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Supplementary Figures S1-S3; Supplementary Table S1.

Purpose: Pancreatic cancer is the fourth leading cause of cancer-related deaths, in which the 5-year survival rate is less than 5%. Current standard of care therapies offer little selectivity and high toxicity. Novel, tumor-selective approaches are desperately needed. Although prior work suggested that β-lapachone (β-lap) could be used for the treatment of pancreatic cancers, the lack of knowledge of the compound's mechanism of action prevented optimal use of this agent.Experimental Design: We examined the role of NAD(P)H:quinone oxidoreductase-1 (NQO1) in β-lap–mediated antitumor activity, using a series of MIA PaCa-2 pancreatic cancer clones varying in NQO1 levels by stable shRNA knockdown. The antitumor efficacy of β-lap was determined using an optimal hydroxypropyl-β-cyclodextran (HPβ-CD) vehicle formulation in metastatic pancreatic cancer models.Results: β-Lap–mediated cell death required ∼90 enzymatic units of NQO1. Essential downstream mediators of lethality were as follows: (i) reactive oxygen species (ROS); (ii) single-strand DNA breaks induced by ROS; (iii) poly(ADP-ribose)polymerase-1 (PARP1) hyperactivation; (iv) dramatic NAD+/ATP depletion; and (v) programmed necrosis. We showed that 1 regimen of β-lap therapy (5 treatments every other day) efficaciously regressed and reduced human pancreatic tumor burden and dramatically extended the survival of athymic mice, using metastatic pancreatic cancer models.Conclusions: Because NQO1 enzyme activities are easily measured and commonly overexpressed (i.e., >70%) in pancreatic cancers 5- to 10-fold above normal tissue, strategies using β-lap to efficaciously treat pancreatic cancers are indicated. On the basis of optimal drug formulation and efficacious antitumor efficacy, such a therapy should be extremely safe and not accompanied with normal tissue toxicity or hemolytic anemia. Clin Cancer Res; 17(2); 275–85. ©2011 AACR.

Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non–tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway. [Cancer Res 2008;68(11):4340–6]

Supplementary Figure 1 from Vascular Endothelial Growth Factor Receptor 2 Mediates Macrophage Infiltration into Orthotopic Pancreatic Tumors in Mice

Supplementary Figure 2 from Vascular Endothelial Growth Factor Receptor 2 Mediates Macrophage Infiltration into Orthotopic Pancreatic Tumors in Mice

Background Surgical readmissions are clinically and financially problematic. Our purpose is to determine if a decrease in postoperative ambulation (steps/day) is associated with hospital readmission. Methods In this prospective cohort study, patients undergoing elective operations wore an accelerometer activity tracker to measure steps/day for 28 consecutive postoperative days. The primary outcome was hospital readmission. The change in steps/day over two consecutive days prior to the day of the readmission were examined. Predetermined thresholds for decreases of consecutive daily ambulation levels were used to calculate sensitivity and specificity for the outcome of hospital readmission. Results 215 patients (aged 63 ± 12 years) were included. Readmission occurred in 10% (n = 21). For each of the first 28-postoperative days, the entire cohort had an average daily step increase of 136 ± 146 steps/day (Spearman correlation rho = 0.990; p 50% from the prior day had a 79% sensitivity and 90% specificity for hospital readmission. Conclusions A decrease of >50% daily ambulation (steps/day) over two consecutive post-discharge days accurately forecasts hospital readmission. The implications of these findings are that monitoring daily ambulation could serve as a form of outpatient telemetry aiding to forecast post-surgical readmissions.

Background: Surgeons must evaluate and communicate the risk associated with operative procedures for patients at high risk of poor postoperative outcomes. Multidisciplinary approaches to complex decision making are needed. Objective: To improve physician decision making for high-risk surgical patients. Design: This is a retrospective review of patients presented to a multidisciplinary committee for three years. Setting/Subjects: Evaluation of patients was done in a single-center U.S. veterans affairs (VA) hospital. All patients who were considered for surgery had a VA Surgical Quality Improvement Program (VASQIP) risk calculator 30-day mortality >5%. Measurements: Thirty-day and one-year mortality were measured. Results: Seventy-six patients were reviewed with an average expected 30-day mortality of 14.2%. Forty-two patients (57%) had a recommended change in the care plan before surgery. Fifty-four patients (71%) proceeded with surgery and experienced a 30-day mortality of 7.4%. Conclusions and Relevance: Multidisciplinary discussion of high-risk surgical patients may help surgeons make perioperative recommendations for patients. Implementation of a multidisciplinary high-risk committee should be considered at facilities that manage high-risk surgical patients.

The COVID-19 pandemic has brought many challenges including barriers to delivering high-quality surgical care and follow-up while minimizing the risk of infection. Telehealth has been increasingly utilized for post-operative visits, yet little data exists to guide surgeons in its use. We sought to determine safety and efficacy of telehealth follow-up in patients undergoing cholecystectomy during the global pandemic at a VA Medical Center (VAMC).This was a retrospective review of patients undergoing cholecystectomy at a level 1A VAMC over a 2-year period from August 2019 to August 2021. Baseline demographics, post-operative complications, readmissions, emergency department (ED) visits and need for additional procedures were reviewed. Patients who experienced a complication prior to discharge, underwent a concomitant procedure, had non-absorbable skin closure, had new diagnosis of malignancy or were discharged home with drain(s) were ineligible for telehealth follow-up and excluded.Over the study period, 179 patients underwent cholecystectomy; 30 (17%) were excluded as above. 20 (13%) missed their follow-up, 52 (35%) were seen via telehealth and 77 (52%) followed-up in person. There was no difference between the two groups regarding baseline demographics or intra-operative variables. There was no significant difference in post-operative complications [4 (8%) vs 6 (8%), p 0.99], ED utilization [5 (10%) vs 7 (9%), p = 0.78], 30-day readmission [3 (6%) vs 6 (8%), p = 0.74] or need for additional procedures [2 (4%) vs 4 (5%), p = 0.41] between telehealth and in-person follow-up.Telehealth follow-up after cholecystectomy is safe and effective in Veterans. There were no differences in outcomes between patients that followed up in-person vs those that were seen via phone or video. Routine telehealth follow-up after uncomplicated cholecystectomy should be considered for all patients.

Stray energy transfer from surgical monopolar radiofrequency energy instruments can cause unintended thermal injuries during laparoscopic surgery. Single-incision laparoscopic surgery transfers more stray energy than traditional laparoscopic surgery. There is paucity of published data concerning stray energy during single-incision robotic surgery. The purpose of this study was to quantify stray energy transfer during traditional, multiport robotic surgery (TRS) compared to single-incision robotic surgery (SIRS). An in vivo porcine model was used to simulate a multiport or single-incision robotic cholecystectomy (DaVinci Si, Intuitive Surgical, Sunnyvale, CA). A 5 s, open air activation of the monopolar scissors was done on 30 W and 60 W coag mode (ForceTriad, Covidien-Medtronic, Boulder, CO) and Swift Coag effect 3, max power 180 W (VIO 300D, ERBE USA, Marietta, GA). Temperature of the tissue (°C) adjacent to the tip of the assistant grasper or the camera was measured with a thermal camera (E95, FLIR Systems, Wilsonville, OR) to quantify stray energy transfer. Stray energy transfer was greater in the SIRS setup compared to TRS setup at the assistant grasper (11.6 ± 3.3 °C vs. 8.4 ± 1.6 °C, p = 0.013). Reducing power from 60 to 30 W significantly reduced stray energy transfer in SIRS (15.3 ± 3.4 °C vs. 11.6 ± 3.3 °C, p = 0.023), but not significantly for TRS (9.4 ± 2.5 °C vs. 8.4 ± 1.6 °C, p = 0.278). The use of a constant voltage regulating generator also minimized stray energy transfer for both SIRS (0.7 ± 0.4 °C, p

Stray energy transfer from monopolar radiofrequency energy during laparoscopy can be potentially catastrophic. Robotic surgery is increasing in popularity; however, the risk of stray energy transfer during robotic surgery is unknown. The purpose of this study was to (1) quantify stray energy transfer using robotic instrumentation, (2) determine strategies to minimize the transfer of energy, and (3) compare robotic stray energy transfer to laparoscopy. In a laparoscopic trainer, a monopolar instrument (L-hook) was activated with DaVinci Si (Intuitive, Sunnyvale, CA) robotic instruments. A camera and assistant grasper were inserted to mimic a minimally invasive cholecystectomy. During activation of the L-hook, the non-electric tips of the camera and grasper were placed adjacent to simulated tissue (saline-soaked sponge). The primary outcome was change in temperature from baseline (°C) measured nearest the tip of the non-electric instrument. Simulated tissue nearest the robotic grasper increased an average of 18.3 ± 5.8 °C; p

Enteral access is required for a variety of reasons from neuromuscular disorders to dysphagia. Gastrostomy tubes (GTs) can be placed endoscopically, surgically, or radiographically and complications include infection, bleeding, leakage and unintentional removal. Routine post-procedural follow-up is limited by inconsistent guidelines and management by different specialty teams. We established a dedicated GT clinic to provide continuity of care and prophylactic GT exchange. We hypothesized that patients followed in the GT clinic would have reduced Emergency Department (ED) utilization.A retrospective review of patients who underwent GT placement from January 2010 to January 2020 was conducted. Baseline demographics, indications for GT placement, number and reason for ED visits and utilization of a multidisciplinary GT clinic were studied.A total of 97 patients were included. The most common indication for placement was dysphagia (88, 91%) and the most common primary diagnosis was head and neck malignancy (51, 51%). The GT clinic is a multidisciplinary clinic staffed by surgeons and residents, dieticians, and wound care specialists and cared for 16 patients in this study. Three patients (19%) in the GT clinic group required ED visits compared to 44 (54%) in the standard of care (SOC) group (p 0.05). There was an average of 0.9 ED visits per patient (range 0-7) in the GT clinic group vs 1.6 ED visits per patient (range 0-20) in the SOC group (p = 0.34). Feeding tubes were prophylactically exchanged an average of 7 times per patient in the GT clinic group vs 3 times per patient in the SOC group (p 0.05).A multidisciplinary clinic dedicated to GT care limits ED visits for associated complications by more than 50%. Follow-up in a dedicated clinic with prophylactic tube exchange decreases ED visits and should be considered at facilities that care for patients with GTs.

Surgical fires are a rare event that still occur at a significant rate and can result in severe injury and death. Surgical fires are fueled by vapor from alcohol-based skin preparations in the presence of increased oxygen concentration and a spark from an energy device. Carbon dioxide (CO2) is used to extinguish electrical fires, and we sought to evaluate its effect on fire creation in the operating room. We hypothesize that CO2 delivered by the energy device will decrease the frequency of surgical fires fueled by alcohol-based skin preparations. An ex vivo model with 15 × 15 cm section of clipped, porcine skin was used. A commercially available electrosurgical pencil with a smoke evacuation tip was connected to a laparoscopic CO2 insufflation system. The electrosurgical pencil was activated for 2 s at 30 watts coagulation mode immediately after application of alcohol-based surgical skin preparations: 70% isopropyl alcohol with 2% chlorhexidine gluconate (CHG-IPA) or 74% isopropyl alcohol with 0.7% iodine povacrylex (Iodine-IPA). CO2 was infused via the smoke evacuation pencil at flow rates from 0 to 8 L/min. The presence of a flame was determined visually and confirmed with a thermal camera (FLIR Systems, Boston, MA). Carbon dioxide eliminated fire formation at a flow rate of 1 L/min with CHG-IPA skin prep (0% vs. 60% with no CO2, p

Treatment options for liver metastases (primarily colorectal cancer) are limited by high recurrence rates and persistent tumor progression. Surgical approaches to management of these metastases typically use heat energy including electrocautery, argon beam coagulation, thermal ablation of surgical margins for hemostasis, and preemptive thermal ablation to prevent bleeding or to effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of procancer cytokines and deleterious immune infiltrates at the site of thermal injury. To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well-characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Furthermore, there were local increases in expression of messenger ribonucleic acid (mRNA) for hypoxia-inducible factor-1α (HIF1α), arginase-1, and vascular endothelial growth factor α and activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (P = 0.03). Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with protumorigenic activation of macrophages and implantation of circulating tumors. Discrete targeting of HIF1α signaling or inhibiting macrophages offers potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is used.

The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.

Stray energy transfer from surgical monopolar radiofrequency energy instruments can cause unintended thermal injuries during laparoscopic surgery. Single-incision laparoscopic surgery transfers more stray energy than traditional laparoscopic surgery. There is paucity of published data concerning stray energy during single-incision robotic surgery. The purpose of this study was to quantify stray energy transfer during traditional, multiport robotic surgery (TRS) compared to single-incision robotic surgery (SIRS).An in vivo porcine model was used to simulate a multiport or single-incision robotic cholecystectomy (DaVinci Si, Intuitive Surgical, Sunnyvale, CA). A 5 s, open air activation of the monopolar scissors was done on 30 W and 60 W coag mode (ForceTriad, Covidien-Medtronic, Boulder, CO) and Swift Coag effect 3, max power 180 W (VIO 300D, ERBE USA, Marietta, GA). Temperature of the tissue (°C) adjacent to the tip of the assistant grasper or the camera was measured with a thermal camera (E95, FLIR Systems, Wilsonville, OR) to quantify stray energy transfer.Stray energy transfer was greater in the SIRS setup compared to TRS setup at the assistant grasper (11.6 ± 3.3 °C vs. 8.4 ± 1.6 °C, p = 0.013). Reducing power from 60 to 30 W significantly reduced stray energy transfer in SIRS (15.3 ± 3.4 °C vs. 11.6 ± 3.3 °C, p = 0.023), but not significantly for TRS (9.4 ± 2.5 °C vs. 8.4 ± 1.6 °C, p = 0.278). The use of a constant voltage regulating generator also minimized stray energy transfer for both SIRS (0.7 ± 0.4 °C, p 0.001) and TRS (0.7 ± 0.4 °C, p 0.001).More stray energy transfer occurs during single-incision robotic surgery than multiport robotic surgery. Utilizing a constant voltage regulating generator minimized stray energy transfer for both setups. These data can be used to guide robotic surgeons in their use of safe, surgical energy.

Background and Aims: It has become clear that vein resection and reconstruction for pancreatic ductal adenocarcinoma (PDAC) is the standard of care as supported by multiple guidelines. However, resection of large peri-pancreatic arteries remains debatable. Materials and Methods: This review examines the current state of vascular resection with curative intent for PDAC in the last 5 years. Herein, we consider venous (superior mesenteric vein, portal vein), as well as arterial (superior mesenteric artery, celiac trunk, hepatic artery) resection or both with or without reconstruction. Results: Improvement of multidrug chemotherapy has revolutionized care for PDAC that should shift traditional surgical thinking from an anatomical classification of resectability to a prognostic and biological classification. Conclusion: The present review gives an overview on the results of pancreatectomy associated with vascular resection, with consideration of new perspectives offered by the availability of better systemic therapies.

Stray energy transfer from monopolar radiofrequency energy during laparoscopy can be potentially catastrophic. Robotic surgery is increasing in popularity; however, the risk of stray energy transfer during robotic surgery is unknown. The purpose of this study was to (1) quantify stray energy transfer using robotic instrumentation, (2) determine strategies to minimize the transfer of energy, and (3) compare robotic stray energy transfer to laparoscopy.In a laparoscopic trainer, a monopolar instrument (L-hook) was activated with DaVinci Si (Intuitive, Sunnyvale, CA) robotic instruments. A camera and assistant grasper were inserted to mimic a minimally invasive cholecystectomy. During activation of the L-hook, the non-electric tips of the camera and grasper were placed adjacent to simulated tissue (saline-soaked sponge). The primary outcome was change in temperature from baseline (°C) measured nearest the tip of the non-electric instrument.Simulated tissue nearest the robotic grasper increased an average of 18.3 ± 5.8 °C; p 0.001 from baseline. Tissue nearest the robotic camera tip increased (9.0 ± 2.1 °C; p 0.001). Decreasing the power from 30 to 15 W (18.3 ± 5.8 vs. 2.6 ± 2.7 °C, p 0.001) or using low-voltage cut mode (18.3 ± 5.8 vs. 3.1 ± 2.1 °C, p 0.001) reduced stray energy transfer to the robotic grasper. Desiccating tissue, in contrast to open air activation, also significantly reduced stray energy transfer for the grasper (18.3 ± 5.8 vs. 0.15 ± 0.21 °C, p 0.001) and camera (9.0 ± 2.1 vs. 0.24 ± 0.34 °C, p 0.001).Stray energy transfer occurs during robotic surgery. The assistant grasper carries the highest risk for thermal injury. Similar to laparoscopy, stray energy transfer can be reduced by lowering the power setting, utilizing a low-voltage cut mode instead of coagulation mode and avoiding open air activation. These practical findings can aid surgeons performing robotic surgery to reduce injuries from stray energy.

Surgical smoke evacuators may reduce the concentration of alcohol vapors from skin preparations at the site of electrosurgical device activation, decreasing operating room fire risk. Our aim was to compare the incidence of flames with and without smoke evacuation in a porcine ex vivo model. A monopolar device was activated after application of either 70% isopropyl alcohol/2% chlorhexidine gluconate (CHG-IPA) or 74% isopropyl alcohol/0.7% iodine povacrylex (iodine-IPA) skin preparations. No suction was compared with standard wall suction and 2 monopolar devices with built-in smoke evacuators. Flames were generated in 60% of CHG-IPA and 47% of iodine-IPA tests without suction. Wall suction did not significantly reduce fires (CHG-IPA 43% vs. 60%, P=0.30; iodine-IPA 57% vs. 47%, P=0.61). Use of both smoke evacuation devices reduced fires for CHG-IPA (17% vs. 60%, P=0.001 and 20% vs. 60%, P=0.004) but not for iodine-IPA. Smoke evacuation devices reduce fire risk when used with a chlorhexidine-alcohol skin preparation.

To determine the impact of radiofrequency (RF) and microwave (MW) energy compared to direct cautery on metatstatic colon cancer growth.Hepatic ablation with MW and RF energy creates a temperature gradient around a target site with temperatures known to create tissue injury and cell death. In contrast, direct heat application (cautery) vaporizes tissue with a higher site temperature but reduced heat gradient on surrounding tissue. We hypothesize that different energy devices create variable zones of sublethal injury that may promote tumor recurrence. To test this hypothesis we applied MW, RF, and cautery to normal murine liver with a concomitant metastatic colon cancer challenge.C57/Bl6 mice received hepatic thermal injury with MW, RF, or cautery to create a superficial 3-mm lesion immediately after intrasplenic injection of 50K MC38 colon cancer cells. Thermal imaging recorded tissue temperature during ablation and for 10 seconds after energy cessation. Hepatic tumor location and volume was determined at day 7.Cautery demonstrated the highest maximum tissue temperatures (129°C) with more rapid return to baseline compared to MW or RF energy. All mice had metastasis at the ablation site. Mean tumor volume was significantly greater in the MW (95.3 mm; P = 0.007) and RF (55.7 mm; P = 0.015) than cautery (7.13 mm). There was no difference in volume between MW and RF energy (P = 0.2).Hepatic thermal ablation promotes colon cancer metastasis at the injury site. MV and RF energy result in greater metastatic volume than cautery. These data suggest that the method of energy delivery promotes local metastasis.

Surgical fires are a rare event that still occur at a significant rate and can result in severe injury and death. Surgical fires are fueled by vapor from alcohol-based skin preparations in the presence of increased oxygen concentration and a spark from an energy device. Carbon dioxide (COAn ex vivo model with 15 × 15 cm section of clipped, porcine skin was used. A commercially available electrosurgical pencil with a smoke evacuation tip was connected to a laparoscopic COCarbon dioxide eliminated fire formation at a flow rate of 1 L/min with CHG-IPA skin prep (0% vs. 60% with no COCarbon dioxide can eliminate surgical fires caused by energy devices in the presence of alcohol-based skin preps. Future studies should determine the optimal technique and flow rate of carbon dioxide in these settings.

Emerging wearable technology has the potential to quantify both preoperative and postoperative patient activity. The purpose of this study was to characterize postoperative recovery trajectories for 1 mo after common surgical procedures.Patients included were scheduled for common elective operations. A wearable activity device was worn for at least 3 d preoperatively and 28 d postoperatively. Postoperative steps per day were compared with preoperative baseline steps, with recovery trajectories reported as a percentage of patients' baseline values. Recovery trajectories were compared between groups based on admission type and operation type.Two hundred ten patients were enrolled, and 143 patients (68%) completed follow-up. Patients took a median 5342 steps per day preoperatively and had significantly decreased steps on the first postoperative day, including those undergoing inguinal hernia repair (22% of baseline steps, P 0.001). Four weeks postoperatively, steps per day had not returned to baseline in patients undergoing minimally invasive abdominal (88% of baseline, P = 0.035), open abdominal (64% of baseline, P = 0.002), and thoracic (32% of baseline, P = 0.002) operations. All groups of patients showed a rapid recovery of steps during the first postoperative week, followed by a slower return to baseline. Recovery trajectories differed based on both admission type and operation type.Wearable activity monitors provide useful technology for quantification of postoperative activity recovery trajectories of steps per day in comparison to preoperative activity levels, with internal validity differentiating recovery trajectories grouping by broad categorization of operation type and by admission type. Activity recovery is a patient-centered outcome that can be used for counseling as well as for intervening to improve activity levels after surgery.

Importance Neutrophils have classically been considered to mount a defensive response against tumor cells, yet recent evidence suggests tumors modulate neutrophil function to support tumor growth and progression. Observations Tumor-associated neutrophils (TANs) are phenotypically distinct from circulating neutrophils in terms of their surface protein composition and cyto/chemokine activity and response. Although TANs have been shown to both promote and inhibit tumor advancement, the preponderant activity augments tumor progression. This review discusses these cancer-promoting molecular pathways, relevant diagnostic studies in patients, and subsequent treatment modalities. The tumor promoting mechanisms of TANs include dampening of CD8 + response via Arginase-1; a neutrophil-secreted neutrophil elastase (NE) upregulation of tumor cellular proliferation pathways; degradation of basement membrane and ECM via NE and MMP-9; upregulation of angiogenesis by VEGF, and HGF; and ICAM-1 dependent tumor intravasation, immune protection in circulation, and extravasation into distant, metastatic tissue beds. Clinicians are constrained in treating TANs systemically as it may induce neutropenia, therefore targeting TANs-mediated tumor progression pathways surgically on a loco-regional level is a viable adjuvant treatment modality. Conclusion and relevance TANs modulate the tumor microenvironment promoting tumor progression. Mechanistic understanding of TANs role in tumor progression will provide unique therapeutic alternatives.

BACKGROUND: The diagnosis of blunt abdominal trauma can be challenging and resource intensive. Observation with serial clinical assessments plays a major role in the evaluation of these patients, but the time required for intra-abdominal injury to become clinically apparent is unknown. The purpose of this study was to determine the amount of time required for an intra-abdominal injury to become clinically apparent after blunt abdominal trauma via physical examination or commonly followed clinical values. METHODS: A retrospective review of patients who sustained blunt trauma resulting in intra-abdominal injury between June 2010 and June 2012 at a Level 1 academic trauma center was performed. Patient demographics, injuries, and the amount of time from emergency department admission to sign or symptom development and subsequent diagnosis were recorded. All diagnoses were made by computed tomography or at the time of surgery. Patient transfers from other hospitals were excluded. RESULTS: Of 3,574 blunt trauma patients admitted to the hospital, 285 (8%) experienced intra-abdominal injuries. The mean (SD) age was 36 (17) years, the majority were male (194 patients, 68%) and the mean (SD) Injury Severity Score (ISS) was 21 (14). The mean (SD) time from admission to diagnosis via computed tomography or surgery was 74 (55) minutes. Eighty patients (28%) required either surgery (78 patients, 17%) or radiographic embolization (2 patients, 0.7%) for their injury. All patients who required intervention demonstrated a sign or symptom of their intra-abdominal injury within 60 minutes of arrival, although two patients were intervened upon in a delayed fashion. All patients with a blunt intra-abdominal injury manifested a clinical sign or symptom of their intra-abdominal injury, resulting in their diagnosis within 8 hours 25 minutes of arrival to the hospital. CONCLUSION: All diagnosed intra-abdominal injuries from blunt trauma manifested clinical signs or symptoms that could prompt imaging or intervention, leading to their diagnosis within 8 hours 25 minutes of arrival to the hospital. All patients who required an intervention for their injury manifested a sign or symptom of their injury within 60 minutes of arrival. (J Trauma Acute Care Surg. 2014;76:1020Y1023. Copyright * 2014 by Lippincott Williams & Wilkins) LEVEL OF EVIDENCE: Therapeutic study, level IV. Epidemiologic study, level III.

Intercellular adhesion molecule-1 (ICAM-1) modulates cell-cell adhesion and is a receptor for cognate ligands on leukocytes. Upregulation of ICAM-1 has been demonstrated in malignant transformation of adenomas and is associated with poor prognosis for many malignancies. ICAM-1 is upregulated on the invasive front of pancreatic metastases and melanomas. These data suggest that the upregulated ICAM-1 expression promotes malignant progression. We hypothesize that the downregulation of ICAM-1 will mitigate tumor progression.Mouse colon adenocarcinoma cells (MC38) were evaluated for the expression of ICAM-1 using Western immunoblot analysis. Short hairpin RNA (shRNA) transduction was used to downregulate ICAM-1. Tumor invasion determined via a modified Boyden chamber was used as a surrogate of tumor progression examining MC38 cells, MC38 ICAM-1 knockdowns, and MC38 transduced with vehicle control. The cells were cultured in full media for 24 h and serum-starved for 24 h. A total of 5 × 10(4) cells were plated and allowed to migrate for 24 h using full media with 10% fetal bovine serum as a chemoattractant. Inserts were fixed and stained with crystal violet. Blinded investigators counted the cells using a stereomicroscope. Statistical analysis was performed by analysis of variance with Fischer protected least significant difference and a P value of0.05 was considered statistically significant.ICAM-1 was constitutively expressed on MC38 cells. Transduction with anti-ICAM-1 shRNA vector downregulated ICAM-1 protein expression by 30% according to the Western blot analysis (P 0.03) and decreased ICAM-1 messenger RNA expression by 70% according to the reverse transcription-polymerase chain reaction. shRNA knockdown cells had a significant reduction in invasion45% (P 0.03). There were no significant differences between the invasion rates of MC38 and MC38 vehicle controls.Downregulation of ICAM-1 mitigates MC38 invasion. These data suggest that targeted downregulation of tumor ICAM-1 is a potential therapeutic target.

Energy-based devices are used in nearly every laparoscopic operation. Radiofrequency energy can transfer to nearby instruments via antenna and capacitive coupling without direct contact. Previous studies have described inadvertent energy transfer through bundled cords and nonelectrically active wires. The purpose of this study was to describe a new mechanism of stray energy transfer from the monopolar instrument through the operating surgeon to the laparoscopic telescope and propose practical measures to decrease the risk of injury.Radiofrequency energy was delivered to a laparoscopic L-hook (monopolar "bovie"), an advanced bipolar device, and an ultrasonic device in a laparoscopic simulator. The tip of a 10-mm telescope was placed adjacent but not touching bovine liver in a standard four-port laparoscopic cholecystectomy setup. Temperature increase was measured as tissue temperature from baseline nearest the tip of the telescope which was never in contact with the energy-based device after a 5-s open-air activation.The monopolar L-hook increased tissue temperature adjacent to the camera/telescope tip by 47 ± 8°C from baseline (P 0.001). By having an assistant surgeon hold the camera/telescope (rather than one surgeon holding both the active electrode and the camera/telescope), temperature change was reduced to 26 ± 7°C (P 0.001). Alternative energy devices significantly reduced temperature change in comparison to the monopolar instrument (47 ± 8°C) for both the advanced bipolar (1.2 ± 0.5°C; P 0.001) and ultrasonic (0.6 ± 0.3°C; P 0.001) devices.Stray energy transfers from the monopolar "bovie" instrument through the operating surgeon to standard electrically inactive laparoscopic instruments. Hand-to-hand coupling describes a new form of capacitive coupling where the surgeon's body acts as an electrical conductor to transmit energy. Strategies to reduce stray energy transfer include avoiding the same surgeon holding the active electrode and laparoscopic camera or using alternative energy devices.

BackgroundThe optimal time to initiate venous thromboembolism pharmacoprophylaxis after blunt abdominal solid organ injury is unknown.MethodsPostinjury coagulation status was characterized using thromboelastography (TEG) in trauma patients with blunt abdominal solid organ injuries; TEG was divided into 12-hour intervals up to 72 hours.ResultsForty-two of 304 patients (13.8%) identified underwent multiple postinjury thromboelastographic studies. Age (P = .45), gender (P = .45), and solid organ injury grade (P = .71) were similar between TEG and non-TEG patients. TEG patients had higher Injury Severity Scores compared with non-TEG patients (33.2 vs 18.3, respectively, P < .01). Among the TEG patients, the shear elastic modulus strength and maximum amplitude values began in the normal range within the first 12-hour interval after injury, increased linearly, and crossed into the hypercoagulable range at 48 hours (15.1 ± 1.9 Kd/cs and 57.6 ± 1.6 mm, respectively; P < .01, analysis of variance).ConclusionsPatients sustaining blunt abdominal solid organ injuries transition to a hypercoagulable state approximately 48 hours after injury. In the absence of contraindications, pharmacoprophylaxis should be considered before this time for effective venous thromboembolism prevention.

The liberal use of computed tomographic (CT) scanning during the evaluation of injured children has increased their exposure to the risks of ionizing radiation. We hypothesized that CT imaging performed for mechanism of injury alone is unnecessary and that serious or life-threatening injury is rarely identified.All pediatric blunt trauma team evaluations (age15 years) at a pediatric Level 2 trauma center over 72 months were reviewed. CT findings in patients with normal Glasgow Coma Scale (GCS) score, vital signs (VS), and physical examination (PE) (Group I) were compared with Group II (GCS score15), Group III (abnormal VS/PE), and Group IV (abnormal GCS score, VS/PE). Variables associated with any positive finding were entered into a multiple logistic regression model to assess for independent contributions. Each patient's total effective radiation dose from CT scans in millisieverts was calculated using an age-adjusted scale.A total 174 children met trauma team activation criteria (mean [SD] age, 7 [5] years; 63% male; mean [SD] Injury Severity Score [ISS], 10 [10]). A total of 153 (88%) were imaged by CT (I, 54 of 66; II, 25 of 25; III, 49 of 57; IV, 25 of 26). No patient in Group I had a serious finding on CT compared with Group II (17 of 77), III (25 of 111), and IV (18 of 72). Mortality was 4%. Radiation dose (mSv) from CT was not different among the groups (I, 17 [14]; II, 29 [13]; III, 21 [16]; IV, 27 [17]). By univariate analysis, GCS score of less than 15 (p0.01) and respiratory rate of greater than 30 (p = 0.09) were associated with a positive CT finding. By logistic regression analysis, GCS score of less than 15 remained the only variable associated significantly with a positive finding (odds ratio, 6.7; 95% confidence interval, 3-14; p0.01).In children imaged based only on mechanism, no patient had a serious positive finding but was subjected to radiation doses associated with an increased risk of future malignancy. The use of CT imaging in injured children in the absence of a physiologic or anatomic abnormality does not seem to be justified.Care management study, level IV.

A child's risk of developing cancer from radiation exposure associated with computed tomography (CT) imaging is estimated to be as high as 1/500. Chest CT (CCT), often as part of a "pan-scan," is increasingly performed after blunt trauma in children. We hypothesized that routine CCT for the initial evaluation of blunt injured children does not add clinically useful information beyond chest radiograph (CXR) and rarely changes management.Pediatric (15 y) trauma team evaluations over 6 y at an academic Level I trauma center were reviewed. Demographic data, injuries, imaging, and management were identified for all patients undergoing CT. Effective radiation dose in milliSieverts (mSv) was calculated using age-adjusted scales.Fifty-seven of 174 children (33%) undergoing CT imaging had a CCT; 55 (97%) of these had a CXR. Pathology was identified in significantly fewer CXRs compared with CCTs (51% versus 83%, P0.001). All 7/57 (12%) emergent or urgent chest interventions were based on information from CXR. In 53 children (93%), the CCT was ordered as part of a pan-scan, resulting in a radiation dose of 37.69 ± 7.80 mSv from initial CT scans. Radiation dose was significantly greater from CCT than from CXR (8.7 ± 1.1 mSv versus 0.017 ± 0.002 mSv, P0.001).Clinically useful information found on CCT had good correlation to information obtained from CXR and did not change patient management, however, did add significantly to the radiation exposure of initial imaging. We recommend selective use of CCT, particularly in the presence of an abnormal mediastinal silhouette on CXR after a significant deceleration injury.

Background Urinary tract infection (UTI) in trauma patients is associated with increased mortality. Whether the urinalysis (UA) is an adequate test for a urinary source of fever in the ICU trauma patient has not been demonstrated. We hypothesized that the UA is a valuable screen for UTI in the febrile, critically ill trauma patient. Study Design All trauma ICU patients in our surgical ICU who had a fever (temperature >38.0°C), urinary catheter, UA, and a urine culture between January 1, 2011 and December 13, 2011 were reviewed. A positive UA was defined as positive leukocyte esterase, positive nitrite, WBC > 10/high power field, or presence of bacteria. A positive urine culture was defined as growth of ≥10 5 colony forming units (cfu) of an organism irrespective of the UA result or ≥10 3 cfu in the setting of a positive UA. A UTI was defined as positive urine culture without an alternative cause of the fever. Results There were 232 UAs from 112 patients that met criteria. The majority (75%) of patients were men; the mean age was 40 (±16) years. Of the 232 UAs, 90 (38.7%) were positive. There were 14 UTIs. The sensitivity, specificity, positive predictive value, and negative predictive value of the UA for UTI were 100%, 65.1%, 15.5%, and 100%, respectively. Conclusions A negative UA reliably excludes a catheter-associated UTI in the febrile, trauma ICU patient with a 100% negative predictive value, and it can rapidly direct the clinician toward more likely sources of fever and reduce unnecessary urine cultures.

Perioperative blood transfusion in pancreatic cancer patients is linked to decreased survival; however, a causal mechanism has not been determined. Previously we have shown that the plasma fraction of stored packed red blood cells (pRBCs) promotes pancreas cancer progression and associated morbidity. We hypothesize these untoward effects will be mitigated by use of a hemoglobin-based oxygen carrier (HBOC).Cytokines and growth factors were measured in the plasma fraction from stored pRBCs and in an HBOC via cytokine array followed by formal enzyme-linked immunosorbent assay (ELISA). In an immunocompetent murine model, pancreas cancer progression was determined in vivo by bioluminescence, tumor weight, and number of metastases.Elevated levels of epidermal growth factor (EGF), platelet-derived growth factor BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) were present in the plasma fraction of stored pRBCs, but were not found in the HBOC. Intravenous delivery of plasma fraction to mice with pancreatic cancer resulted in increased bioluminescence activity compared with mice that received HBOC. Metastatic events and pancreatic primary tumor weights were significantly higher in animals receiving plasma fraction from stored pRBCs compared with animals receiving HBOC.Intravenous receipt of the acellular plasma fraction of stored pRBCs promotes pancreatic cancer progression in an immunocompetent mouse model. These untoward events are mitigated by use of an HBOC.

Analogous to organ injury scales developed for trauma, a scoring system is needed for acute care surgery. The purpose of this study was to develop a disease severity score (DSS) for acute appendicitis, the most common surgical emergency.A panel of acute care surgery experts reviewed the literature and developed a DSS for acute appendicitis as follows: grade 1, inflamed; Grade 2, gangrenous; Grade 3, perforated with localized free fluid; Grade 4, perforated with a regional abscess; and Grade 5, perforated with diffuse peritonitis. We applied the DSS to 1,000 consecutive patients undergoing appendectomy from 1999 to 2009 and examined its association with outcomes (mortality, length of hospital stay, incidence of in-hospital, and postdischarge complications). Of the 1,000 patients, 82 were excluded owing to negative or interval appendectomy or advanced end-stage renal disease.Among 918 eligible patients, the DSS distribution was Grade 1 at 62.4%, Grade 2 at 13.0%, Grade 3 at 18.7%, Grade 4 at 4.4%, and Grade 5 at 1.5%. Statistical analyses indicated a stepwise risk increase in adverse outcomes with higher DSS grades (c statistics ≥ 0.75 for all outcomes). Covariates (age, sex, and type of surgical access) did not add to the predictive power of DSS.Based on this single-institution study, the proposed appendicitis DSS seems to be a useful tool. This DSS can inform future, national efforts, which can build on the knowledge provided by the present investigation. This DSS may be useful for comparing therapeutic modalities, planning resource use, improving programs, and adjusting reimbursementEpidemiologic study, level III.

Background Chest CT is more sensitive than a chest X-ray (CXR) in diagnosing rib fractures; however, the clinical significance of these fractures remains unclear. Objectives The purpose of this study was to determine the added diagnostic use of chest CT performed after CXR in patients with either known or suspected rib fractures secondary to blunt trauma. Methods Retrospective cohort study of blunt trauma patients with rib fractures at a level I trauma center that had both a CXR and a CT chest. The CT finding of ≥ 3 additional fractures in patients with ≤ 3 rib fractures on CXR was considered clinically meaningful. Student’s t-test and chi-square analysis were used for comparison. Results We identified 499 patients with rib fractures: 93 (18.6%) had CXR only, 7 (1.4%) had chest CT only, and 399 (79.9%) had both CXR and chest CT. Among these 399 patients, a total of 1,969 rib fractures were identified: 1,467 (74.5%) were missed by CXR. The median number of additional fractures identified by CT was 3 (range, 4 - 15). Of 212 (53.1%) patients with a clinically meaningful increase in the number of fractures, 68 patients underwent one or more clinical interventions: 36 SICU admissions, 20 pain catheter placements, 23 epidural placements, and 3 SSRF. Additionally, 70 patients had a chest tube placed for retained hemothorax or occult pneumothorax. Overall, 138 patients (34.5%) had a change in clinical management based upon CT chest. Conclusions The chest X-ray missed ~75% of rib fractures seen on chest CT. Although patients with a clinical meaningful increase in the number of rib fractures were more likely to be admitted to the intensive care unit, there was no associated improvement in pulmonary outcomes.

BackgroundAttempts are made with emergency department thoracotomy (EDT) to salvage trauma patients who present to the hospital in extremis. The EDT allows for relief of cardiac tamponade, internal cardiac massage, and proximal hemorrhage control. Minimally invasive techniques, such as endovascular hemorrhage control (EHC) are available, but their noninferiority to EDT remains unproven. Before adopting EHC, it is important to evaluate the current outcomes of EDT. We hypothesized that EDT survival has improved during the last 4 decades, and outcomes stratified by pre-hospital CPR and injury patterns will provide benchmarks for success-to-rescue and survival outcomes for patients in extremis.Study designConsecutive trauma patients undergoing EDT from 1975 to 2014 were prospectively observed as part of quality improvement. Predicted probabilities of survival were adjusted for pre-hospital CPR, mechanism of injury, injury pattern, patient demographics, and time period of EDT using logistic regression. Success-to-rescue was defined as return of spontaneous circulation with blood pressure permissive for transfer to the operating room.ResultsThere were 1,708 EDTs included, with an overall 419 (24%) success-to-rescue patients and 106 survivors (6%), and 1,394 (79%) of these patients had pre-hospital CPR and 900 (54%) had penetrating wounds. The most common injury patterns were chest (29%), multisystem with head (27%), and multisystem without head (21%). Penetrating injury was associated with higher survival than blunt trauma (9% vs 3% p < 0.001). Success-to-rescue increased from 22% in 1975 to 1979 to 35% over the final 5 years (p < 0.001); survival increased from 5% to 14% (p < 0.001).ConclusionsOutcomes of EDT have improved over the past 40 years. In the last 5 years, STR was 35% and overall survival was 14%. These prospective observational data provide benchmarks to define the role of EHC as an alternative approach for patients arriving in extremis.

Background We demonstrated previously that shock index, pediatric age-adjusted identifies severely injured children accurately after blunt trauma. We hypothesized that an increased shock index, pediatric age-adjusted would identify more accurately injured children requiring the highest trauma team activation than age-adjusted hypotension. Methods We reviewed all children age 4–16 admitted after blunt trauma with an injury severity score ≥15 from January 2007–June 2013. Criteria used as indicators of need for activation of the trauma team included blood transfusion, emergency operation, or endotracheal intubation within 24 hours of admission. Shock index, pediatric age-adjusted represents maximum normal shock index based on age. Cutoffs included shock index >1.22 (ages 4–6), >1.0 (7–12), and >0.9 (13–16). Age-adjusted cutoffs for hypotension were as follows: systolic blood pressure Results A total of 559 children were included; 21% underwent operation, 37% endotracheal intubation, and 14% transfusion. Hypotension alone predicted poorly the need for operation (13%), endotracheal intubation (17%), or transfusion (22%). Operation (30%), endotracheal intubation (40%), and blood transfusion (53%) were more likely in children with an increased shock index, pediatric age-adjusted; 25 children required all three interventions, 3 (12%) were hypotensive at presentation, 15 (60%) had an increased shock index, pediatric age-adjusted (P Conclusion An increased shock index, pediatric age-adjusted is superior to age-adjusted hypotension to identify injured children likely to require emergency operation, endotracheal intubation, or early blood transfusion.

Massive transfusion protocols (MTPs) have become standard of care in the management of bleeding injured patients, yet strategies to guide them vary widely. We conducted a pragmatic, randomized clinical trial (RCT) to test the hypothesis that an MTP goal directed by the viscoelastic assay thrombelastography (TEG) improves survival compared with an MTP guided by conventional coagulation assays (CCA).This RCT enrolled injured patients from an academic level-1 trauma center meeting criteria for MTP activation. Upon MTP activation, patients were randomized to be managed either by an MTP goal directed by TEG or by CCA (ie, international normalized ratio, fibrinogen, platelet count). Primary outcome was 28-day survival.One hundred eleven patients were included in an intent-to-treat analysis (TEG = 56, CCA = 55). Survival in the TEG group was significantly higher than the CCA group (log-rank P = 0.032, Wilcoxon P = 0.027); 20 deaths in the CCA group (36.4%) compared with 11 in the TEG group (19.6%) (P = 0.049). Most deaths occurred within the first 6 hours from arrival (21.8% CCA group vs 7.1% TEG group) (P = 0.032). CCA patients required similar number of red blood cell units as the TEG patients [CCA: 5.0 (2-11), TEG: 4.5 (2-8)] (P = 0.317), but more plasma units [CCA: 2.0 (0-4), TEG: 0.0 (0-3)] (P = 0.022), and more platelets units [CCA: 0.0 (0-1), TEG: 0.0 (0-0)] (P = 0.041) in the first 2 hours of resuscitation.Utilization of a goal-directed, TEG-guided MTP to resuscitate severely injured patients improves survival compared with an MTP guided by CCA and utilizes less plasma and platelet transfusions during the early phase of resuscitation.

Nearly all critically ill surgical patients are anemic within 72 hours of intensive care unit (ICU) admission.1 Although most anemic ICU patients receive a packed red blood cell (pRBC) transfusion, such transfusions are associated independently with worse outcomes and have been shown to afford questionable benefit in terms of oxygen consumption.2 Many of the adverse effects of pRBC transfusions are believed to be the result of a storage lesion, which is characterized by time-dependent accumulation of inflammatory mediators as well as depletion of essential nutrients such as adenosine triphosphate and 2,3-diphosphoglycerate. Storage of pRBCs also impairs both erythrocyte deformability and oxygen offloading, as well as results in time-dependent hemolysis.3 Based on these experimental findings, we sought to investigate the relationship between the age of transfused blood and the resultant change in recipient hematocrit level among critically ill surgical patients. Because the primary goal of pRBC transfusion is to increase oxygen delivery via an increase in the hematocrit level, this relationship is of clinical relevance. However, despite numerous investigations concerning the adverse effects of the storage lesion, the specific relationship between age of blood and change in hematocrit level has not been investigated among critically ill patients. The hypothesis of this study was that transfusion of older blood, as compared with newer blood, results in a lesser increment in the hematocrit level. Furthermore, to assess the clinical relevance of the increment in hematocrit, we hypothesized that a lesser increment in post-transfusion hematocrit level would be associated with the need for a subsequent pRBC transfusion.

Background/Purpose Early postinjury death after packed red blood cell (pRBC) transfusion is attributed to uncontrolled hemorrhage and coagulopathy. The adverse immunomodulatory effects of blood transfusion are implicated in subsequent morbidity. We hypothesized that injured children requiring pRBC transfusion demonstrate patterns in outcome similar to those observed in adults. Methods Our prospectively collected trauma registry was queried for demographics, treatment, and outcome (2006-2009). Outcomes of children who received pRBC transfusion were compared with those of age- and Injury Severity Score (ISS)–matched children who did not receive pRBC transfusion by both univariate and multivariable analysis. Results Eight percent (43/512) of injured children received a pRBC transfusion: 20 early and 23 late. The likelihood of pRBC transfusion increased with increasing ISS (ISS 25, 72%). One-half of injured children who received an early pRBC transfusion died; however, most deaths were because of central nervous system injury. Both ventilator and intensive care unit days were increased in children who received pRBC transfusion as compared with those who did not. Conclusion Early pRBC transfusion is associated with a high mortality in children. Late blood transfusion is associated with worse outcomes, although this relationship may not be causal. This pilot study provides evidence of an association between pRBC transfusion, morbidity, and mortality among injured children that warrants refinement in larger, prospective investigations.

The histologic presence of macrophages (tumor-associated macrophages, TAMs) and neutrophils (tumor-associated neutrophils, TANs) has been linked to poor clinical outcomes for solid tumors. The exact mechanism for this association with worsened prognosis is unclear. It has been theorized that TAMs are immunomodulated to an alternatively activated state and promote tumor progression. Similarly, TANs have been shown to promote angiogenesis and tumor detachment. TAMs and TANs were characterized for activation state and production of prometastatic mediators in an immunocompetent murine model of pancreatic adenocarcinoma. Specimens from liver metastases were evaluated by immunofluorescence and immunoblotting. TAMS have upregulated expression of CD206 and CD163 markers of alternative activation, (4.14 ± 0.55-fold and 7.36 ± 1.13-fold over control, respectively, P < 0.001) but do not have increased expression of classically activated macrophage markers CCR2 and CCR5. TAMs also express oncostatin M (OSM). We found that TANs, not TAMs, predominantly produce matrix metalloproteinase-9 (MMP-9) in this metastatic tumor microenvironment, while MMP-2 production is pan-tumoral. Moreover, increased expression of VEGF colocalized with TAMs as opposed to TANs. TAMs and TANs may act as distinct effector cells, with TAMs phenotypically exhibiting alternative activation and releasing OSM and VEGF. TANs are localized at the invasive front of the metastasis, where they colocalize with MMP-9. Improved understanding of these interactions may lead to targeted therapies for pancreas adenocarcinoma.

Perioperative blood transfusion has been linked to decreased survival in pancreatic cancer; however, the exact causal mechanism has not been elucidated. Allogeneic transfusions are known to expose patients to foreign cells and lipid mediators. We hypothesize that stored packed red cells (pRBCs) contain pro-cancer cytokines that augment tumor progression. We analyzed the plasma fraction of stored pRBCs for pro-cancer cytokines and evaluated the affect of both storage time and leukocyte reduction on these mediators. Chemiarray™ analysis for pro-cancer cytokines was performed on the acellular plasma fraction of stored leukocyte-reduced (LR) and non-leukocyte-reduced (NLR) pRBCs at day 1 (D.1–fresh) and day 42 (D.42–outdate) of storage. Elevated expression of monocyte chemotactic protein-1 (MCP-1), regulated on activation, normal T cell expressed and secreted (RANTES), angiogenin, tumor necrosis factor-alpha (TNF-α), epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) was found. Specific enzyme-linked immunosorbent assay was performed for each of these factors in LR and NLR blood at D.1, day 28, and D.42. Data were analyzed by ANOVA. A p value ≤0.05 was considered significant; N ≥ 4 per group. Migration assays were performed using inhibitors of EGF (gefitinib) and PDGF (imatinib) on murine pancreatic adenocarcinoma cells (Pan02) exposed to D.1 and D.42 LR and NLR plasma. Proliferation assays were performed on Pan02 cells to test the inhibition of PDGF. MCP-1 levels increased with storage time in LR blood, 86.3 ± 6.3 pg/ml at D.1 vs. 121.2 ± 6.1 pg/ml at D.42 (p = 0.007), and NLR blood, 78.2 ± 7.3 pg/ml at D.1 vs. 647.8 ± 220.7 pg/ml at D.42 (p = 0.02). RANTES levels are lower in LR compared to NLR stored blood, 3.0 ± 1.9 vs. 15.8 ± 0.7 pg/ml at D.42 (p

Background Recent data indicate comparable efficacy and safety for levetiracetam (LEV) when compared with phenytoin (PHT) for prophylaxis of early seizures after traumatic brain injury. The purpose of this study was to conduct a cost-minimization analysis, from the perspective of both the acute care institution (cost) and patient (charges), comparing these two strategies. Methods A decision tree was constructed to include baseline event probabilities obtained from detailed literature review, costs, and charges. Monte Carlo simulation was used to derive the mean costs and charges per patient treated with the LEV when compared with the PHT strategy. Adverse event probabilities, costs, charges, and frequency of laboratory determination for the PHT group were varied in sensitivity analyses. Results Literature review indicated equal efficacy of PHT versus LEV for early seizure prevention. The PHT strategy was superior to the LEV strategy from both the institutional (mean cost per patient $151.24 vs. $411.85, respectively) and patient (mean charge per patient $2,302.58 vs. $3,498.40, respectively) perspectives. Varying both baseline adverse event probabilities and frequency of laboratory testing did not alter the superiority of the PHT strategy. LEV replaced PHT as the dominant strategy only when the cost/charge of treating mental status deterioration was increased markedly above baseline. Conclusions From both institutional and patient perspectives, PHT is less expensive than LEV for routine pharmacoprophylaxis of early seizures among traumatic brain injury patients. Pending compelling efficacy data, LEV should not replace PHT as a first-line agent for this indication.