Background: Underutilization of operative management of early stage pancreatic cancer is associated with sociodemographic variables, including age, race, facility type, insurance, and education. It is currently unclear how these variables are associated with survival in patients who undergo surgery. Methods: Patients with clinical stage I pancreatic adenocarcinoma were identified within the National Cancer Database (2010-2016). Utilization of surgery and nonoperative management was determined. Nonclinical factors associated with nonoperative management were identified by multivariable analysis. The association between nonclinical factors and survival was assessed in patients who received operative management. Results: A total of 17,833 patients with clinical stage I pancreatic cancer were identified, and 41.2% underwent operative intervention. Approximately 46% of nonoperatively managed patients lacked a contraindication. Operatively managed patients had longer overall survival (OS) than those who were nonoperatively managed or untreated (25.1 months vs. 11.1 months vs. 5.1 months, p < 0.0001). Factors associated with nonoperative management included age, black/Hispanic race, nonacademic facilities, nonprivate health insurance, lower education level, and lower income. In operatively managed patients, nonclinical factors associated with lower OS included Medicaid (hazard ratio [HR] 1.27) and treatment at nonacademic facilities (HR 1.20-1.22). Patients on Medicaid received less adjuvant therapy and had higher 30-and 90-day mortality rates. Patients treated at nonacademic facilities received less neoadjuvant therapy, had worse pathologic outcomes, and had higher 30-and 90-day mortality rates. Conclusions: Surgical management is underutilized in clinical stage I pancreatic cancer. Primary insurance payor and facility type appear to be associated with OS in patients who undergo operative management.

Objective: The aim of this study was to evaluate the role of surgical transgastric necrosectomy (TGN) for walled-off pancreatic necrosis (WON) in selected patients. Background: WON is a common consequence of severe pancreatitis and typically occurs 3 to 5 weeks after the onset of acute pancreatitis. When symptomatic, it can require intervention. Methods: A retrospective review of patients with WON undergoing surgical management at 3 high-volume pancreatic institutions was performed. Surgical indications, intervention timing, technical methodology, and patient outcomes were evaluated. Patients undergoing intervention <30 days were excluded. Differences across centers were evaluated using a P value of <0.05 as significant. Results: One hundred seventy-eight total patients were analyzed (mean WON diameter = 14 cm, 64% male, mean age = 51 years) across 3 centers. The majority required inpatient admission with a median preoperative length of hospital stay of 29 days (25% required preoperative critical care support). Most (96%) patients underwent a TGN. The median duration of time between the onset of pancreatitis symptoms and operative intervention was 60 days. Thirty-nine percent of the necrosum was infected. Postoperative morbidity and mortality were 38% and 2%, respectively. The median postoperative length of hospital length of stay was 8 days, with the majority of patients discharged home. The median length of follow-up was 21 months, with 91% of patients having complete clinical resolution of symptoms at a median of 6 weeks. Readmission to hospital and/or a repeat intervention was also not infrequent (20%). Conclusion: Surgical TGN is an excellent 1-stage surgical option for symptomatic WON in a highly selected group of patients. Precise surgical technique and long-term outpatient follow-up are mandatory for optimal patient outcomes.

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Structural and kinetic data show that Arg-599 of β-galactosidase plays an important role in anchoring the "open" conformations of both Phe-601 and an active-site loop (residues 794-803). When alanine was substituted for Arg-599, the conformations of Phe-601 and the loop shifted towards the "closed" positions because interactions with the guanidinium side chain were lost. Also, Phe-601, the loop, and Na+, which is ligated by the backbone carbonyl of Phe-601, lost structural order, as indicated by large B-factors. IPTG, a substrate analog, restored the conformations of Phe-601 and the loop of R599A-β-galactosidase to the open state found with IPTG-complexed native enzyme and partially reinstated order. ᴅ-Galactonolactone, a transition state analog, restored the closed conformations of R599A-β-galactosidase to those found with ᴅ-galactonolactone-complexed native enzyme and completely re-established the order. Substrates and substrate analogs bound R599A-β-galactosidase with less affinity because the closed conformation does not allow substrate binding and extra energy is required for Phe-601 and the loop to open. In contrast, transition state analog binding, which occurs best when the loop is closed, was several-fold better. The higher energy level of the enzyme•substrate complex and the lower energy level of the first transition state means that less activation energy is needed to form the first transition state and thus the rate of the first catalytic step (k2) increased substantially. The rate of the second catalytic step (k3) decreased, likely because the covalent form is more stabilized than the second transition state when Phe-601 and the loop are closed. The importance of the guanidinium group of Arg-599 was confirmed by restoration of conformation, order, and activity by guanidinium ions.

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