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Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)–mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6–induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:KrasG12D/+ (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the \"autophagic switch,\" regulating mitochondrial STAT3 signaling.

Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies. L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4 mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples. We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4 mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models. Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted.

Minimally invasive distal pancreatectomy has become increasingly used in practice. While laparoscopic approach is the most commonly used technique, robotic distal pancreatectomy (RDP) has emerged as a safe, feasible and effective approach for distal pancreatectomy. Most studies have shown that RDP improved perioperative surgical outcomes and has equivalent oncologic outcomes to open technique. Widespread adoption is limited by a steep learning curve, higher costs and the need for institutional training protocols in place for safe integration of the platform into practice.

Context. —Autoimmune pancreatitis is an uncommon, inflammatory disease of the pancreas that presents with clinical features, such as painless jaundice and a pancreatic mass, similar to those caused by pancreatic cancer. Patients with autoimmune pancreatitis frequently have elevated serum immunoglobulin G fraction 4 (IgG4) levels, and their pancreatic tissue may show IgG4-positive plasma cell infiltration. It is imperative to differentiate autoimmune pancreatitis from pancreatic cancer because autoimmune pancreatitis typically responds to corticosteroid treatment. A previous Japanese study reported that serum IgG4 greater than 135 mg/dL was 97% specific and 95% sensitive in predicting autoimmune pancreatitis. Objective. —To prospectively measure serum IgG4 levels in pancreatic cancer patients to ascertain whether increased levels might be present in this North American population. Design. —We collected blood samples and phenotypic information on 71 consecutive pancreatic cancer patients and 103 healthy controls who visited our clinics between October 2004 and April 2006. IgG4 levels were determined using a single radial immunodiffusion assay. A serum IgG4 level greater than 135 mg/dL was considered elevated. Results. —Five cancer patients had IgG4 elevation, with a mean serum IgG4 level of 160.8 mg/dL. None of our cancer patients with plasma IgG4 elevation demonstrated evidence of autoimmune pancreatitis. One control subject demonstrated elevated serum IgG4 unrelated to identified etiology. Conclusions. —As many as 7% of patients with pancreatic cancer have serum IgG4 levels above 135 mg/dL. In patients with pancreatic mass lesions and suspicion of cancer, an IgG4 level measuring between 135 and 200 mg/dL should be interpreted cautiously and not accepted as diagnostic of autoimmune pancreatitis without further evaluation.

Pancreatic ductal adenocarcinoma （PDAC） driven by oncogenic K-Ras remains among the most lethal human cancers despite recent advances in modern medicine. The pathogenesis of PDAC is partly attributable to intrinsic chromosome instability and extrinsic inflammation activation. However, the molecular link between these two events in pancreatic tumorigenesis has not yet been fully established. Here, we show that intracellular high mobility group box 1 （HMGB1） remarkably suppresses oncogenic K-Ras-driven pancreatic tumorigenesis by inhibiting chromosome instability-mediated pro-inflammatory nucleosome release. Conditional genetic ablation of either single or both al- leles of HMGB1 in the pancreas renders mice extremely sensitive to oncogenic K-Ras-driven initiation of precursor lesions at birth, including pancreatic intraepithelial neoplasms, intraductal papillary mucinous neoplasms, and mu- cinous cystic neoplasms. Loss of HMGB1 in the pancreas is associated with oxidative DNA damage and chromosomal instability characterized by chromosome rearrangements and telomere abnormalities. These lead to inflammatory nucleosome release and propagate K-Ras-driven pancreatic tumorigenesis. Extraceilular nucleosomes promote inter- leukin 6 （IL-6） secretion by infiltrating macrophages/neutrophils and enhance oncogenic K-Ras signaling activation in pancreatic lesions. Neutralizing antibodies to IL-6 or histone H3 or knockout of the receptor for advanced glyca- tion end products all limit K-Ras signaling activation, prevent cancer development and metastasis/invasion, and pro- long animal survival in Pdxl-Cre;K-RasG12D/＋;Hmgbl-/- mice. Pharmacological inhibition of HMGB1 loss by glycyr- rhizin limits oncogenic K-Ras-driven tumorigenesis in mice under inflammatory conditions. Diminished nuclear and total cellular expression of HMGB1 in PDAC patients correlates with poor overall survival, supporting intracellular HMGB1 as a novel tumor suppressor with prognostic and therapeutic relevance in PDAC.

Trauma team performance, measured by the non-technical skills scale T-NOTECHS, has been shown to impact patient outcomes. We assess how personnel movements affect non-technical skills and time of resuscitation(TOR) using trauma video review. A prospective study of blunt and/or penetrating trauma activations recorded between May and November 2023 ​at a Level-I trauma center. Regressions controlling for confounders were used to measure the association between foot traffic and the outcomes of interest1: TOR2 T-NOTECHS score(Smith et al., 2015; Mackenzie et al., 2007; Maiga et al., 2024; Vella et al., 2024; Pucher et al., 2014; Dumas et al., 2020; Succar et al., 2024; Steinemann et al., 2012; Andersson et al., 2012; Conrad et al., 2010; Lies and Zhang, 2015) .5-155-15 We identified 77 trauma activations, with 40 ​%(n ​= ​32/77) penetrating injuries. There was a median of 17[14–18] individuals at the start of trauma activations. During resuscitations, individuals entered the room a median of 12[8–18] times and exited the room 17[11–22] times. The median TOR was 8[6–10] min and the median T-NOTECHS was 7[6–8]. Regression analysis showed foot traffic was independently associated with increased TOR(β 0.34, p-value <0.01) and worse total T-NOTECHS score(β 0.06, p ​< ​0.01). Higher foot traffic is associated with poorer team performance and delays in resuscitation. Future directions should further explore environmental and personal factors that may impede performance metrics. •Current impact of environmental factors on trauma activations is unknown.•The platform allows the assessment of environmental factors such as foot traffic.•Delays in resuscitation were seen with higher foot traffic in and out of the room.•Higher foot traffic was also linked with worse T-NOTECHS score.

Cancer-associated fibroblasts (CAFs) are indispensable architects of the tumor microenvironment. They perform the essential functions of extracellular matrix deposition, stromal remodeling, tumor vasculature modulation, modification of tumor metabolism, and participation in crosstalk between cancer and immune cells. In this review, we discuss our current understanding of the principal differences between normal fibroblasts and CAFs, the origin of CAFs, their functions, and ultimately, highlight the intimate connection of CAFs to virtually all of the hallmarks of cancer. We address the remarkable degree of functional diversity and phenotypic plasticity displayed by CAFs and strive to stratify CAF biology among different tumor types into practical functional groups. Finally, we summarize the status of recent and ongoing trials of CAF-directed therapies and contend that the paucity of trials resulting in Food and Drug Administration (FDA) approvals thus far is a consequence of the failure to identify targets exclusive of pro-tumorigenic CAF phenotypes that are mechanistically linked to specific CAF functions. We believe that the development of a unified CAF nomenclature, the standardization of functional assays to assess the loss-of-function of CAF properties, and the establishment of rigorous definitions of CAF subpopulations and their mechanistic functions in cancer progression will be crucial to fully realize the promise of CAF-targeted therapies.

BackgroundSurgical safety checklists reduce adverse events, but monitoring adherence to checklists is confounded by observation bias. The ORBB platform can monitor checklist compliance and correlate compliance with outcomes. This study aims to evaluate the association between checklist compliance and patient outcomes using the ORBB platform.MethodsThis is a retrospective analysis of data from the electronic medical record of cases performed in ORBB-equipped operating rooms at a single quaternary referral center. All patients who did not opt out and underwent surgery at UT Southwestern Medical Center in ORBB-equipped rooms from August 2020 to September 2022 were included. The ORBB platform was set-up in five operating rooms and surgical safety checklist compliance was monitored by way of AI-based video review.ResultsOverall, 4581 patients were included in this analysis.. Performance on the checklist was associated with lower mortality (OR, 0.96; 95% CI, 0.94–0.98; P < 0.05), and decreased length of stay (estimate [E]: −0.02 days; 95% CI, −0.03 to −0.005; P < 0.05). Performance during “timeouts” was associated with mortality (OR, 0.97; 95% CI, 0.94–0.99; P < 0.05). “Debriefings” were independently associated with mortality (OR, 0.98; 95% CI, 0.96–0.99; P < 0.05), length of stay (Estimate, −0.0009 days; 95% CI, −0.02 to −0.001; P < 0.05), and ICU admission (OR, 0.99; 95% CI, 0.98–0.99; P < 0.05).ConclusionProcedures performed by surgical teams who performed better on the surgical safety checklist tended to have better outcomes. This innovative technology could substantially enhance our ability to understand and mitigate threats to patients in real-time.

BackgroundSimulation and video-based assessment (VBA) offer residents the opportunity to develop operative skills while ensuring patient safety. This study aims to determine whether simulation training can predict residents’ operative performance, focusing on the gastrojejunal (GJ) anastomosis during robotic pancreatoduodenectomy.MethodsTwenty-seven general surgery residents completed simulated robotic GJ drills and subsequently performed GJs in the operating room (OR). Both simulated and intraoperative performances were video recorded and retrospectively assessed by two blinded graders using the Objective Structural Assessment of Technical Skills (OSATS) scale, time to completion, and occurrence of errors. Intraoperative GJ OSATS scores were compared in cases with and without Clinically Relevant Delayed Gastric Emptying (CRDGE). Statistical analysis was performed using Spearman’s rho, Chi-square, and Kruskal–Wallis tests.ResultsFor simulated GJs, the median OSATS score was 29 (IQR 27–33), time to completion was 30 min (IQR 27–35), and 11 cases had at least one error. Intraoperative GJs had a median OSATS of 30 (IQR 27–31), time to completion of 41 min (IQR 36–51), and errors occurred in nine cases. The OSATS score on the simulated GJs demonstrated a significant positive correlation to the OSATS score on the operative GJs (r = 0.74; p < 0.001) and less time to completion (r =  − 0.68; p < 0.001). A shorter simulated GJ completion time significantly correlated with a higher intraoperative OSATS score (r =  − 0.52; p < 0.01). Residents with at least one error in the simulated GJs had lower OSATS scores and higher times intraoperatively. Those cases with CRDGE had significantly lower intraoperative OSATS scores than those without CRDGE.ConclusionPerformance on a simulated robotic GJ environment is a robust predictor of OR GJ performance, demonstrating predictive validity. VBA of residents’ operative GJ performance is associated with the presentation of CRDGE. Simulation-based training may be crucial to optimizing surgical outcomes before operating on patients.