Jeffrey M. Sutton

Factors influencing readmission after pancreaticoduodenectomy: a multi-institutional study of 1302 patients.

Objective and Background:Morbidity, mortality, and length of hospital stay after pancreaticoduodenectomy (PD) have significantly decreased over recent decades. Despite this progress, early readmission rates after PD have been reported as high as 50%. Few reports have delineated factors associated with readmission after PD. Methods:The medical records of 6 high-volume institutions were reviewed for patients who underwent PD between 2005 and 2010. Data collection included patient characteristics, medical comorbidities, and perioperative factors. Analysis included readmissions up to 90 days after PD. Results:A total of 1302 patients underwent PD across all institutions. The 30-day and 90-day readmission rates were 15% and 19%, respectively. The most common reasons for 30-day readmission included infectious complications (n = 65) and delayed gastric emptying (n = 29). The most common reasons for readmission after 90 days included wound infections and intra-abdominal abscess (n = 75) and failure to thrive (n = 38). On multivariate analysis, factors associated with higher readmission rates included a preoperative diagnosis of chronic pancreatitis, higher transfusion requirements, and postoperative complications including intra-abdominal abscess and pancreatic fistula (all P < 0.02). Factors not associated with higher readmission rates included advanced age, body mass index, cardiovascular/pulmonary comorbidities, diabetes, steroid use, Whipple type (standard vs pylorus preserving PD), preoperative endobiliary stenting, and vascular reconstruction. Conclusions:These multi-institutional data represent a large experience of PD without the biases typically of single center studies. Factors related to infection, nutritional status, and delayed gastric emptying were the most common reasons for readmission after PD. Postoperative complications including pancreatic fistula predicted higher rates of readmission.

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.

Total pancreatectomy and islet cell autotransplantation as a means of treating patients with genetically linked pancreatitis

BACKGROUND For patients with severe chronic pancreatitis, total or completion pancreatectomy with islet cell autotransplantation (IAT) can alleviate pain and avoid the complications of diabetes. Several genetic mutations, specifically, PRSS1, CFTR, and SPINK1, are associated with chronic pancreatitis. Few reports have focused on the benefit of this operation for this subset of patients. METHODS Between February 2000 and July 2009, 118 patients were treated with total pancreatectomy and IAT for chronic pancreatitis. Patients with known genetic mutations were then selected for further analysis. RESULTS Of the 188 patients, 16 (13.6%) patients were identified as having genetic mutations, including CFTR (n = 10), PRSS1 (n = 4), and SPINK1 (n = 2) mutations. Mean patient age was 31.4 years (range, 15-59) with an equal male-to-female ratio (50:50). Preoperatively, patients required an average of 185 ± 60 morphine equivalents (MEQ) (median, 123 MEQ) for preoperative pain control. No patients were taking insulin before operation. After resection with IAT, patients were discharged from the hospital with a daily average of 22 ± 4 units of insulin with 6 (38%) patients requiring fewer than 15 units of insulin at the time of discharge. At a mean follow-up of 22 months, mean insulin requirements decreased to 15 U/d (P = .0172). A total of 7 (44%) patients required 15 or fewer units daily, and 4 (25%) patients were completely insulin-independent. Average daily narcotic usage at most recent follow-up decreased to 70 MEQ (median, 0) with 10 (63%) patients currently narcotic-independent. Analyses of the 36-item short-form health survey and the McGill Pain Questionnaire demonstrated a significant improvement in quality-of-life parameters and pain assessment. CONCLUSION In patients who suffer from genetically linked chronic pancreatitis, pancreatic resection with IAT should be considered as an early therapeutic option to decrease chronic abdominal pain while preserving endogenous endocrine function.

A necessary role for GluR1 serine 831 phosphorylation in appetitive incentive learning.

It is widely thought that regulation of post-synaptic AMPA receptors is a critical component in changes in synaptic efficacy underlying learning and memory. The regulation of AMPA receptors occurs through trafficking of the receptor and/or modulation of the receptors channel properties and both of these processes depend on phosphorylation of the receptor. Using homologous recombination (knock-in) techniques we targeted two phosphorylation sites on the AMPA-GluR1 receptor: the CaMKII/PKC Ser 831 site and the PKA Ser 845 site. Mice with either or both of these sites mutated were then tested on an incentive learning task that assessed their ability to acquire a simple association between a cue and reward and to then use this cue as a reinforcer to guide their behavior (conditioned reinforcement). We report that, whereas WT mice showed enhanced responding for the reward-associated cue, mice with mutations of both phosphorylation sites or the Ser 831 site alone, failed to show such a conditioned reinforcement effect. By contrast, mice with only the Ser 845 site deficient showed normal CS+ reinforced responding. Thus, action at the Ser 831 phosphorylation site was necessary for normal conditioned reinforcement. Finally, the behavioral deficit was highly specific: performance on a number of other measures of motivated performance, including responding reinforced by the food itself, was unaffected by the mutations. Our findings provide novel evidence for a molecular mechanism in a form of appetitive incentive learning critical in regulating normal motivated behavior, as well as maladaptive forms such as addiction and eating disorders.

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.

Value of intraoperative neck margin analysis during whipple for pancreatic adenocarcinoma: A multicenter analysis of 1399 patients

Introduction:During pancreaticoduodenectomy (PD) for ductal adenocarcinoma, a frozen section (FS) neck margin is typically assessed, and if positive, additional pancreas is removed to achieve an R0 margin. We analyzed the association of this practice with improved overall survival (OS). Methods:Patients who underwent PD for pancreatic ductal adenocarcinoma from January 2000 to August 2012 at 8 academic centers were classified by neck margin status as negative (R0) or microscopically positive (R1) on the basis of FS and permanent section (PS). Impact on OS of converting an FS-R1-neck margin to a PS-R0-neck margin by additional resection was assessed. Results:A total of 1399 patients had FS neck margins analyzed. Median OS was 19.7 months. On FS, 152 patients (10.9%) were R1, and an additional 51 patients (3.6%) had false-negative FS-R0 margins. PS-R0-neck was achieved in 1196 patients (85.5%), 131 patients (9.3%) remained PS-R1, and 72 patients (5.1%) were converted from FS-R1-to-PS-R0 by additional resection. Median OS for PS-R0-neck patients was 21.1 months versus 13.7 months for PS-R1-neck patients (P < 0.001) and 11.9 months for FS-R1-to-PS-R0 patients (P < 0.001). Both FS-R1-to-PS-R0 and PS-R1-neck patients had larger tumors (P = 0.001), more perineural invasion (P = 0.02), and more node positivity (P = 0.08) than PS-R0-neck patients. On multivariate analysis controlling for adverse pathologic factors, FS-R1-to-PS-R0 conversion remained associated with significantly worse OS compared with PS-R0-neck patients (hazard ratio: 1.55; P = 0.009). Conclusions:For patients who undergo pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, additional resection to achieve a negative neck margin after positive frozen section is not associated with improved OS.

Effect of pretransplant diabetes on short-term outcomes after liver transplantation: A National cohort study

We sought to analyse the effect of pretransplant diabetes on post‐operative outcomes and resource utilization following liver transplantation.

A role for alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid GluR1 phosphorylation in the modulatory effects of appetitive reward cues on goal-directed behavior.

Alpha‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptor regulation has been shown to be critically involved in synaptic plasticity underlying learning and memory. This regulation occurs through trafficking of the receptor and modulation of the receptor’s channel properties, both of which depend on protein phosphorylation. Using homologous recombination (knock‐in) techniques we targeted two phosphorylation sites on the AMPA‐GluR1 receptor: the Ser831 site, phosphorylated by calcium calmodulin‐dependent protein kinase II/protein kinase C, and the Ser845 site, phosphorylated by protein kinase A. Mice with mutations that prevented phosphorylation at one or both of these sites were tested on a single‐outcome Pavlovian‐instrumental transfer task often used to assess the acquisition of incentive motivation by cues for food reinforcement. Mice were separately trained to associate a Pavlovian cue with food and to perform an instrumental lever‐press response to earn that same reward. During a transfer test, the cue was presented while the mice were lever‐pressing under extinction conditions. Whereas wild‐type control mice showed substantial enhancement of lever‐pressing when the cue was presented (i.e. showed Pavlovian‐instrumental transfer), mice with mutations at both of these phosphorylation sites showed no evidence of such transfer. By contrast, mice with either serine site mutated alone showed normal transfer. These results suggest critical roles for GluR1 phosphorylation pathways in a form of incentive learning that can play an important part in regulating normal motivated behavior as well as maladaptive behaviors such as addiction and eating disorders.

Neoadjuvant therapy for pancreas cancer: past lessons and future therapies.

Pancreatic adenocarcinoma remains a most deadly malignancy, with an overall 5-year survival of 5%. A subset of patients will be diagnosed with potentially resectable disease, and while complete surgical resection provides the only chance at cure, data from trials of postoperative chemoradiation and/or chemotherapy demonstrate a modest survival advantage over those patients who undergo resection alone. As such, most practitioners believe that completion of multimodality therapy is the optimal treatment. However, the sequence of surgery, chemotherapy and radiation therapy is frequently debated, as patients may benefit from a neoadjuvant approach by initiating chemotherapy and/or chemoradiation prior to resection. Here we review the rationale for neoadjuvant therapy, which includes a higher rate of completion of multimodality therapy, minimizing the risk of unnecessary surgical resection for patients who develop early metastatic disease, improved surgical outcomes and the potential for longer overall survival. However, there are no prospective, randomized studies of the neoadjuvant approach compared to a surgery-first strategy; the established and ongoing investigations of neoadjuvant therapy for pancreatic cancer are discussed in detail. Lastly, as the future of therapeutic regimens is likely to entail patient-specific genetic and molecular analyses, and the treatment that is best applied based on those data, a review of clinically relevant biomarkers in pancreatic cancer is also presented.

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

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.