in elderly (≥70 years) recipients? A case-controlled analysis

43,785 of added costs in comparison with patients who were not readmitted in the first 90 days. This is the first national report showing that more than one‐third of LT recipients are readmitted to their center within 30 days and that readmissions are associated with center variation and increased resource utilization. Liver Transpl 21:953‐960, 2015.

Factors associated with 30-day readmission after restorative proctocolectomy with IPAA: a national study.

BACKGROUND Elderly patients are evaluated for liver transplantation (LT) with increasing frequency, but outcomes in this group have not been well defined. METHODS A linkage of the Scientific Registry of Transplant Recipients (SRTR) and the University HealthSystem Consortium (UHC) databases identified 12,445 patients who underwent LT during 2007-2011. Two cohorts were created consisting of, respectively, elderly recipients aged ≥70 years (n = 323) and recipients aged 18-69 years (n = 12,122). A 1:1 case-matched analysis was performed based on propensity scores. RESULTS Elderly recipients had lower Model for End-stage Liver Disease (MELD) scores at LT (median 15 versus 19; P < 0.0001), more often underwent transplantation at high-volume centres (46% versus 33%; P < 0.0001) and more often received grafts from donors aged >60 years (24% versus 15%; P < 0.0001). The two cohorts had similar hospital lengths of stay, in-hospital mortality, hospital costs and 30-day readmission rates. There were no differences in graft survival between the two cohorts (P = 0.10), but elderly recipients had worse longterm overall survival (P = 0.009). However, a case-controlled analysis confirmed similar perioperative hospital outcomes, graft survival and longterm patient survival in the two matched cohorts. CONCLUSIONS Elderly LT recipients accounted for <3% of all LTs performed during 2007-2011. Selected elderly recipients have perioperative outcomes and survival similar to those in younger adults.

Cost effectiveness after a pancreaticoduodenectomy: bolstering the volume argument

BACKGROUND:Hospital readmission has been identified by many payers as a surrogate for surgical quality. The 30-day readmission rate and factors associated with hospital readmission after restorative proctocolectomy with IPAA have not been well studied. OBJECTIVE:The purpose of this work was to identify the rate of and factors associated with hospital readmission within 30 days of restorative proctocolectomy with IPAA. DESIGN:A retrospective review of patients undergoing IPAA from 2009 to 2012 in the University HealthSystem Consortium database was performed. Hospitals were stratified into quartiles according to the number of cases performed annually. SETTING:This study was conducted using a national database of university hospitals. PATIENTS:A total of 4952 patients within the 4-year study period were included in the analysis. MAIN OUTCOME MEASURES:The primary outcome measured was readmission within 30 days of discharge. RESULTS:The 30-day readmission rate was 22.8% overall, although high-volume centers performed significantly better than low-volume centers (high vs low volume: 19.7% vs 28.2%; p < 0.001). When controlling for confounding variables, multivariate analysis identified female sex (OR, 1.191; p = 0.02), government-based (vs private) insurance (OR, 1.364; p < 0.001), and higher preoperative severity of illness (OR, 1.491; p = 0.001) to be associated with readmission. In addition, a significant volume-dependent relationship on 30-day readmission was identified, wherein undergoing operation at the higher-volume hospitals was protective for predicting readmission. Hierarchical regression modeling indicated that 31% of the variation in readmission rates among individual hospitals was accounted for by hospital volume. LIMITATIONS:This study was limited by its retrospective nature and limited postoperative complication data. CONCLUSIONS:The national 30-day readmission after IPAA creation was 22.8%, at least double that of other colorectal procedures. This high rate of readmission was mitigated by centers performing the highest volume of cases. Avoidance of referral to centers performing very few of these procedures annually may improve perioperative outcomes and reduce associated morbidity.

Association of Preoperative Risk Factors With Malignancy in Pancreatic Mucinous Cystic Neoplasms: A Multicenter Study

BACKGROUND The cost implication of variability in pancreatic surgery is not well described. It was hypothesized that for a pancreaticoduodenectomy (PD), lower volume centres demonstrate worse peri-operative outcomes at higher costs. METHODS From 2009-2011, 9883 patients undergoing a PD were identified from the University HealthSystems Consortium (UHC) database and stratified into quintiles by annual hospital case volume. A decision analytic model was constructed to assess cost effectiveness. Total direct cost data were based on Medicare cost/charge ratios and included readmission costs when applicable. RESULTS The lowest volume centres demonstrated a higher peri-operative mortality rate (3.5% versus 1.3%, P < 0.001) compared with the highest volume centres. When both index and readmission costs were considered, the per-patient total direct cost at the lowest volume centres was