Todd A. Baker

Role of interventional radiology in the management of complications after pancreaticoduodenectomy.

BACKGROUND This study evaluated the role of interventional radiology (IR) procedures to manage complications after pancreaticoduodenectomy. METHODS A retrospective review was made of the records of patients with postsurgical complications managed with IR. RESULTS Among the 440 patients reviewed, the mortality, morbidity and reoperation rates were 1.6%, 36%, and 2%, respectively. Complications occurred in 159 patients, of which 39 (25%) required > or = 1 IR procedures. Of those 39 patients, 72% underwent percutaneous drainage of an intra-abdominal abscess, 18% underwent percutaneous biliary drainage, and 10% underwent angiography for gastrointestinal bleeding or pseudoaneurysm. The reoperation rate among the 159 patients with complications was 6% (n = 9). Reoperation was avoided in 90% of patients receiving IR. Four patients underwent reoperation despite IR for persistent abscess, pancreatic fistula, anastomotic disruption, or mesenteric venous bleeding. CONCLUSIONS The majority of complications occurring after pancreaticoduodenectomy can be managed effectively using IR, thus minimizing morbidity and the need for reoperation.

A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes to myocardial injury during cold ischemia

Molecular mechanisms leading to myocardial injury during warm or cold ischemia are insufficiently understood. Although proteasomes are thought to contribute to myocardial ischemia-reperfusion injury, their roles during the ischemic period remain elusive. Because donor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation, we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts in context of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiac proteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of hearts in University of Wisconsin (UW) solution for up to 48h. Addition of the specific proteasome inhibitor epoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reduced edema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified 20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to a subset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATP negatively regulates its activity and that maximal activation occurs at ATP concentrations in the low mumol/L range. These data suggest that proteasome activation is a pathophysiologically relevant mechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be a cell-destructive protease that is activated as ATP levels decline. Proteasome inhibition during cold ischemia preserves the ultrastructural integrity of the cardiomyocyte.

Prolongation of myocardial viability by proteasome inhibition during hypothermic organ preservation

Recently, we provided evidence for a possible role of the cardiac proteasome during ischemia, suggesting that a subset of 26S proteasomes is a cell-destructive protease, which is activated as the cellular energy supply declines. Although proteasome inhibition during cold ischemia (CI) reduced injury of ischemic hearts, it remains unknown whether these beneficial effects are maintained throughout reperfusion, and thus, may have pathophysiological relevance. Therefore, we evaluated the effects of epoxomicin (specific proteasome inhibitor) in a rat heterotopic heart transplantation model. Donor hearts were arrested with University of Wisconsin solution (UW) and stored for 12 h/24 h in 4 °C UW±epoxomicin, followed by transplantation. Efficacy of epoxomicin was confirmed by proteasome peptidase activity measurements and analyses of myocardial ubiquitin pools. After 12hCI, troponin I content of UW was lower with epoxomicin. Although all hearts after 12hCI started beating spontaneously, addition of epoxomicin to UW during CI reduced cardiac edema and preserved the ultrastructural integrity of the post-ischemic cardiomyocyte. After 24hCI in UW±epoxomicin, hearts did not regain contractility. When hearts were perfused with epoxomicin during cardioplegia, the cardiac proteasome was inhibited immediately, all of these hearts started beating after 24hCI in UW plus epoxomicin and cardiac edema and myocardial ultrastructure were comparable to hearts after 12hCI. Epoxomicin did not affect markers of lipid peroxidation or neutrophil infiltration in post-ischemic hearts. These data further support the concept that proteasome activation during ischemia is of pathophysiological relevance and suggest proteasome inhibition as a promising approach to improve organ preservation strategies.

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

CXC chemokine receptor (CXCR)-4 agonists have been shown to attenuate inflammation and organ injury in various disease models, including trauma/hemorrhage. The pathophysiological role of CXCR4 during the early response to tissue injury, however, remains unknown. Therefore, we investigated the effects of AMD3100, a drug that antagonizes binding of stromal cell-derived factor (SDF)-1α and ubiquitin to CXCR4 during the initial response to polytrauma in pigs. Fifteen minutes before polytrauma (femur fractures/lung contusion; control: sham), 350 nmol/kg AMD3100, equimolar AMD3100 and ubiquitin (350 nmol/kg each) or vehicle were administered intravenously. After a 60-min shock period, fluid resuscitation was performed for 360 min. Ubiquitin binding to peripheral blood mononuclear cells was significantly reduced after intravenous AMD3100. SDF-1α plasma levels increased transiently >10-fold with AMD3100 in all animals. In injured animals, AMD3100 increased fluid requirements to maintain hemodynamics and enhanced increases in peripheral blood granulocytes, lymphocytes and monocytes, compared with its effects in uninjured animals. Cytokine release from leukocytes in response to Toll-like receptor (TLR)-2 and TLR-4 activation was increased after in vitro AMD3100 treatment of normal whole blood and after in vivo AMD3100 administration in animals subjected to polytrauma. Coadministration of AMD3100/ubiquitin reduced lactate levels, prevented AMD3100-induced increases in fluid requirements and sensitization of the tumor necrosis factor (TNF)-α and interleukin (IL)-6 release upon TLR-2/4 activation, but did not attenuate increases in leukocyte counts and SDF-1α plasma levels. Our findings suggest that CXCR4 controls leukocyte mobilization after trauma, regulates leukocyte reactivity toward inflammatory stimuli and mediates protective effects during the early phase of trauma-induced inflammation.

Effects of exogenous ubiquitin in a polytrauma model with blunt chest trauma

Objective: To determine whether treatment with the CXC chemokine receptor 4 agonist ubiquitin results in beneficial effects in a polytrauma model consisting of bilateral femur fractures plus blunt chest trauma (Injury Severity Score 18–25). Design: Treatment study. Setting: Research laboratory. Subjects: Seventeen Yorkshire pigs. Interventions: Intravenous injection of 1.5 mg/kg ubiquitin or albumin (control) at 60 mins after polytrauma. Measurements and Main Results: Anesthetized, mechanically ventilated pigs underwent polytrauma, followed by a simulated 60-min shock phase. At the end of the shock phase, ubiquitin or albumin were administered and animals were resuscitated to a mean arterial blood pressure of 70 mm Hg until t = 420 mins. After intravenous ubiquitin, ubiquitin plasma concentrations increased 16-fold to 2870 ± 1015 ng/mL at t = 90 mins and decreased with t1/2 = 60 mins. Endogenous plasma ubiquitin increased two-fold in the albumin group with peak levels of 359 ± 210 ng/mL. Plasma levels of the cognate CXC chemokine receptor 4 ligand stromal cell-derived factor-1&agr; were unchanged in both groups. Ubiquitin treatment reduced arterial lactate levels and prevented a continuous decrease in arterial oxygenation, which occurred in the albumin group during resuscitation. Wet weight to dry weight ratios of the lung contralateral from the injury, heart, spleen and jejunum were lower with ubiquitin. With ubiquitin treatment, tissue levels of Interleukin-8, Interleukin-10, Tumor Necrosis Factor &agr;, and stromal cell-derived factor-1&agr; were reduced in the injured lung and of Interleukin-8 in the contralateral lung, respectively. Conclusions: Administration of exogenous ubiquitin modulates the local inflammatory response, improves resuscitation, reduces fluid shifts into tissues, and preserves arterial oxygenation after blunt polytrauma with lung injury. This study further supports the notion that ubiquitin is a promising protein therapeutic and implies CXC chemokine receptor 4 as a drug target after polytrauma.

Ubiquitin and stromal cell-derived factor-1α in bronchoalveolar lavage fluid after burn and inhalation injury.

The objective of the study was to determine whether the CXC chemokine receptor (CXCR) 4 ligands ubiquitin and stromal cell-derived factor (SDF)-1&agr; are detectable in bronchoalveolar lavage fluid (BALF) after burn and inhalation injury and whether their concentrations in BALF are associated with injury severity, physiological variables, or clinical outcomes. BALF was obtained on hospital admission from 51 patients (48 ± 18 years) with burn (TBSA: 23 ± 24%) and inhalation injury (controls: 10 healthy volunteers, 42 ± 8 years). BALF was analyzed for total protein and for ubiquitin and SDF-1&agr; by enzyme-linked immunosorbent assay. Ubiquitin/SDF-1&agr; levels were normalized to total BALF protein content. The extent of inhalation injury was determined during bronchoscopy using a standardized scoring system. Percent TBSA, Baux scores, revised Baux scores, and clinical variables were documented. Ubiquitin and SDF-1&agr; were detectable in 40% of normal BALF specimens. After injury, ubiquitin was detectable in 90% (P < .01 vs control) and SDF-1&agr; in 10% of the specimens (P < .05 vs control). While SDF-1&agr; levels were reduced in patients (P < .01), ubiquitin levels were increased (P < .01). Ubiquitin concentrations correlated inversely with grade of inhalation injury, revised Baux scores, and resuscitation fluid requirements (Spearman correlation coefficients [r]: −.3, −.33, and −.45, respectively). Ubiquitin levels correlated positively with arterial oxygenation at the time of bronchoscopy (r: .35). BALF levels of CXCR4 agonists are differentially regulated after burn and inhalation injury. Increases in BALF ubiquitin after inhalation injury may maintain CXCR4-mediated lung protection and repair processes. The finding that BALF ubiquitin decreased with higher grades of inhalation injury may provide a biological correlate for an insufficient local inflammatory response after severe inhalation injury.

Biplanar flap reconstruction for pressure ulcers: experience in patients with immobility from chronic spinal cord injuries

BACKGROUND Surgical therapy for advanced-stage pressure ulcers recalcitrant to healing is a widely accepted practice. The present study examined the incidence of wound recurrence after reconstruction with fasciocutaneous versus combined (biplanar) muscle and fasciocutaneous flaps. METHODS A retrospective review identified 90 nonambulatory patients with spinal cord injury who underwent reconstruction for persistent decubitus ulcers from 2002 to 2008. Electronic medical records were surveyed for patient comorbidities and postoperative complications. Statistical methods included the Fisher exact test and the Mann-Whitney U test with a 2-sided P value of less than .05. RESULTS Among 90 patients reviewed, 33% (n = 30) received fasciocutaneous flaps and 66% (n = 60) underwent biplanar reconstruction. Comorbidities were the same between cohorts with the exception of a greater prevalence of diabetes in the biplanar group (27% vs 50%; P < .05). The incidence of recurrence for biplanar flaps (25%) was significantly lower than for fasciocutaneous reconstruction (53%; P < .01). CONCLUSIONS Biplanar flap reconstruction should be considered for chronically immobilized patients at high risk for recurrent decubitus ulceration.

Ubiquitin Urine Levels in Burn Patients.

The objective of this study was to determine whether urine ubiquitin levels are elevated after burns and to assess whether urine ubiquitin could be useful as a noninvasive biomarker for burn patients. Forty burn patients (%TBSA: 20 ± 22; modified Baux scores: 73 ± 26) were included (control: 11 volunteers). Urine was collected in 2-hour intervals for 72 hours, followed by 12-hour intervals until discharge from the intensive care unit. Ubiquitin concentrations were analyzed by enzyme linked immunosorbent assay and Western blot. Total protein was determined with a Bradford assay. Patient characteristics and clinical parameters were documented. Urine ubiquitin concentrations, renal ubiquitin excretion, and excretion rates were correlated with patient characteristics and outcomes. Initial urine ubiquitin concentrations were 362 ± 575 ng/ml in patients and 14 ± 18 ng/ml in volunteers (P < .01). Renal ubiquitin excretion on day 1 was 292.6 ± 510.8 &mgr;g/24 hr and 21 ± 27 &mgr;g/24 hr in volunteers (P < .01). Initial ubiquitin concentrations correlated with modified Baux scores (r = .46; P = .02). Ubiquitin levels peaked at day 6 postburn, whereas total protein concentrations and serum creatinine levels remained within the normal range. Total renal ubiquitin excretion and excretion rates were higher in patients with %TBSA ≥20 than with %TBSA <20, in patients who developed sepsis/multiple organ failure than in patients without these complications and in nonsurvivors vs survivors. These data suggest that ubiquitin urine levels are significantly increased after burns. Renal ubiquitin excretion and/or excretion rates are associated with %TBSA, sepsis/multiple organ failure, and mortality. Although these findings may explain previous correlations between systemic ubiquitin levels and outcomes after burns, the large variability of ubiquitin urine levels suggests that urine ubiquitin will not be useful as a noninvasive disease biomarker.

Locally advanced esophageal cancer: Actual 5-year survival comparing neoadjuvant and adjuvant chemoradiation.

149 Background: Patients undergoing esophagectomy for locally advanced esophageal cancer are often candidates for chemoradiotherapy (CRT). It is unclear if there is a survival advantage for CRT when administered in the neoadjuvant (NCRT) versus the adjuvant (ACRT) setting. We report a single institution experience with actual long-term follow-up of patients with resected esophageal cancer treated with NCRT or ACRT. METHODS Following IRB approval, a retrospective review of 123 patients undergoing Ivor-Lewis esophagectomy between January 1, 1990 through December 31, 2001 was conducted. Clinicopathologic variables were analyzed, and survival was determined from hospital records, the Social Security Death Index, and direct patient follow-up. All patients were followed for at least five years, and survival was assessed by Kaplan-Meier analysis. RESULTS Of the 123 patients, 65 had surgery alone for early esophageal cancer and were excluded from the analysis. Of the remaining 58, 31 received NCRT and 27 received ACRT. There was no difference between groups for length of operation, blood loss, or complication rate. With all patients having at least 5 years of follow-up, the overall 1-year survival was 65% and 67% (p=0.866), 3-year survival was 42% and 33% (p=0.508), and 5-year survival was 26% and 22% (p=0.755) for the NCRT and ACRT groups, respectively (Table 1). Among those in the NCRT group, patients with a complete or partial response (n=20) had an improved 1-year survival as compared to those with no response at all (n=11; p=0.025). However, this difference did not persist at 3 and 5-years (p=0.224 and p=0.896, respectively). CONCLUSIONS In this study, all patients with locally advanced esophageal carcinoma who underwent Ivor-Lewis esophagectomy with either NCRT or ACRT were followed for at least 5 years. Not only was there no difference in perioperative morbidity or mortality, but the overall 5-year survival was almost identical between groups. Therefore, as NCRT may be better tolerated and more easily administered, we advocate its use over ACRT in those with locally advanced esophageal cancer. No significant financial relationships to disclose.