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Supplementary Figure 2 contains results showing 1) increased hypoxia and NET formation in human resected metastatic colorectal cancer tumors. 2) Protumorigenic effects of NETs in Hep1-6 cancer cell lines. 3)Increased HMGB1 levels in patients after major liver resection.

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.

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Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1α, TFAM, and NRF-1. In vitro, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1α upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression.Significance:Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.

Supplementary Figure 1. Flow cytometric analysis of purity of neutrophil isolation technique from bone marrow of mice.

Supplementary Figure 1: Contains result showing 1) PCR analysis of the hypoxic cancer cells showed an elevated mRNA expression of neutrophil attractant chemokines 2) Increased in neutrophil cell migration in the presence of cancer hypoxic media 3) Increased levels of HMGB1 in both mice and human hypoxic cancer cell lines; Supplementary Figure 2: Contains result showing 1) Immunofluorescence imagining of TOM20 in the tumor tissue of mice treated with DNAse and NEi. 2) Decreased in mitochondrial DNA assay and ATP levels in DNAse/NEI treated mice. 3) Western blot analysis of mitochondrial biogenesis associated genes (PGC-1α, NRF1 and TFAM) showed decreased expression in NET depleted tumors. 4) Increased in the number of mitochondria in NET treated MC38 cells observed by TME. 5) Increased in the staining of neutrophil elastase in human CRLM tissue. 6) Immunofluorescence imaging indicated release of NE during NET formation: Supplementary Figure 3: Contains result showing 1 and 2) Protein expression for PGC-1a, NRF1, TFAM and phosphorylated p38 were observed in a control and TLR4 siRNA transfected cells. 3) Increased mitochondrial masss observed in cancer cell treated with rNE or NETs observed by Mitotracker staining. 4 and 5) Flowcytometry and MTT analysis showed an increase in the proliferation of cancer cells after treating with either NETs or rNE; Supplementary Figure 4: Schematic diagrams of the proposed role of NETs in the tumor growth.; Supplementary Material and Methods

Supplementary methods

Supplementary Figure 3. Schematic diagrams of the proposed role of NETs in the progression of metastatic disease after surgical stress.

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.

Simple Summary Neutrophil Extracellular Traps (NETs) are formed following the activation of neutrophils and play an important role in the development of cancer, especially metastatic disease. In this review, we will portray the role of Neutrophils/NETs in the tumor microenvironment and circulation. We will furthermore discuss the role of neutrophil reverse migration, NET-mediated pre-metastatic niche formation, and possible treatment strategies to decrease metastatic cascade. Abstract Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression.

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

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

Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1α, TFAM, and NRF-1. In vitro, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1α upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression. Significance: Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.

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.

Hepatic ischemia reperfusion (I/R) is a clinically relevant model of acute sterile inflammation leading to a reverberating, self-sustaining inflammatory response with resultant necrosis. We hypothesized that computerized dynamic network analysis (DyNA) of 20 inflammatory mediators could help dissect the sequence of post-I/R mediator interactions that induce injury. Although the majority of measured inflammatory mediators become elevated in the first 24 h, we predicted that only a few would be secreted early in the process and serve as organizational centers of downstream intermediator complexity. In support of this hypothesis, DyNA inferred a central organizing role for IL-17A during the first 3 h of reperfusion. After that, DyNA revealed connections among almost all the inflammatory mediators, representing an ongoing cytokine storm. Blocking IL-17A immediately after reperfusion disassembled the inflammatory networks and protected the liver from injury. Disassembly of the networks was not achieved if IL-17A blockage was delayed two or more hours postreperfusion. Network disassembly was accompanied by decrease in neutrophil infiltration and neutrophil extracellular trap (NET) formation. By contrast, administration of recombinant IL-17A increased neutrophil infiltration, NET formation, and liver necrosis. The administration of DNase, a NET inhibitor, significantly reduced hepatic damage despite prior administration of IL-17A, and DNase also disassembled the inflammatory networks. In vitro, IL-17A was a potent promoter of NET formation. Therefore, computational analysis identified IL-17A’s early, central organizing role in the rapid evolution of a network of inflammatory mediators that induce neutrophil infiltration and NET formation responsible for hepatic damage after liver I/R.

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.

The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator–activated receptor gamma coactivator 1 alpha (PGC-1α) and up-regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC-1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC-1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine-induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll-like receptor-9. This binding leads to activation of p38 and subsequent phosphorylation of PGC-1α, with resultant up-regulation of mitochondrial biogenesis. Conclusion: Taken together, our findings suggest that during hypoxia HMGB1 up-regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017;66:182–197).

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.

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.

Background: The cellular and molecular response of liver cells to hypoxic stress is not fully understood. We used computational modeling to gain insights into the inflammatory response of primary human hepatocytes (HC) to hypoxic stress in vitro. Methods: Primary HC from cancer patients were exposed to hypoxia (1% O 2 ) or normoxia (21% O 2 ) for 1–48 h, and the cell supernatants were assayed for 21 inflammatory mediators. Data were analyzed by Two-Way ANOVA, Dynamic Bayesian Network (DBN) inference, Dynamic Network Analysis (DyNA), and Time-interval Principal Component Analysis (TI-PCA). Results: The chemokines MCP-1/CCL2 and IP-10/CXCL10, along with the cytokines interleukin (IL)-2 and IL-15 were altered significantly over time in hypoxic vs . normoxic HC. DBN inference suggested central, coordinating roles for MCP-1 and IL-8 in regulating a largely conserved inflammatory program in both hypoxic and normoxic HC. DyNA likewise suggested similar network trajectories of decreasing complexity over time in both hypoxic and normoxic HC, though with differential connectivity of MCP-1, IP-10, IL-8, and Eotaxin. TI-PCA pointed to IL-1β as a central characteristic of inflammation in hypoxic HC across all time intervals, along with IL-15 and IL-10, vs . Eotaxin, IL-7, IL-10, IL-15, and IL-17A in normoxic HC. Conclusions: Thus, diverse human HC appear to respond in a largely conserved fashion to cell culture stress, with distinct characteristics based on the presence or absence of hypoxia.

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

A rapid response system (RRS) is a program designed to respond in a timely, organized, and comprehensive manner to a patient’s urgent unmet medical need within a healthcare facility. The goals of the rapid response team (RRT) are to restore homeostasis, prevent further physiologic deterioration, and establish an optimal environment of care. RRTs are now in widespread use in the US because of the Joint Commission’s national patient safety goals, which required that healthcare organizations improve recognition and response to changes in a patient’s condition. Recent meta-analyses have now concluded that RRT is effective in reducing the incidence of cardiac arrests within hospitals. There is still controversy, however, on the impact of RRT on ultimate clinical outcomes, including mortality. In this chapter, we review the history and evolution of RRTs, rationale for its existence, its impact on patient outcomes, and current controversies.

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.

The transfusion of red blood cells (RBCs), although necessary for treatment of anemia and blood loss, has also been linked to increased morbidity and mortality. RBCs stored for longer durations and transfused in larger volumes are often cited as contributory to adverse outcomes. The potential mechanisms underlying deleterious effects of RBC transfusion are just beginning to be elucidated. In this narrative review, we explore the hypothesis that prolonged RBC storage results in elaboration of substances which may function as danger associated molecular pattern molecules that activate the innate immune system with consequences unfavorable to healthy homeostasis. The nature of these chemical mediators and the biological responses to them offers insight into the mechanisms of these pathological responses. Three major areas of activation of the innate immune apparatus by stored RBCs have been tentatively identified: RBC hemolysis, recipient neutrophil priming, and reactive oxygen species production. The possible mechanisms by which each might perturb the innate immune response are reviewed in a search for potential novel pathways through which transfusion can lead to an altered inflammatory response.

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.