Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear. PATIENTS AND METHODS: This cohort study assessing the impact of G-CSF administration was conducted on 351 patients with PDAC treated with neoadjuvant therapy (NAT) and pancreatic resection at a high-volume tertiary care academic center from 2014 to 2019. Participants were identified from a prospectively maintained database and had a median follow-up of 45.8 months. RESULTS: Patients receiving G-CSF (n=138; 39.3%) were younger (64.0 vs 66.7 years; P=.008), had lower body mass index (26.5 vs 27.9; P=.021), and were more likely to receive 5-FU-based chemotherapy (42.0% vs 28.2%; P<.0001). No differences were observed in baseline or clinical tumor staging. Patients receiving G-CSF were more likely to have an elevated (>5.53) post-NAT neutrophil-to-lymphocyte ratio (45.0% vs 29.6%; P=.004). G-CSF recipients also demonstrated higher circulating levels of neutrophil extracellular traps (+709 vs -619 pg/mL; P=.006). On multivariate analysis, G-CSF treatment was associated with perineural invasion (hazard ratio [HR], 2.65; 95% CI, 1.16-6.03; P=.021) and margin-positive resection (HR, 1.67; 95% CI, 1.01-2.77; P=.046). Patients receiving G-CSF had decreased overall survival (OS) compared with nonrecipients (median OS, 29.2 vs 38.7 months; P=.001). G-CSF administration was a negative independent predictor of OS (HR, 2.02; 95% CI, 1.45-2.79; P<.0001). In the inverse probability weighted analysis of 301 matched patients, neoadjuvant G-CSF administration was associated with reduced OS. CONCLUSIONS: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration may be associated with worse oncologic outcomes and should be further evaluated.

High Dose of Metformin Decreases Susceptibility to Occlusive Arterial Thrombosis in Diabetic Mice.

Introduction: Metformin is the most prescribed medication in Diabetes Mellitus(DM). Metformin has shown to decrease mean platelet volume, with promising antiplatelet effects. High doses of Metformin have also been associated with hypercoagulation. We hypothesize that Metformin will protect DM mice from occlusive arterial thrombus formation by altering platelet activation and mitochondrial bioenergetics. Methods: DM was developed by low dose of Streptozotocin, non-DM (healthy) mice are controls. Either vehicle or Metformin was administered twice daily via oral gavage for 7-days. Ferric chloride (FeCl3) arterial thrombosis and tail bleeding time were performed. Whole blood aggregometry, platelet activation/adhesion and mitochondrial bioenergetics were evaluated. Results: Metformin decreased susceptibility of DM mice to arterial thrombosis. Platelet bioenergetics show DM mice have increased platelet mitochondrial respiration, but no differences were observed with Metformin treatment. In non-DM (healthy) mice, Metformin modulated ADP-dependent increase in platelet adhesion. Non-DM (healthy) mice, Metformin shortens bleeding time with faster thrombotic occlusion. Metformin also increased platelet mitochondrial maximal respiration and spare respiratory capacity uniquely in non-DM (healthy) mice. Conclusion: Metformin regulates platelet bioenergetics and ADP-mediated platelet function in DM mice which attenuates susceptibility to arterial thrombosis. Future studies will evaluate clinically relevant doses of Metformin that regulates thrombotic function in diabetic platelets.

High Dose of Metformin Decreases Susceptibility to Occlusive Arterial Thrombosis in Diabetic Mice.

Introduction: Metformin is the most prescribed medication in Diabetes Mellitus(DM). Metformin has shown to decrease mean platelet volume, with promising antiplatelet effects. High doses of Metformin have also been associated with hypercoagulation. We hypothesize that Metformin will protect DM mice from occlusive arterial thrombus formation by altering platelet activation and mitochondrial bioenergetics. Methods: DM was developed by low dose of Streptozotocin, healthy (non-DM) mice are controls. Either vehicle or Metformin was administered twice daily via oral gavage for 7-days. Ferric chloride (FeCl3) arterial thrombosis and tail bleeding time were performed. Whole blood aggregometry, platelet activation/adhesion and mitochondrial bioenergetics were evaluated. Results: Metformin decreased susceptibility of DM mice to arterial thrombosis. Platelet bioenergetics show DM mice have increased platelet mitochondrial respiration, but no differences were observed with Metformin treatment. In healthy mice, Metformin modulated ADP-dependent increase in platelet adhesion. In healthy mice, Metformin shortens bleeding time with faster thrombotic occlusion. Metformin also increased platelet mitochondrial maximal respiration and spare respiratory capacity uniquely in healthy mice. Conclusion: Metformin regulates platelet bioenergetics and ADP-mediated platelet function in DM mice which attenuates susceptibility to arterial thrombosis. Future studies will evaluate clinically relevant doses of Metformin that regulates thrombotic function in diabetic platelets.

The John S. Najarian symposium: The past, present, and future of surgery and transplantation, May 20, 2022, Minneapolis, MN.

Dr John S Najarian (1927-2020), chairman of the Department of Surgery at the University of Minnesota from 1967 to 1993, was a pioneer in surgery, clinical immunology and transplantation. A Covid-delayed Festschrift was held in his honor on May 20, 2022. The speakers reflected on his myriad contributions to surgery, transplantation, and resident/fellow training, as well as current areas of ongoing research to improve clinical outcomes. Of note, Dr Najarian was a founder of the journal Clinical Transplantation.

A preliminary investigation of the role of intraindividual sleep variability in substance use treatment outcomes.

INTRODUCTION: Poor sleep health is common among individuals in early treatment for substance use disorders (SUDs) and may serve an important role in predicting SUD outcomes. However, sleep parameters have been inconsistently linked with risk of relapse, perhaps because previous research has focused on mean values of sleep parameters (e.g., total sleep time [TST], sleep efficiency [SE], and sleep midpoint [SM]) across multiple nights rather than night-to-night fluctuations (i.e., intraindividual variability [IIV]). The current study assessed sleep across the first week of SUD treatment, with the aim of prospectively examining the relationship between mean and IIV of TST, SE, and SM and treatment completion and relapse within one-month post-treatment. METHODS: Treatment-seeking adults (N = 23, Mage = 40.1, 39% female) wore an actigraph to assess sleep for one week at the beginning of an intensive outpatient program treatment. Electronic medical record and follow-up interviews were utilized to determine treatment outcomes. RESULTS: Greater IIV in TST was associated with higher odds of relapse (OR = 3.55, p =.028). Greater IIV in SM was associated with lower odds of treatment completion, but only when removing mean SM from the model (OR = 0.75, p =.046). DISCUSSION: Night-to-night variability in actigraphy-measured TST is more strongly associated with SUD treatment outcomes than average sleep patterns across the week. Integrating circadian regulation into treatment efforts to improve SUD treatment outcomes may be warranted. Given the small sample size utilized in the present study, replication of these analyses with a larger sample is warranted.

Web-based provider training of cognitive behavioral therapy of insomnia: engagement rates, knowledge acquisition, and provider acceptability.

Insomnia is common but severely underreported and undertreated. One possible reason for this problem is the lack of providers in cognitive behavioral therapy for insomnia (CBT-I). To address this we created CBTIweb.org, an online training platform for providers to learn the basics of sleep, assessing insomnia, and CBT-I. The present study assessed the reach of CBTIweb by examining engagement, knowledge acquisition, and perceived acceptability. Participants who registered for CBTIweb self-reported their practice setting and personal characteristics (i.e. degree, profession, licensure status). Knowledge acquisition was assessed with pre- and post-tests, and provider acceptability was assessed via a survey. In the first three months after launching CBTIweb, 2586 providers registered and 624 of these completed the training within three months of registering. Chi-square tests of independence revealed no differences in completion rates by education or profession, though trainees were more likely to initiate and complete treatment than licensed providers. Paired t tests revealed significant knowledge acquisition, and most providers positively rated the website navigation, content, aesthetics, and understanding of core CBT-I skills. This study demonstrated CBTIweb is an effective platform for training health professionals to be minimally proficient in the gold standard treatment for insomnia disorder.

The Risk of Incarceration During Nonoperative Management of Incisional Hernias: A Population-based Analysis of 30,998 Patients.

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 ±â€Š15.9 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.

The Use of Machine Learning to Create a Risk Score to Predict Survival in Patients with Hepatocellular Carcinoma: A TCGA Cohort Analysis.

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 < 0.01) compared to group 0 (median not reached). Similar results were observed when overall survival (OS) was analyzed. On multivariate Cox regression, higher scores were associated with significantly shorter DFS (1 point: HR 2.57 (1.38-4.80), 2 points: 3.91 (2.11-7.24), and 3 points: 5.09 (2.70-9.58), p < 0.01). Conclusion: Long-term outcomes of patients with HCC can be predicted using a simplified scoring system based on tumor mRNA gene expression levels. This tool could assist clinicians and researchers in identifying patients at increased risks for recurrence to tailor specific treatment and follow-up strategies for individual patients.

Neutrophil Extracellular Traps (NETs) in Cancer Metastasis.

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.

Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment.

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.

A framework for localizing global climate solutions and their carbon reduction potential.

Localized carbon reduction strategies are especially critical in states and regions that lack top-down climate leadership. This paper illustrates the use of coupled systems in assessments of subnational climate solutions with a case study of Georgia, a state located in the southeastern United States that does not have statewide climate goals or plans. The paper illustrates how robust place-specific plans for climate action could be derived from foundational global and national work and by embedding that research into the context of socio-ecological-technological systems. Our replicable methodology advances the traditional additive sectoral wedge analysis of carbon abatement potential by incorporating solution interdependencies and by spanning both carbon sources and sinks. We estimate that a system of 20 solutions could cut Georgia's carbon footprint by 35% in 2030 relative to a business-as-usual forecast and by 50% relative to Georgia's emissions in 2005. We also produce a carbon abatement cost curve that aligns private and social costs as well as benefits with units of avoided CO2-e. The solutions are affiliated with various social co-costs and co-benefits that highlight societal concerns extending beyond climate impacts, including public health, environmental quality, employment, and equity.

Sleep and substance use disorder treatment: A preliminary study of subjective and objective assessment of sleep during an intensive outpatient program.

BACKGROUND AND OBJECTIVES: Characteristics of sleep concerns and their relationship to mental health in heterogeneous substance use disorder (SUD) treatment settings are not well understood. The purpose of this preliminary study was to assess sleep using subjective and objective measures at two time points during SUD treatment and compare sleep changes to changes in mental health measures. METHODS: Treatment-seeking participants completed an assessment battery at the beginning of treatment (Time 1, N = 30) and again upon treatment completion (Time 2, approximately 4 weeks later, N = 22). The majority of participants were White (80%), male (63%), and presenting for alcohol use disorder (60.0%), though almost half reported polysubstance abuse (43%). Comorbidity was common (53%). Sleep and mental health questionnaires with 1 week of actigraphy and sleep diaries were completed at both time points. RESULTS: Most participants met the criteria for a sleep disorder and mean scores on questionnaires showed poor sleep quality, insomnia symptoms, and frequent nightmares, with sleep quality and insomnia improving over time but remaining clinically significant. Nightmares did not improve. Actigraphy indicated poor sleep at both time points. Improvement in insomnia was related to improvement in measures of mental health while changes in actigraphy variables were not related to these measures. DISCUSSION AND CONCLUSIONS: Multiple types of sleep disturbance are prevalent in this population, with nightmares persisting throughout treatment and insomnia symptoms showing a relationship with mental health symptoms. SCIENTIFIC SIGNIFICANCE: This was the first study to longitudinally assess mental health with subjective and objective measures of sleep across multiple types of SUDs in a community SUD treatment setting.

Spatiotemporally specific roles of TLR4, TNF, and IL-17A in murine endotoxin-induced inflammation inferred from analysis of dynamic networks.

BACKGROUND: Bacterial lipopolysaccharide (LPS) induces a multi-organ, Toll-like receptor 4 (TLR4)-dependent acute inflammatory response. METHODS: Using network analysis, we defined the spatiotemporal dynamics of 20, LPS-induced, protein-level inflammatory mediators over 0-48 h in the heart, gut, lung, liver, spleen, kidney, and systemic circulation, in both C57BL/6 (wild-type) and TLR4-null mice. RESULTS: Dynamic Network Analysis suggested that inflammation in the heart is most dependent on TLR4, followed by the liver, kidney, plasma, gut, lung, and spleen, and raises the possibility of non-TLR4 LPS signaling pathways at defined time points in the gut, lung, and spleen. Insights from computational analyses suggest an early role for TLR4-dependent tumor necrosis factor in coordinating multiple signaling pathways in the heart, giving way to later interleukin-17A-possibly derived from pathogenic Th17 cells and effector/memory T cells-in the spleen and blood. CONCLUSIONS: We have derived novel, systems-level insights regarding the spatiotemporal evolution acute inflammation.

Baseline Plasma Inflammatory Profile Is Associated With Response to Neoadjuvant Chemotherapy in Patients With Pancreatic Adenocarcinoma.

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.

A putative "chemokine switch" that regulates systemic acute inflammation in humans.

Systemic inflammation is complex and likely drives clinical outcomes in critical illness such as that which ensues following severe injury. We obtained time course data on multiple inflammatory mediators in the blood of blunt trauma patients. Using dynamic network analyses, we inferred a novel control architecture for systemic inflammation: a three-way switch comprising the chemokines MCP-1/CCL2, MIG/CXCL9, and IP-10/CXCL10. To test this hypothesis, we created a logical model comprising this putative architecture. This model predicted key qualitative features of systemic inflammation in patient sub-groups, as well as the different patterns of hospital discharge of moderately vs. severely injured patients. Thus, a rational transition from data to data-driven models to mechanistic models suggests a novel, chemokine-based mechanism for control of acute inflammation in humans and points to the potential utility of this workflow in defining novel features in other complex diseases.

Translating a Global Emission-Reduction Framework for Subnational Climate Action: A Case Study from the State of Georgia.

Subnational entities are recognizing the need to systematically examine options for reducing their carbon footprints. However, few robust and comprehensive analyses are available that lay out how US states and regions can most effectively contribute. This paper describes an approach developed for Georgia-a state in the southeastern United States called "Drawdown Georgia", our research involves (1) understanding Georgia's baseline carbon footprint and trends, (2) identifying the universe of Georgia-specific carbon-reduction solutions that could be impactful by 2030, (3) estimating the greenhouse gas reduction potential of these high-impact 2030 solutions for Georgia, and (4) estimating associated costs and benefits while also considering how the solutions might impact societal priorities, such as economic development opportunities, public health, environmental benefits, and equity. We began by examining the global solutions identified by Project Drawdown. The resulting 20 high-impact 2030 solutions provide a strategy for reducing Georgia's carbon footprint in the next decade using market-ready technologies and practices and including negative emission solutions. This paper describes our systematic and replicable process and ends with a discussion of its strengths, weaknesses, and planned future research.

Functional Threshold Power Is Not Equivalent to Lactate Parameters in Trained Cyclists.

ABSTRACT: Jeffries, O, Simmons, R, Patterson, SD, and Waldron, M. Functional threshold power is not equivalent to lactate parameters in trained cyclists. J Strength Cond Res 35(10): 2790-2794, 2021-Functional threshold power (FTP) is derived from a maximal self-paced 20-minute cycling time trial whereby the average power output is scaled by 95%. However, the physiological basis of the FTP concept is unclear. Therefore, we evaluated the relationship of FTP with a range of laboratory-based blood lactate parameters derived from a submaximal threshold test. Twenty competitive male cyclists completed a maximal 20-minute time trial and an incremental exercise test to establish a range of blood lactate parameters. Functional threshold power (266 ± 42 W) was strongly correlated (r = 0.88, p < 0.001) with the power output associated with a fixed blood lactate concentration 4.0 mmol·L-1 (LT4.0) (268 ± 30 W) and not significantly different (p > 0.05). While mean bias was 2.9 ± 24.6 W, there were large limits of agreement (LOA) between FTP and LT4.0 (-45 to 51 W). All other lactate parameters, lactate threshold (LT) (236 ± 32 W), individual anaerobic threshold (244 ± 33 W), and LT thresholds determined using the Dmax method (221 ± 25 W) and modified Dmax method (238 ± 32 W) were significantly different from FTP (p < 0.05). While FTP strongly correlated with LT4.0, the large LOA refutes any equivalence as a measure with physiological basis. Therefore, we would encourage athletes and coaches to use alternative field-based methods to predict cycling performance.

IL-17A - A regulator in acute inflammation: Insights from in vitro, in vivo and in silico studies.

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.

Exercise Training Decreases Hepatic Injury and Metastases Through Changes in Immune Response to Liver Ischemia/Reperfusion in Mice.

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.

Video review reveals technical factors predictive of biliary stricture and cholangitis after robotic pancreaticoduodenectomy.

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 diameter), increased distance of the HJ (>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.