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Despite its increased application in pancreatic ductal adenocarcinoma (PDAC), complete response to neoadjuvant therapy (NAT) is rare. Given the critical role of host immunity in regulating cancer, we sought to correlate baseline inflammatory profiles to significant response to NAT. PDAC patients receiving NAT were classified as responders (R) or nonresponders (NR) by carbohydrate antigen 19-9 response, pathologic tumor size, and lymph node status in the resected specimen. Baseline (treatment-naive) plasma was analyzed to determine levels of 27 inflammatory mediators. Logistic regression was used to correlate individual mediators with response. Network analysis and Pearson correlation maps were derived to determine baseline inflammatory mediator profiles. Forty patients (20R and 20NR) met study criteria. The R showed significantly higher overall survival (59.4 vs. 21.25 mo, P=0.002) and disease-free survival (50.97 vs. 10.60 mo, P=0.005), compared with NR. soluble interleukin-2 receptor alpha was a significant predictor of no response to NAT (P=0.045). Analysis of inflammatory profiles using the Pearson heat map analysis followed by network analysis depicted increased inflammatory network complexity in NR compared with R (1.69 vs. 1), signifying a more robust baseline inflammatory status of NR. A panel of inflammatory mediators identified by logistic regression and Fischer score analysis was used to create a potential decision tree to predict NAT response. We demonstrate that baseline inflammatory profiles are associated with response to NAT in PDAC, and that an upregulated inflammatory status is associated with a poor response to NAT. Further analysis into the role of inflammatory mediators as predictors of chemotherapy response is warranted.

Background Cholangitis due to anastomotic stricture of the hepaticojejunostomy (HJ) following pancreaticoduodenectomy (PD), while uncommon, adversely affects postoperative quality-of-life. While prior studies have identified patient-related risk factors for these biliary complications, technical risk factors have not been systematically examined. Video review of surgical procedures has helped define technical details predictive of postoperative complications in bariatric and hepato-pancreato-biliary (HPB) surgery. Similarly, the present study utilized video review to identify technical factors associated with cholangitis and anastomotic biliary stricture following robotic PD. Methods This was an observational study. A blinded experienced HPB surgeon reviewed videos of post-learning-curve HJs performed during robotic PD and extracted 20 technical variables. Other demographic and clinical variables were collected from a prospectively maintained database. Results 241 robotic PD videos were reviewed. 29 (12.0%) developed cholangitis and/or biliary stricture, with a median time-to-event of 189 (IQR 78–365) days. Several clinical and technical factors were independently predictive of cholangitis and/or biliary stricture: preoperative radiotherapy, small duct size ( 10 mm) from the hilar plate, and continuous suturing technique. Conclusion Post-hoc video review of HJ is a powerful method to predict biliary complications. Moreover, altering specific technical factors might enable surgeons to improve postoperative outcomes.

Objective The aim of the study was to quantify the risk of incarceration of incisional hernias. Background Operative repair is the definitive treatment for incisional ventral hernias but is often deferred if the perceived risk of elective operation is elevated secondary to comorbid conditions. The risk of incarceration during nonoperative management (NOM) factors into shared decision making by patient and surgeon; however, the incidence of acute incarceration remains largely unknown. Methods A retrospective analysis of adult patients with an International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis of incisional hernia was conducted from 2010 to 2017 in 15 hospitals of a single healthcare system. The primary outcome was incarceration necessitating emergent operation. The secondary outcome was 30-, 90-, and 365-day mortality. Univariate and multivariate analyses were used to determine independent predictors of incarceration. Results Among 30,998 patients with an incisional hernia (mean age 58.1 ± 15.9 years; 52.7% female), 23,022 (78.1%) underwent NOM of whom 540 (2.3%) experienced incarceration, yielding a 1- and 5-year cumulative incidence of 1.24% and 2.59%, respectively. Independent variables associated with incarceration included: age older than 40 years, female sex, current smoker, body mass index 30 or greater, and a hernia-related inpatient admission. All-cause mortality rates at 30, 90, and 365 days were significantly higher in the incarceration group at 7.2%, 10%, and 14% versus 1.1%, 2.3%, and 5.3% in patients undergoing successful NOM, respectively. Conclusions Incarceration is an uncommon complication of NOM but is associated with a significant risk of death. Tailored decision making for elective repair and considering the aforementioned risk factors for incarceration provides an initial step toward mitigating the excess morbidity and mortality of an incarceration event.

Introduction. Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver malignancies and is currently the fourth most common cause of cancer-related death worldwide. Due to varying underlying etiologies, the prognosis of HCC differs greatly among patients. It is important to develop ways to help stratify patients upon initial diagnosis to provide optimal treatment modalities and follow-up plans. The current study uses Artificial Neural Network (ANN) and Classification Tree Analysis (CTA) to create a gene signature score that can help predict survival in patients with HCC. Methods. The Cancer Genome Atlas (TCGA-LIHC) was analyzed for differentially expressed genes. Clinicopathological data were obtained from cBioPortal. ANN analysis of the 75 most significant genes predicting disease-free survival (DFS) was performed. Next, CTA results were used for creation of the scoring system. Cox regression was performed to identify the prognostic value of the scoring system. Results. 363 patients diagnosed with HCC were analyzed in this study. ANN provided 15 genes with normalized importance >50%. CTA resulted in a set of three genes (NRM, STAG3, and SNHG20). Patients were then divided in to 4 groups based on the CTA tree cutoff values. The Kaplan–Meier analysis showed significantly reduced DFS in groups 1, 2, and 3 (median DFS: 29.7 months, 16.1 months, and 11.7 months, p

Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1–2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2–3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.

Background and aims Liver ischemia/reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic growth, which is consistent with the notion that the liver IRI can serve as a premetastatic niche. Exercise training (ExT) confers a sustainable protection, reducing IRI in some animal models, and has been associated with improved survival in patients with cancer; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown. Approach and results Mice were randomized into exercise (ExT) and sedentary groups before liver IRI and tumor injection. Computerized dynamic network analysis of 20 inflammatory mediators was used to dissect the sequence of mediator interactions after ischemia/reperfusion (I/R) that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NET formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present 3 weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor-suppressing T cells within the tumor microenvironment. Conclusions ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver premetastatic niches induced by liver IRI through the use of ExT as a nonpharmacologic therapy before curative surgical approaches.

Innate immunity can initiate platelet activation during the development of thrombosis through a process, termed immunothrombosis. Neutrophils form neutrophil extracellular traps (NETs) that have been shown to interact directly with platelets and play pro-coagulant roles in a variety of infectious and sterile inflammatory settings. Hepatic surgical stress initiated by ischemia/reperfusion (I/R) injury has wide systemic consequences on distant organs. However, the mechanisms of this remote injury phenomenon are not well-understood. Here, we sought to determine the role of NETs in causing systemic immunothrombosis and distant organ injury following a local inflammatory insult with liver I/R. Postoperative thromboelastographic revealed that the speed of clot formation (alpha-angle) was significantly increased whereas time to clot formation (R-time) were decreased by in patients undergoing liver resection, indicating a hypercoagulable state after surgery. In mice subjected to liver I/R, circulating platelet activation and platelet-neutrophil aggregates were significantly increased. Injured distant organs such as the lung and kidney displayed NETs and platelet-rich micro-thrombi in the microvasculature following liver I/R. The immune-thrombi and organ damage were dramatically decreased when NETs were inhibited by DNase treatment. Depletion of Tlr4 on platelets limited NET-induced activation of platelets but had no effect on NET formation. Furthermore, platelet-specific TLR4 KO mice had significantly reduced distant organ injury with decreased circulating platelet activation, platelet-neutrophil aggregates following liver I/R in comparison to their control counterparts. These data establish that after an acute local inflammatory process, NET-activated platelets can lead to a systemic pro-coagulant state with resultant remote organ injury by immunothrombosis.

Supplemental digital content is available in the text., Objective This study aimed to determine whether Pennsylvania ACT 13 of 2002 (Mcare) requiring the written and verbal disclosure of “serious events” was accompanied by increased malpractice claims or compensation costs in a large U.S. health system. Main Outcomes and Measures The primary outcome was the rate of malpractice claims. The secondary outcome was the amount paid for compensation of malpractice claims. The analyses tested the relationship between the rate of serious event disclosures and the outcome variables, adjusted for the year of the event, category of claim, and the degree of “harm” related to the event. Results There were 15,028 serious event disclosures and 1302 total malpractice claims among 1,587,842 patients admitted to UPMC hospitals from May 17, 2002, to June 30, 2011. As the number of serious event disclosures increased, the number of malpractice claims per 1000 admissions remained between 0.62 and 1.03. Based on a matched analysis of claims that were disclosed and those that were not (195 pairs), disclosure status was significantly associated with increased claim payout (disclosures had 2.71 times the payout; 95% confidence interval, 1.56–4.72). Claims with higher harm levels H and I were independently associated with higher payouts than claims with lower harm levels A to D (11.15 times the payout; 95% confidence interval, 2.30–54.07). Conclusions and Relevance Implementation of a mandated serious event disclosure law in Pennsylvania was not associated with an overall increase in malpractice claims filed. Among events of similar degree of harm, disclosed events had higher compensation paid compared with those that had not been disclosed.

Objective Chronic venous insufficiency (CVI) affects 25 million adults in the United States. Little emphasis has been placed on inflammatory changes associated with CVI. We hypothesize that in patients with early to mid-stage benign varicose vein disease, differences in circulating inflammatory mediators will be manifested in blood draining the involved area vs circulating blood in control subjects. Methods Patients undergoing either endovenous ablation or sclerotherapy for Clinical, Etiology, Anatomy, and Pathophysiology clinical class 3 to 5 disease underwent phlebotomy from regional veins at the time of the procedure. The patient's age, gender, clinical class, duration of symptoms, presence of superficial truncal reflux by duplex ultrasound, and treatment modality were recorded. Plasma from patients and banked blood samples from healthy volunteers (HVs) were subjected to Luminex (EMD Millipore, Billerica, Mass) to evaluate the expression of an established panel of 20 inflammatory mediators. Mediator concentrations were compared between patients and HVs using Mann-Whitney U tests. Importantly, computational analysis allowed us to compare not only the panel of inflammatory mediators but also the inflammatory networks connecting these mediators to one another. Principal components were analyzed to assess network robustness in each group. Results CVI venous blood revealed significantly lower levels of monokine induced by γ interferon, soluble interleukin (IL) 2 receptor α chain, IL-4, IL-6, IL-7, tumor necrosis factor α, eotaxin, and granulocyte-macrophage colony-stimulating factor than blood from controls. Inflammatory networks were significantly less complex and less robust in the CVI patients compared with HVs. Based on principal component analysis, responses among HVs were more varied than those of CVI patients. Conclusions We demonstrate that patients with CVI have significant differences not only in blood-borne inflammatory mediators but also in the interconnectedness of these mediators with one another and in their principal inflammatory characteristics. Results suggest hypoinflammation in chronic nonhealing changes in CVI. These novel findings, if validated in larger cohorts, may help predict the risk of disease progression or response to therapy in the future and may guide mechanistic studies on tissue responses to CVI.

// Samer Tohme 1,* , Marina V. Kameneva 1,2,3,* , Hamza O. Yazdani 1 , Vikas Sud 1 , Julie Goswami 1 , Patricia Loughran 1,4 , Hai Huang 1 , Richard L. Simmons 1 and Allan Tsung 1 1 Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA 2 McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA 3 Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA 4 Center for Biologic Imaging, Department of Cell Biology, University of Pittsburgh, PA, USA * These authors have contributed equally to this work Correspondence to: Samer Tohme, email: // Keywords : liver, Ischemia reperfusion injury, drag reducing polymers, liver metastasis, metastatic colorectal cancer Received : January 09, 2017 Accepted : March 10, 2017 Published : May 31, 2017 Abstract Introduction: Surgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver. Methods: Experiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion. Results: After three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines. Conclusions: DRPs significantly attenuated metastatic tumor development and growth. DRPs warrant further investigation as a potential treatment for liver I/R injury in the clinical setting to improve cancer-specific outcomes.

Rapid response teams (RRTs) have been widely accepted as useful adjuncts to the care of inpatients with unanticipated emergencies. One study suggested that leadership of such teams could be assigned to midlevel providers, especially when nonhospitalized person (NHP)-related emergencies occur. However, in our tertiary medical center, a critical care medicine (CCM) physician always leads all RRT events including those related to NHPs.In this study, we postulate reasons in favor of a single structured RRT led by an intensivist for both inpatients and NHPs.An observational study conducted at an academic medical center. Demographic and clinical characteristics of NHP-related RRT events were evaluated over a 9-month period.Rapid response teams were activated 1,952 times, of which, 154 events were NHP related. Only 42 RRT activations occurred for employees and visitors. Most of the NHP activations (112 events) occurred in response to events involving persons who were on the premises because of preexisting illnesses, either visiting physician offices (46 events), undergoing ambulatory diagnostic procedures (30 events), in transit to the emergency department (13 events), or undergoing emergency psychiatry evaluation (11 events). Most patients (83 NHPs) required admission to the hospital including 22 NHPs to intensive care units (ICUs) either directly from the event location or subsequently from the emergency department. The physician team leader admitted 20 NHPs directly from the scene, of which, 13 were admitted directly to ICUs.Nonhospitalized patients requiring RRT activation often have complex pre-existent illnesses. A standardized team composition for both inpatients and NHPs in crisis is an appropriate administrative structure enhancing patient safety in hospitals where ambulatory and inpatient facilities are combined.

Purpose: We sought to identify a MODS score parameter that highly correlates with adverse outcomes and then use this parameter to test the hypothesis that multiple severity-based MODS clusters could be identified after blunt trauma. Methods: MOD score across days (D) 2–5 was subjected to Fuzzy C-means Clustering Analysis (FCM) followed by eight Clustering Validity Indices (CVI) to derive organ dysfunction patterns among 376 blunt trauma patients admitted to the intensive care unit (ICU) who survived to discharge. Thirty-one inflammation biomarkers were assayed (Luminex™) in serial blood samples (3 samples within the first 24 h and then daily up to D 5) and were analyzed using Two-Way ANOVA and Dynamic Network analysis (DyNA). Results: The FCM followed by CVI suggested four distinct clusters based on MOD score magnitude between D2 and D5. Distinct patterns of organ dysfunction emerged in each of the four clusters and exhibited statistically significant differences with regards to in-hospital outcomes. Interleukin (IL)-6, MCP-1, IL-10, IL-8, IP-10, sST2, and MIG were elevated differentially over time across the four clusters. DyNA identified remarkable differences in inflammatory network interconnectivity. Conclusion: These results suggest the existence of four distinct organ failure patterns based on MOD score magnitude in blunt trauma patients admitted to the ICU who survive to discharge.

Long-term complications following pancreatoduodenectomy (PD) can significantly impact quality of life and healthcare utilization. Most reports focus on short-term (within 90 days) PD outcomes; however, the incidence and risk factors for long-term complications (> 90 days) remain to be evaluated. We sought to identify the incidence, outcomes, and risk factors for long-term complications post-PD. All PD survivors between 2010 and 2017 were identified from a single-institutional database. Long-term complications (> 90 days post-PD and not resulting from cancer recurrence), including biliary stricture, cholangitis, pancreatitis, peptic ulcer, small bowel obstruction, and incisional hernia, were identified. Logistic regression was used to identify perioperative predictors of long-term complications. Of 906 PDs, 628 long-term survivors met criteria for analysis (mean age of 65.3 years, 47% female). Median follow-up and overall survival were 51.1 months (95% CI 47.6, 55.7) and 68.5 months (95% CI 57.9, 81.4), respectively. A total of 198 (31.5%) experienced at least one long-term complication. Complications included incisional hernia (17.7%), biliary stricture or cholangitis (8.0%), pancreatitis (5.7%), small bowel obstruction (4.3%), and peptic ulcer (3.2%). In total, 108 (17.2%) of the complications required an intervention, nearly half of which were surgical. On multivariable analysis, several predictors of long-term complications were identified: obesity (BMI ≥ 30 kg/m2), postoperative wound infection, prolonged index length of stay, readmission (< 90 days), operative approach (open vs. robotic), and pylorus-preservation. Long-term complications occur in nearly a third of PDs and nearly one-fifth of all PDs require re-intervention. Several modifiable predictors of long-term complications were identified.

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. Neutropenia is a common side effect of cytotoxic chemotherapy, managed with administration of recombinant granulocyte-colony stimulating factor (G-CSF, Filgrastim). The interleukin 17 – G-CSF – neutrophil extracellular trap (NET) axis promotes oncogenesis and progression of PDAC, inhibiting adaptive immunity. We evaluated the impact of G-CSF administration during neoadjuvant therapy (NAT) on oncologic outcomes in patients with operable pancreatic cancer. Methods: A retrospective review of all patients with localized PDAC treated with NAT prior to pancreatic resection between 2014 – 2020 was completed at a single institution. G-CSF administration, type, and dose were collected from inpatient and outpatient medical records. Results: Of 351 patients treated, 138 (39%) received G-CSF during NAT with a median follow-up of 45.8 months. Patients who received G-CSF were younger (64.0 vs 66.7, p = 0.008), had lower BMI (26.5 vs 27.9, p = 0.021), and were more likely to receive 5-FU based chemotherapy (42% vs 28.2%, p < 0.0001), NAT dose reduction (40.6% vs 25.4%, p = 0.003), or experience febrile neutropenia (8.7% vs 3.3%, p = 0.029). No differences were observed in baseline or pathologic tumor staging. In patients who received G-CSF, 130 (94%) received Pegfilgrastim with a median cumulative dose of 12 mg (IQR 6-12). Patients who received G-CSF were more likely to have an elevated post-NAT neutrophil to lymphocyte ratio (45% vs 29.6%, p = 0.004) and systemic immune-inflammation index (39.5% vs 29.6%, p = 0.061). Receiving G-CSF was an independent predictor of perineural invasion (HR 2.4, 95 CI [1.08, 5.5], p = 0.031) and margin positive resection (HR 1.69, 95 CI [1.01, 2.83], p = 0.043). Patients who received G-CSF had decreased overall survival compared to patients who did not receive G-CSF (median OS: 29.2 vs 38.7 months, p = 0.0001). Receiving G-CSF during NAT was an independent negative predictor of progression free (HR 1.38, 95 CI [1.04, 1.83], p = 0.022) and overall survival (HR 2.02, 95 CI [1.45, 2.79], p < 0.0001). In a subset of patients with available pre- and post-NAT serum specimens (n = 28), G-CSF administration resulted in an increased number of citrullinated histone H3 complexes following NAT (+1378±1502 vs -300.7±1147 pg/ml, p = 0.007), indicative of enhanced peripheral NET formation. Conclusions: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration is associated with worse oncologic outcomes and should be administered with caution. Prospective randomized as well as confirmatory clinical studies are in order.

Acute inflammation following sterile injury is both inevitable and necessary to restore homeostasis and promote tissue repair. However, when excessive, inflammation can jeopardize the viability of organs and cause detrimental systemic effects. Identifying key-regulators of the immune cascade induced by surgery is vital to attenuating excessive inflammation and its subsequent effects. In this review, we describe the emerging role of IL-17A as a key-regulator in acute inflammation. The role of IL-17A in chronic disease states, such as rheumatoid arthritis, psoriasis and cancer has been well documented, but its significance in acute inflammation following surgery, sepsis, or traumatic injury has not been well studied. We aim to highlight the role of IL-17A in acute inflammation caused by trauma, liver ischemia, and organ transplantation, as well as in post-operative surgical infections. Further investigation of the roles of this cytokine in acute inflammation may stimulate novel therapies or diagnostic modalities.

Background Achieving margin negative resection is a significant determinant of outcome in pancreatic adenocarcinoma (PDA). However, because of the fibrotic nature of PDA, it can be difficult to discriminate fibrosis from active disease intra-operatively. We sought to determine if post-hoc video review of robotic pancreatico-duodenectomy (RPD) could predict the portal/superior mesenteric vein (PV/SMV) margin status on final pathology. Methods Experienced pancreatic surgeons, blinded to patient and operative variables, reviewed the PV/SMV margin for available RPD videos of consecutive PDA patients from 9/2012 through 6/2017. Results 107 RPD videos were reviewed. Of 76 patients (71%) predicted to have a negative vein margin on video review, 20 patients (26%) had a pathologic positive margin. 25 of 31 patients (81%) predicted to have positive margin on video review were positive on pathology. The specificity of video prediction was 90.3% with a sensitivity of 55.6% and an accuracy of 75.7%. Conclusion Post-hoc video review prediction is unable to reliably predict a positive (R1) margin at the portal vein/SMV, suggesting that intra-operative clinical assessment may be suboptimal in determining the need for more extensive resections.

IMPORTANCE: Technical proficiency at robotic pancreaticoduodenectomy (RPD) and video assessment are promising tools for understanding postoperative outcomes. Delayed gastric emptying (DGE) remains a major driver of cost and morbidity after pancreaticoduodenectomy. OBJECTIVE: To determine if technical variables during RPD are associated with postoperative DGE. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study was conducted of technical assessment performed in all available videos (n = 192) of consecutive RPDs performed at a single academic institution from October 3, 2008, through September 27, 2016. EXPOSURES: Video review of gastrojejunal anastomosis during RPD. MAIN OUTCOMES AND MEASURES: Delayed gastric emptying was classified according to International Study Group of Pancreatic Surgery criteria. Video analysis reviewed technical variables specific in the construction of the gastrojejunal anastomosis. Using multivariate analysis, DGE was correlated with known patient variables and technical variables, individually and combined. RESULTS: Of 410 RPDs performed, video was available for 192 RPDs (80 women and 112 men; mean [SD] age, 65.7 [11.1] years). Delayed gastric emptying occurred in 41 patients (21.4%; grade A, 15; grade B, 14; and grade C, 12). Patient variables contributing to DGE on multivariate analysis were advanced age (odds ratio [OR] 1.11; 95% CI, 1.05-1.16; P

Patients expect safe accountable care from their healthcare providers. Quality is doing the right thing, in the right way, at the right time, for the right reason, and to the right person. A number of governmental and non-governmental organizations have emerged to set standards for quality and safety. Rapid response systems (RRSs) are an important part of safety structure and this chapter aims to provide a basic understanding of the patient safety and quality movement, medical error and adverse events, and the role of the rapid response team (RRT) in identifying and reporting threats to patient safety. It offers a brief introduction of just culture, disclosure, and second victim.

Tissue plasminogen activator (tPA) has been reported to treat intraoperative pulmonary thromboembolism (PTE) during liver transplantation (LT). However, tPA administration is often delayed due to fear of uncontrolled bleeding and storage in a refrigerator outside of operating rooms. Various dosages of tPA were used. We hypothesize that a policy of tPA storage and low dosage use improves patient outcomes. At a transplantation center, a multidisciplinary committee has implemented a tPA policy since April 2014, which includes the following: (1) timely administering of low-dose tPA (0.5-4 mg) for intraoperative PTE; (2) keeping 2 vials of tPA (2 mg/vial) in the operating room at room temperature; and (3) transferring unused tPA vials to the cardiology catheterization laboratory for next-day use. A prospective observational study was conducted to record the incidence and outcome of PTE during LTs. Over the next 19 months, 99 adult deceased donor LTs were performed with 1 (1.0%) intraoperative PTE. A 45-year-old woman with hepatitis C developed PTE within 5 minutes after graft reperfusion. A 2-mg tPA was immediately administered via a central venous line with hemodynamic improvement and clot lysis. Thromboelastography was normalized in 90 minutes. Five LT cases developing intraoperative PTE have been reported to receive “standard” dosages of tPA (20-110 mg) or urokinase (4400 IU/kg), which were administered more than 20 minutes after the diagnosis of PTE. One intraoperative death and one later mortality were noted with intracranial hemorrhages/infarction of 3 cases. The multidisciplinary low-dose tPA policy for PTE was suggested to be effective.

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. (Hepatology 2018).

Venous thromboembolic (VTE) disease, consisting of deep venous thrombosis (DVT) and pulmonary embolism (PE) is a leading cause of morbidity and mortality. Current prophylactic measures are insufficient to prevent all occurrence in part due to an incomplete understanding of the underlying pathophysiology. Mounting evidence describes interplay between activation of the innate immune system and thrombus development. Recent work has demonstrated that platelet release of HMGB1 leads to increased microvascular complications following injury. Additionally, platelet HMGB1 was found to enhance DVT and increase the formation of neutrophil extracellular traps (NETs), although the role of HMGB1 induced NET release in thrombosis remains unexplored. Utilizing a transgenic mouse lacking HMGB1 specifically from platelets and megakaryocytes we now demonstrate the specific role of platelet-derived HMGB1 in acute and subacute/chronic venous thrombosis. Platelets account for the majority of circulating HMGB1 and HMGB1 deposition within the developing clot. The pro-thrombotic effect of platelet-derived HMGB1 is mediated through enhanced neutrophil recruitment, NET formation and specifically release of extracellular DNA during NET formation. Taken together, these data suggest that platelet HMGB1 mediated NET release is a primary regulator of DVT formation in mice.

Introduction: Evidence is accumulating that neutrophil extracellular traps (NETs) are present within tumors and confer a worse outcome. The exact mechanisms of their role in tumor progression have been far from answered. Methods: Preoperative serum and tumor tissue were obtained from colorectal cancer liver metastases (CCLM) patients. In vivo, subcutaneous and liver metastasis tumor models were done in WT and nu/nu mice. Hepatocellular and colon murine and human cancer cell lines were used. DNase injection or PAD4KO mice were used to suppress NETs. In vitro, human and mice neutrophils were isolated and stimulated with PMA to form NETs to treat multiple cancer cell lines and examine NETs effect on their bioenergetics. Results:Tumors from CCLM patients showed increased NETs. Preoperative serum MPO-DNA, a NET marker, was found to be significantly elevated in CCLM patients compared to healthy controls. Patients with high MPO-DNA had significantly shorter overall and disease-free survival than patients with low MPO-DNA. The median disease-free survival was 5.8 times shorter (5.5vs.31 months, p Conclusion:NETs actively recruited to the tumor microenvironment can alter the metabolic programming of cancer cells by upregulating biogenesis and maintain mitochondrial fission, fusion and mitophagy which result in increased tumor growth. NETs represent a promising therapeutic target to halt cancer progression. Citation Format: Samer Tohme, Hamza Yazdani, Richard L. Simmons, Allan Tsung, David Bartlett. Neutrophil extracellular traps regulate mitochondrial quality control in cancer cells to promote tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2818.

Introduction: An emergency surgical airway (ESA) is widely recommended for securing the airway in critically ill patients who cannot be intubated or ventilated. Little is known of the frequency, clinical circumstances, management methods, and outcomes of hospitalized critically ill patients in whom ESA is performed outside the emergency department or operating room environments. Methods: We retrospectively reviewed all adult patients undergoing ESA in our intensive care units (ICUs) and other hospital units from 2008 to 2012 following activation of our difficult airway management team (DAMT). Results: Of 207 DAMT activations for native airway events, 22 (10.6%) events culminated in an ESA, with 59% of these events occurring in ICUs with the remainder outside the ICU in the context of rapid response team activations. Of patients undergoing ESA, 77% were male, 63% were obese, and 41% had a history of a difficult airway (DA). Failed planned or unplanned extubations preceded 61% of all ESA events in the ICUs, while bleeding from the upper or lower respiratory tract led to ESA in 44% of events occurring outside the ICU. Emergency surgical airway was the primary method of airway control in 3 (14%) patients, with the remainder of ESAs performed following failed attempts to intubate. Complications occurred in 68% of all ESAs and included bleeding (50%), multiple cannulation attempts (36%), and cardiopulmonary arrest (27%). Overall hospital mortality for patients undergoing ESA was 59%, with 38% of deaths occurring at the time of the airway event. Conclusion: An ESA is required in approximately 10% of DA events in critically ill patients and is associated with high morbidity and mortality. Efforts directed at early identification of patients with a difficult or challenging airway combined with a multidisciplinary team approach to management may reduce the overall frequency of ESA and associated complications.

Blunt trauma patients may present with similar demographics and injury severity yet differ with regard to survival. We hypothesized that this divergence was due to different trajectories of systemic inflammation and utilized computational analyses to define these differences.Retrospective clinical study and experimental study in mice.Level 1 trauma center and experimental laboratory.From a cohort of 493 victims of blunt trauma, we conducted a pairwise, retrospective, case-control study of patients who survived over 24 hours but ultimately died (nonsurvivors; n = 19) and patients who, after ICU admission, went on to be discharged(survivors; n = 19).None in patients. Neutralizing anti-interleukin-17A antibody in mice.Data on systemic inflammatory mediators assessed within the first 24 hours and over 7 days were analyzed with computational modeling to infer dynamic networks of inflammation. Network density among inflammatory mediators in nonsurvivors increased in parallel with organ dysfunction scores over 7 days, suggesting the presence of early, self-sustaining, pathologic inflammation involving high-mobility group protein B1, interleukin-23, and the Th17 pathway. Survivors demonstrated a pattern commensurate with a self-resolving, predominantly lymphoid response, including higher levels of the reparative cytokine interleukin-22. Mice subjected to trauma/hemorrhage exhibited reduced organ damage when treated with anti-interleukin-17A.Variable type 17 immune responses are hallmarks of organ damage, survival, and mortality after blunt trauma and suggest a lymphoid cell-based switch from self-resolving to self-sustaining inflammation.

Surgery is a crucial intervention and provides a chance of cure for patients with cancer. The perioperative period is characterized by an increased risk for accelerated growth of micrometastatic disease and increased formation of new metastatic foci. The true impact for cancer patients remains unclear. This review summarizes the often fragmentary clinical and experimental evidence supporting the role of surgery and inflammation as potential triggers for disease recurrence. Surgery induces increased shedding of cancer cells into the circulation, suppresses antitumor immunity allowing circulating cells to survive, upregulates adhesion molecules in target organs, recruits immune cells capable of entrapping tumor cells, and induces changes in the target tissue and in the cancer cells themselves to enhance migration and invasion to establish at the target site. Surgical trauma induces local and systemic inflammatory responses that can also contribute to the accelerated growth of residual and micrometastatic disease. Furthermore, we address the role of perioperative factors, including anesthesia, transfusions, hypothermia, and postoperative complications, as probable deleterious factors contributing to early recurrence. Through the admittedly limited understanding of these processes, we will attempt to provide suggestions for potential new therapeutic approaches to target the protumorigenic perioperative window and ultimately improve long-term oncological outcomes. Cancer Res; 77(7); 1548–52. ©2017 AACR.

Clostridium difficile associated disease (CDAD) is the result of colonic bacterial overgrowth with this gram positive anaerobic organism and the production of toxins that typically induce diarrhea. Most patients with CDAD respond to treatment with oral metronidazole or vancomycin, but a subset of patients will develop a severe systemic illness, multiple organ failure, and death. There are no reliable combinations of clinical or laboratory findings that will distinguish patients who will respond to medical therapy and those who will progress to a more complicated state. Early surgical consultation should be considered in patients with ileus, severe abdominal pain, significant tenderness, immunosuppression, advanced age, high white blood cell or band counts, acute renal failure, mental status changes, or cardiopulmonary compromise. The standard operation for fulminant colitis is subtotal colectomy but the high mortality of the operation, and the long-term morbidity even in survivors combine to act as deterrents to early surgical consultation and operation. Novel operative approaches that preserve the colon and minimize operative morbidity may prove to remove the barriers to earlier surgical treatment for fulminant CDAD and improve outcomes.

CDI is increasing in incidence and severity. Clinicians must have a low threshold to consider the diagnosis and to treat patients with the clinical syndrome and risk factors before laboratory confirmation of the diagnosis. In patients who have signs of advanced disease, escalation of care with antimicrobial strategies and multidisciplinary care including surgical consultation is necessary. Furthermore, lowering the threshold for surgery compared with traditional approaches likely results in improved survival. Novel surgical approaches may obviate total abdominal colectomy and the associated immediate and long-term morbidity in this often fragile patient population, thus allowing clinicians to embrace surgical therapy earlier in the course of severe, complicated disease.

Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-α and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation., Author summary Gram-negative bacterial lipopolysaccharide (LPS) is both a central mediator of sepsis and a canonical inducer of acute inflammation via Toll-like receptor 4 (TLR4). Sepsis involves the systemic spillover of inflammation that normally remains localized in individual organs. The goal of this study was to gain insights into 1) early vs. later drivers of LPS-induced inflammation in various compartments, and 2) the systemic spillover from affected organs vs. local production of inflammatory mediators in the blood. This study involved a large number of data points on the dynamics of inflammatory mediators at the protein level, data-driven computational modeling of principal characteristics and cross-correlations, and validation of key hypotheses. In addition to verifying key mechanisms in LPS/TLR4-driven acute inflammation, this approach yielded key insights into the progression of inflammation across tissues, and also suggested the presence of TLR4-independent pathways (especially in the gut). This is, to our knowledge, the first study examining the dynamic evolution of some key inflammatory mediators and their interactions with each other in both the systemic circulation and within a number of targeted parenchymal organs in mice.

Acute mesenteric ischemia continues to be associated with high mortality. We hypothesized that delays in surgical consultation and operation are independently associated with increased mortality and sought to identify modifiable characteristics associated with delayed management. We conducted a retrospective cohort study of 72 patients diagnosed with acute mesenteric ischemia. Twenty-six (36%) patients died, of which 14 (54%) had care withdrawn. Delay in operation (>6 hours after surgical consultation) was associated with increased mortality (adjusted OR 3.7; 90% CI, 1.1-12). For patients for whom care was not withdrawn, delay in surgical consultation (>24 hours after disease onset) was associated with increased mortality (adjusted OR, 9.4; 90% CI, 1.3-65), as was delay in operation (adjusted OR, 4.9; 90% CI, 1.1-22). For those managed medically, early surgical consultation was associated with improved mortality (Odds Ratio [OR], 0; 90% Confidence Interval [CI], 0-0.34). Patients with delayed surgical consultation were more likely to have abdominal distension, elevated lactate concentration, acute renal failure, vasopressor administration, and a lack of abdominal pain. The acquisition of CT imaging trended toward an association with delayed surgical consultation ( P = 0.06). We conclude that early surgical consultation is associated with improved outcome even for patients managed without operative intervention, and that CT imaging may delay appropriate care.

Introduction of new innovative immunosuppressive strategies has been the milestone of the recent evolution of intestinal and multivisceral transplantation. With new insights into the mechanisms of organ engraftment and acquired tolerance, the Pittsburgh tolerogenic protocol was recently introduced and consisted of two main therapeutic principles: recipient pretreatment with lymphoid ablating antibodies and minimal post-transplant immunosuppression with tacrolimus monotherapy. The reported herein improved survival and the striking ability to wean immunosuppression among the intestinal and multivisceral recipients pretreated with a single-dose of Thymoglobulin (rATG) or Campath-1H (alemtuzumab) supports our working hypothesis with successful induction of variable tolerance. It is important, however, that careful monitoring of subtle histologic changes in serial endoscopic-guided mucosal biopsies be carried out for early diagnosis of allograft immune activation with prompt restoration of the baseline immunosuppressive therapy. Future scientific discoveries with better understanding of the mechanisms of immune tolerance and clinical introduction of reliable assays will increase the chance and safety of achieving complete tolerance among the intestinal and other solid organ recipients. This review will focus on the historic evolution of the immunosuppressive and other management strategies utilized for the intestinal and multivisceral recipients at the University of Pittsburgh with special reference to allograft immunity and the successful achievement of partial tolerance.

Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether, as a result of its ability to ensnare moving cells, NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase, which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophil–derived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration, and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse. Cancer Res; 76(6); 1367–80. ©2016 AACR.

Intra-abdominal candidiasis (IAC) is poorly understood compared to candidemia. We described the clinical characteristics, microbiology, treatment and outcomes of IAC, and identified risk factors for mortality. We performed a retrospective study of adults diagnosed with IAC at our center in 2012–2013. Risk factors for mortality were evaluated using multivariable logistic regression. We identified 163 patients with IAC, compared to 161 with candidemia. Types of IAC were intra-abdominal abscesses (55%), secondary peritonitis (33%), primary peritonitis (5%), infected pancreatic necrosis (5%), and cholecystitis/cholangitis (3%). Eighty-three percent and 66% of secondary peritonitis and abscesses, respectively, stemmed from gastrointestinal (GI) tract sources. C. albicans (56%) and C. glabrata (24%) were the most common species. Bacterial co-infections and candidemia occurred in 67% and 6% of patients, respectively. Seventy-two percent of patients underwent an early source control intervention (within 5 days) and 72% received early antifungal treatment. 100-day mortality was 28%, and highest with primary (88%) or secondary (40%) peritonitis. Younger age, abscesses and early source control were independent predictors of survival. Younger age, abscesses and early antifungal treatment were independently associated with survival for IAC stemming from GI tract sources. Infectious diseases (ID) consultations were obtained in only 48% of patients. Consulted patients were significantly more likely to receive antifungal treatment. IAC is a common disease associated with heterogeneous manifestations, which result in poor outcomes. All patients should undergo source control interventions and receive antifungal treatment promptly. It is important for the ID community to become more engaged in treating IAC.

The authors describe two cases in which Günther Tulip inferior vena cava filters migrated to the chest, necessitating open-heart surgery for retrieval. In the first case, a 52-year-old man was transferred to their hospital from an outside facility after the filter migrated to the main pulmonary artery during attempted filter placement. In the second case, a 72-year-old man, a Günther Tulip filter was found to have migrated to the tricuspid valve after cardiopulmonary arrest and subsequent resuscitation, including emergent central venous line placement. The authors present the relevant details of both cases, discuss possible preventive strategies, and review the available literature about migration of the Günther Tulip filter.

Bariatric surgery (BS) is currently the most effective treatment for severe obesity. However, these weight loss procedures may result in the development of gut failure (GF) with the need for total parenteral nutrition (TPN). This retrospective study is the first to address the anatomic and functional spectrum of BS-associated GF with innovative surgical modalities to restore gut function.Over 2 decades, 1500 adults with GF were referred with history of BS in 142 (9%). Of these, 131 (92%) were evaluated and received multidisciplinary care. GF was due to catastrophic gut loss (Type-I, 42%), technical complications (Type-II, 33%), and dysfunctional syndromes (Type-III, 25%). Primary bariatric procedures were malabsorptive (5%), restrictive (19%), and combined (76%). TPN duration ranged from 2 to 252 months.Restorative surgery was performed in 116 (89%) patients with utilization of visceral transplantation as a rescue therapy in 23 (20%). With a total of 317 surgical procedures, 198 (62%) were autologous reconstructions; 88 (44%) foregut, 100 (51%) midgut, and 10 (5%) hindgut. An interposition alimentary conduit was used in 7 (6%) patients. Reversal of BS was indicated in 84 (72%) and intestinal lengthening was required in 10 (9%). Cumulative patient survival was 96% at 1 year, 84% at 5 years, and 72% at 15 years. Nutritional autonomy was restored in 83% of current survivors with persistence or relapse of obesity in 23%.GF is a rare but serious life-threatening complication after BS. Successful outcome is achievable with comprehensive management, including reconstructive surgery and visceral transplantation.

Background Hepatobiliary and pancreatic (HPB) operations have a high incidence of post‐operative nosocomial infections. The aim of the present study was to determine whether hospitalization up to 1 year before HPB surgery is associated with an increased risk of post‐operative infection, surgical‐site infection (SSI) and infection resistant to surgical chemoprophylaxis. Methods A retrospective cohort study of patients undergoing HPB surgeries between January 2008 and June 2013 was conducted. A multivariable logistic regression model was used for controlling for potential confounders to determine the association between pre‐operative admission and post‐operative infection. Results Of the 1384 patients who met eligibility criteria, 127 (9.18%) experienced a post‐operative infection. Pre‐operative hospitalization was independently associated with an increased risk of a post‐operative infection [adjusted odds ratio (aOR): 1.61, 95% confidence interval [CI]: 1.06–2.46] and SSI (aOR: 1.79, 95% CI: 1.07–2.97). Pre‐operative hospitalization was also associated with an increased risk of post‐operative infections resistant to standard pre‐operative antibiotics (OR: 2.64, 95% CI: 1.06–6.59) and an increased risk of resistant SSIs (OR: 3.99, 95% CI: 1.25–12.73). Discussion Pre‐operative hospitalization is associated with an increased incidence of post‐operative infections, often with organisms that are resistant to surgical chemoprophylaxis. Patients hospitalized up to 1 year before HPB surgery may benefit from extended spectrum chemoprophylaxis.

To provide evidence that iNOS expression solely in leukocytes plays a role in postoperative ileus.Intestinal handling initiates a molecular and cellular muscularis inflammation that has been associated with iNOS expression and ileus. The specific cellular source of iNOS is a matter of speculation.Chimeric mice were constructed that selectively express the iNOS gene only in their leukocytes or only in their parenchymal cells by lethal radiation and reconstitution with reciprocal bone marrow. Mild intestinal manipulation was used to induce postoperative ileus.Intestinal manipulation caused a significant leukocyte extravasation into the muscularis of all groups. Postoperative iNOS mRNA expression was evident in iNOS and transplanted iNOS mice with iNOS bone marrow but not in iNOS animals. The loss of the iNOS gene in leukocytes of iNOS mice reduced iNOS mRNA expression by 59%. iNOS-deficient mice and iNOS animals with iNOS leukocytes presented with a significant improvement in postoperative intestinal transit and in vitro smooth muscle contractility, whereas the replacement with iNOS bone marrow in iNOS mice completely reversed this improvement.These results clearly show that iNOS expressed in leukocytes within the intestinal muscularis plays a major role in mediating smooth muscle dysfunction and subsequently postoperative ileus.

Objective: To study the impact of time of day, day of week and level of patient monitoring on medical emergency team (MET) activation. Design: Retrospective observational study of all MET and cardiac arrest events between October 2001 and March 2005. Setting: University of Pittsburgh Medical Center Presbyterian Hospital, a tertiary care teaching facility in the United States. Interventions: None. Measurements and Main Results: Cardiac arrest and MET event rate during the day (7 am to 6:59 pm) and night (7 pm to 6:59 am) overall; for weekdays and weekends; and from unmonitored, monitored, and intensive care units (ICUs). There were 605 cardiac arrest and 4,072 MET events. MET event rate was higher during the day than at night in unmonitored units (62% day vs. 38% night; p

To investigate the initiation of a complex inflammatory response within the human intestinal muscularis intraoperatively so as to determine the clinical applicability of the inflammatory hypothesis of postoperative ileus.Mild intestinal manipulation in rodents initiates the activation of transcription factors, upregulates proinflammatory cytokines, and increases the release of kinetically active mediators (nitric oxide and prostaglandins), all of which results in the recruitment of leukocytes and a suppression in motility (i.e., postoperative ileus).Human small bowel specimens were harvested during abdominal procedures at various times after laparotomy. Histochemical and immunohistochemical techniques were applied to intestinal muscularis whole-mounts. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed for interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Signal transducers and activators of transcription (STAT) protein phosphorylation was determined by electromobility shift assay. Organ bath experiments were performed on jejunal circular smooth muscle strips. GW274150C and DFU were used in vitro as iNOS and COX-2 inhibitors.Normal human muscularis externa contained numerous macrophages that expressed increased lymphocyte function associated antigen-1 (LFA-1) immunoreactivity as a function of intraoperative time. RT-PCR demonstrated a time-dependent induction of IL-6, IL-1beta, TNF-alpha, iNOS, and COX-2 mRNAs within muscularis extracts after incision. Mediators were localized to macrophages with STAT protein activation in protein extracts demonstrating local IL-6 functional activity. DFU alone or in combination with GW274150C increased circular muscle contractility. Specimens harvested after reoperation developed leukocytic infiltrates and displayed diminished in vitro muscle contractility.These human data demonstrate that surgical trauma is followed by resident muscularis macrophage activation and the upregulation, release, and functional activity of proinflammatory cytokines and kinetically active mediators.

OBJECTIVE: The aim of this study was to determine the underlying characteristics of inpatients sustaining crisis events in the radiology department (RD). METHODS: This is a retrospective case series undertaken in a 715-bed university-based tertiary care referral center in the United States, with a well-established medical emergency response team (MET). Adult hospitalized inpatients sustaining crisis events in the radiology suites of the University of Pittsburgh Medical Center from November 1, 2008, to October 31, 2010, were reviewed. RESULTS: Ninety-six MET activations met our criteria. There were 92 conditions classified as C. Four conditions were characterized as A, defined as cardiopulmonary arrest. Three condition C calls progressed to cardiopulmonary arrest and were reclassified as A.A number of variables including admission diagnosis, comorbid conditions, time elapsed from admission to condition, admission source of patient, unit of origin before event, and the type of imaging study ordered were analyzed to determine any links or patterns between precursor events, the likelihood of deterioration, and the patient's subsequent clinical outcome.Forty (42%) of the conditions occurred within 24 hours of admission, and 49 (51%) occurred within the first 48 hours. Forty-six of the studies ordered were computed tomographic scans. Of those patients who sustained their condition within the first 48 hours, 41 (84%) were either outside hospital transfers or emergency department admissions.A significant proportion of acute deteriorations occurred in patients with traumatic brain injuries or strokes. Ten events (10%) were due to radiology accidents.Irrespective of etiology, the intervention of the MET allowed the study to be completed in 68 (71%) cases. Of these, 28 (41%) had their condition diagnosed by the study. Of the 10 patients who sustained a radiology accident, no patients had an adverse effect to their outcome; all were returned to their unit of origin. CONCLUSIONS: Inpatient deterioration in the RD often occurred early in the course of the patient's hospitalization, with more than 40% taking place in the first 24 hours of admission. The MET seemed to have a positive impact on many patients, allowing a substantial percentage of studies to be completed. Interpretation of those studies often identified the etiology of the deterioration.Further study of outside hospital transfers, emergency department admissions, and intensive care unit patients who deteriorate in the RD is warranted to clarify risk factors and to identify early signs of deterioration. Language: en

In spite of the well-established side effects associated with their use (1), corticosteroids have remained a part of long-term immunosuppression after renal transplantation. With the introduction of tacrolimus, however, steroid withdrawal has been possible in some 70% of successfully transplanted adults and children (2–9). In the latter group, significant catch-up growth has been achieved, particularly in preadolescent children (5, 6). An important question, however, concerns the outcome after steroid withdrawal in pediatric patients on tacrolimus. Although this question has been studied in adults (4, 7–9), it has not been investigated in detail in children. We looked at our pediatric renal transplant patients receiving tacrolimus-based immunosuppression and examined the short- and medium-term outcomes after steroid withdrawal.

Background Inducible nitric oxide synthase (iNOS) is up-regulated in rejecting allografts and is protective against allograft arteriosclerosis; it suppresses neointimal smooth muscle cell accumulation and inhibits adhesion of platelets and leukocytes to the endothelium. However, the functional importance of endothelial NOS (eNOS) in the rejecting allografts remains unclear. Methods We examined the effects of selective eNOS deficiency in aortic allografts in a murine chronic rejection model using grafts from eNOS knockout (KO) mice (C57BL/6 background; H2b) and normal C3H (H2K) as recipients. Grafts from wild-type C57BL/6 mice served as controls. Grafts from iNOS KO mice served as a second group of controls where the contribution from iNOS was eliminated but eNOS was preserved. Aortic grafts were harvested and analyzed at days 10-14, 18-22, and 26-30 after transplantation. Results Endothelial NOS-deficient grafts showed significantly increased intima/media ratios at days 26-30 compared to controls. Immunostaining demonstrated that in eNOS KO grafts, eNOS was not detectable whereas iNOS was expressed prominently in infiltrating recipient mononuclear cells. In control grafts, eNOS expression was preserved in the endothelium even by day 30, and associated with a decrease in intimal thickening. We further demonstrated that early overexpression of iNOS by ex vivo gene transfer completely prevented the development of arteriosclerosis associated with eNOS deficiency. Conclusions We found that eNOS plays a protective role in allografts, and that in eNOS-deficient allografts, early overexpression of iNOS is capable of preventing the development of allograft arteriosclerosis. In allografts with dysfunctional vascular endothelium and impaired eNOS activity as a result of ischemia or native arteriosclerotic disease, iNOS gene therapy may serve to improve their long-term survival and function.

Between March 27, 1989 and December 31, 1997, 1316 kidney transplantations alone were performed under tacrolimus-based immunosuppression at our center. Posttransplant lymphoproliferative disorders (PTLD) developed in 25 (1.9%) cases; the incidence in adults was 1.2% (15/1217), whereas in pediatric patients it was 10.1% (10/99; P seronegative recipient. Of 7 pediatric cases in whom both the donor and recipient EBV serologies were known, 6 (86%) were EBV seropositive donor --> seronegative recipient. Acute rejection was observed before the diagnosis of PTLD in 8 (53%) of 15 adults and 3 (30%) of 10 pediatric patients. Initial treatment of PTLD included a marked decrease or cessation of immunosuppression with concomitant ganciclovir therapy; two adults and two pediatric patients required chemotherapy. With a mean follow-up of 24.9+/-30.1 months after transplantation, the 1- and 5-year actuarial patient and graft survival rates in adults were 93% and 86%, and 80% and 60%, respectively. Two adults died, 3.7 and 46.2 months after transplantation, of complications related to PTLD, and 10 (including the 2 deaths) lost their allograft 3.7-84.7 months after transplantation. In children, the 1- and 5-year actuarial patient and graft survival rates were 100% and 100%, and 100% and 89%, respectively. No child died; one child lost his allograft 41.3 months after transplantation. One child had presumed recurrent PTLD that responded to discontinuation of tacrolimus and reinitiation of antiviral therapy. The mean serum creatinine level in adults was 2.5+/-1.2 mg/dl, and in children, it was 1.3+/-0.6 mg/ dl. Under tacrolimus-based immunosuppression, PTLD is less common after renal transplantation in adults than in children, but PTLD in children is associated with more favorable outcomes than in adults.

Background. Tacrolimus has been used as a primary immunosuppressive agent in adult and pediatric renal transplant recipients, with reasonable outcomes. Methods. Between December 14, 1989 and December 31, 1996, 82 pediatric renal transplantations alone were performed under tacrolimus-based immunosuppression without induction anti-lymphocyte antibody therapy. Patients undergoing concomitant or prior liver and/or intestinal transplantation were not included in the analysis. The mean recipient age was 10.6±5.2 years (range: 0.7-17.9). Eighteen (22%) cases were repeat transplantations, and 6 (7%) were in patients with panel-reactive antibody levels over 40%. Thirty-four (41%) cases were with living donors, and 48 (59%) were with cadaveric donors. The mean donor age was 27.3±14.6 years (range: 0.7-50), and the mean cold ischemia time in the cadaveric cases was 26.5±8.8 hr. The mean number of HLA matches and mismatches was 2.8±1.2 and 2.9±1.3; there were five (6%) O-Ag mismatches. The mean follow-up was 4.0±0.2 years. Results. The 1- and 4-year actuarial patient survival was 99% and 94%. The 1- and 4-year actuarial graft survival was 98% and 84%. The mean serum creatinine was 1.1±0.5 mg/dl, and the corresponding calculated creatinine clearance was 88±25 ml/min/1.73 m 2 . A total of 66% of successfully transplanted patients were withdrawn from prednisone. In children who were withdrawn from steroids, the mean standard deviation height scores (Z-score) at the time of transplantation and at 1 and 4 years were -2.3±2.0, -1.7±1.0, and +0.36±1.5. Eighty-six percent of successfully transplanted patients were not taking anti-hypertensive medications. The incidence of acute rejection was 44%; between December 1989 and December 1993, it was 63%, and between January 1994 and December 1996, it was 23% (P=0.0003). The incidence of steroid-resistant rejection was 5%. The incidence of delayed graft function was 5%, and 2% of patients required dialysis within 1 week of transplantation. The incidence of cytomegalovirus was 13%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 12%. The incidence of early Epstein-Barr virus-related posttransplant lymphoproliferative disorder (PTLD) was 9%; between December 1989 and December 1992, it was 17%, and between January 1993 and December 1996, it was 4%. All of the early PTLD cases were treated successfully with temporary cessation of immunosuppression and institution of antiviral therapy, without patient or graft loss. Conclusions. These data demonstrate the short- and medium-term efficacy of tacrolimus-based immunosuppression in pediatric renal transplant recipients, with reasonable patient and graft survival, routine achievement of steroid and anti-hypertensive medication withdrawal, gratifying increases in growth, and, with further experience, a decreasing incidence of both rejection and PTLD.

Since the 1960s simple inexpensive cold lactated Ringers with additives has been used for short-term cold preservation of kidneys from living donors. We performed 266 living donor kidney transplantations from January 22, 2003 to October 30, 2006. Donor allografts were recovered laparoscopically and flushed with cold heparin, lactated Ringer's and procaine (HeLP) solution. Warm and cold ischemic times were typically

Tacrolimus was used as the primary immunosuppressive agent in 69 pediatric renal transplantations between December 17, 1989, and June 30, 1995. Children undergoing concomitant or prior liver and/or intestinal transplantation were excluded from analysis. The mean recipient age was 10.3±5.0 years (range, 0.7-17.5 years). Seventeen (24.6%) children were undergoing retransplantation, and six (8.7%) had a panel reactive antibody level of 40% or higher. Thirty-nine (57%) cases were with cadaveric kidneys, and 30 (43%) were with living donors. The mean donor age was 28.0±14.7 years (range, 1.0-50.0 years), and the mean cold ischemia time for the cadaveric kidneys was 27.0±9.4 hr. The antigen match was 2.7±1.2, and the mismatch was 3.1±1.2. All patients received tacrolimus and steroids, without antibody induction, and 26% received azathioprine as well. The mean follow-up was 32±20 months. One- and 4-year actuarial patient survival rates were 100% and 95%. One- and 4-year actuarial graft survival rates were 99% and 85%. The mean serum creatinine level was 1.2±0.8 mg/dl, and the calculated creatinine clearance was 82±26 ml/min/1.73 m 2 . The mean tacrolimus dose was 0.22±0.14 mg/kg/day, and the level was 9.5±4.8 ng/ml. The mean prednisone dose was 2.1±4.9 mg/day (0.07±0.17 mg/kg/day), and 73% of successfully transplanted children were off prednisone. Seventy-nine percent were not taking any antihypertensive medications. The mean serum cholesterol level was 158±54 mg/dl. The incidence of delayed graft function was 4.3%. The incidence of rejection was 49%, and the incidence of steroid-resistant rejection was 6%. The incidence of rejection decreased to 27% in the most recent 26 cases (January 1994 through June 1995). The incidence of new-onset diabetes was 10.1%; six of the seven affected children were able to be weaned off insulin. The incidence of cytomegalovirus disease was 13%, and that of posttransplant lymphoproliferative disorder was 10%; the incidence of posttransplant lymphoproliferative disorder in the last 40 transplants was 5% (two cases). All of the children who developed posttransplant lymphoproliferative disorder are alive and have functioning allografts. Based on this data, we believe that tacrolimus is a superior immunosuppressive agent in pediatric renal transplant patients, with excellent short- and medium-term patient and graft survival, an ability to withdraw steroids in the majority of patients, and, with more experience, a decreasing rate of rejection and viral complications.