A trans-Canadian positive deviance seminar for paraesophageal hernia surgery: Reporting national postoperative outcomes and consensus recommendations.

BACKGROUND: The incidence of adverse events (AEs) and length of stay (LOS) varies significantly following paraesophageal hernia surgery. We performed a Canadian multicenter positive deviance (PD) seminar to review individual center and national level data and establish holistic perioperative practice recommendations. METHODS: A national virtual PD seminar was performed in October 2021. Recent best evidence focusing on AEs and LOS was presented. Subsequently, anonymized center-level AE and LOS data collected between 01/2017 and 01/2021 from a prospective, web-based database that tracks postoperative outcomes was presented. The top two performing centers with regards to these metrics were chosen and surgeons from these hospitals discussed elements of their treatment pathways that contributed to these outcomes. Consensus recommendations were then identified with participants independently rating their level of agreement. RESULTS: Twenty-eight surgeons form 8 centers took part in the seminar across 5 Canadian provinces. Of the 680 included patients included, Clavien-Dindo grade I and II/III/IV/V complications occurred in 121/39/12/2 patients (17.8%/5.7%/1.8%/0.3%). Respiratory complications were the most common (effusion 12/680, 1.7% and pneumonia 9/680, 1.3%). Esophageal and gastric perforation occurred in 7 and 4/680, (1.0% and 0.6% respectively). Median LOS varied significantly between institutions (1 day, range 1-3 vs. 7 days, 3-8, p < 0.001). A strong level of agreement was achieved for 10/12 of the consensus statements generated. CONCLUSION: PD seminars provide a supportive forum for centers to review best evidence and experience and generate recommendations based on expert opinion. Further research is ongoing to determine if this approach effectively accomplishes this objective.

Postoperative Adverse Events are Associated with Oncologic Recurrence Following Curative-intent Resection for Lung Cancer.

BACKGROUND: Up to 50% of patients suffer short-term postoperative adverse events (AEs) and metastatic recurrence in the long-term following curative-intent lung cancer resection. The association between AEs, particularly infectious in nature, and disease recurrence is controversial. We sought to evaluate the association of postoperative AEs on risk of developing recurrence and recurrence-free survival (RFS) following curative-intent lung resection surgery. METHODS: All lung cancer resections at a single institution (January 2008-July 2015) were included, with prospective collection of AEs using the Thoracic Morbidity & Mortality System. Cox proportional hazards models were used to estimate the effect of AEs on recurrence, with results presented as hazard ratio (HR) with 95% confidence interval (CI). An a priori, clinically driven approach to predictor variable selection was used. Kaplan-Meier curves were used examine the relationship between AE and RFS. p < 0.05 was considered statistically significant. RESULTS: 892 patients underwent curative-intent resection. 342 (38.3%) patients experienced an AE; 69 (7.7%) patients developed infectious AEs. 17.6% (n = 157) of patients had disease recurrence after mean follow-up of 26.5 months. Severe (Grade IV) AEs were associated with increased risk of recurrence (3.40; 95% CI 1.56-7.41) and a trend to decreased RFS. Major infectious AEs were associated with increased risk of recurrence (HR 1.71; CI 1.05-2.8) and earlier time to recurrence (no infectious AE 66 months, minor infectious 41 months, major infectious 54 months; p = 0.02). CONCLUSION: For patients undergoing curative-intent lung cancer resection, postoperative AEs associated with critical illness or major infection were associated with increased risk of oncologic recurrence.

Correction to: Postoperative Adverse Events are Associated with Oncologic Recurrence Following Curative­intent Resection for Lung Cancer.

The original version of this article unfortunately contained a mistake in author names. The given and family names of all the authors was transposed. The author names are corrected with this correction. The original article has been corrected.

Outcomes after completion total gastrectomy for gastric remnant cancer: experience from a Canadian tertiary centre.

BACKGROUND: There is controversy about the safety and outcomes of completion total gastrectomy (CTG) for gastric adenocarcinoma. We compared a cohort of patients who underwent CTG for gastric remnant cancer (GRC) after partial gastrectomy for benign disease with patients who underwent primary total gastrectomy (PTG) for sporadic gastric cancer. METHODS: We retrospectively reviewed a single-institution, prospectively maintained clinical database of patients who had undergone gastrectomy from 2005 to 2016 for demographic, surgical, clinical and tumour pathology data, as well as postoperative, pathologic and oncologic outcomes including complications, length of stay, disease-free survival and overall survival. We used the χ2 and Wilcoxon rank-sum tests to compare groups and performed the Mantel-Cox log-rank test for Kaplan-Meier survival estimates. We compared the CTG group to all patients in the PTG group and to a 5:1 propensity-matched PTG cohort. RESULTS: We analyzed data for 64 patients (9 CTG, 55 PTG). The groups were equivalent at baseline and had similar operative, perioperative treatment and pathologic characteristics. After propensity matching, the reoperation rate for complications was higher after CTG than PTG (22% v. 0%, p = 0.03), but there was no significant difference in the overall complication rate or length of stay. At 5 years, there was no difference in disease-free survival (28% v. 58%, p = 0.4) or overall survival (33% v. 44%, p = 0.7). CONCLUSION: Our findings suggest that CTG for gastric adenocarcinoma can be undertaken safely a priori with no additional risk of recurrence or death compared to PTG for sporadic gastric cancer.

CONTEXTE: Les avis divergent en ce qui concerne l'innocuité et les résultats de la gastrectomie totale complémentaire (GTC) dans les cas d'adénocarcinome gastrique. Nous avons comparé une cohorte de patients soumis à la GTC pour cancer gastrique résiduel (CGR) après une gastrectomie partielle pour maladie bénigne à des patients ayant subi une gastrectomie totale primaire (GTP) pour cancer gastrique sporadique. MÉTHODES: Nous avons passé en revue rétrospectivement une base de données (maintenue de manière prospective) regroupant des patients soumis à une gastrectomie entre 2005 et 2016 dans un seul établissement; et nous avons recueilli les données démographiques, chirurgicales, cliniques et anatomopathologiques tumorales, de même que les résultats oncologiques, y compris complications, durée du séjour, survie sans maladie et survie globale. Nous avons utilisé les tests du χ2 et de Wilcoxon pour comparer les groupes et nous avons estimé la survie selon le méthode Kaplan-Meier à l'aide du test log-rank de Mantel-Cox. Nous avons comparé le groupe GTC à tous les patients du groupe GTP et à une cohorte assortie selon un score de propension 5:1. RÉSULTATS: Nous avons analysé les données de 64 patients (9 GTC, 55 GTP). Les groupes étaient équivalents au départ et présentaient des caractéristiques similaires pour ce qui est de la chirurgie, des soins périopératoires et des analyses anatomopathologiques. Suite à l'appariement par score de propension, le taux de réintervention pour complications a été plus élevé après la GTC qu'après la GTP (22 % c. 0 %, p = 0,03), mais on n'a noté aucune différence significative pour ce qui est du taux de complications global ou de la durée du séjour. Après 5 ans, il n'y avait pas de différence de survie sans maladie (28 % c. 58 %, p = 0,4) ou de survie globale (33 % c. 44 %, p = 0,7). CONCLUSION: Selon nos observations, a priori, la GTC peut être effectuée sans danger dans les cas d'adénocarcinome gastrique, sans risque additionnel de récurrence ou de décès, comparativement à la GTP pour cancer gastrique sporadique.

Neutrophil extracellular traps sequester circulating tumor cells via ß1-integrin mediated interactions.

Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis. Neutrophils through release of neutrophil extracellular traps (NETs) in response to infections were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. To be able to intervene on this process, understanding the exact molecular nature of these mechanisms is crucial. We therefore hypothesize and demonstrate that ß1-integrin is an important factor mediating the interactions between circulating tumor cells and NETs. We show that ß1-integrin expression on both cancer cells and NETs is important for the adhesion of circulating tumor cells to NETs both in vitro and in vivo. Using a murine model of intra-abdominal sepsis to mimic the postoperative inflammatory environment, we show that ß1-integrin expression is upregulated in the context of inflammation in vivo. Ultimately, we show that this increased early cancer cell adhesion to NETs in vivo and this effect is abrogated when mice are administered DNAse 1. Our data therefore sheds light on the first molecular mechanism by which NETs can trap circulating tumor cells (CTCs), broadening our understanding of this process.

Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation.

Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis. TLR2 recognizes gram-positive bacterial cell wall components activating innate immunity. We demonstrate that lower respiratory tract infection with Streptococcus pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through host TLR2 activation. Infected mice demonstrate increased H59 and human A549 NSCLC adhesion to hepatic sinusoids in vivo compared with noninfected controls, a response that is significantly diminished in TLR2 knock-out mice. Intra-tracheal injection of purified TLR2 ligand lipoteichoic acid into mice similarly augments in vivo adhesion of H59 cells to hepatic sinusoids. Additionally, H59 and A549 NSCLC cells incubated with bronchoepithelial conditioned media show increased cell adhesion to extracellular matrix components in vitro and hepatic sinusoids in vivo in a manner that is dependent on bronchoepithelial TLR2 activation and interleukin-6 secretion. TLR2 is therefore a potential therapeutic target for gram-positive pneumonia-driven NSCLC metastasis.

Evolving Management of Zenker's Diverticulum in the Endoscopic Era: A North American Experience.

BACKGROUND: Open surgical cricopharyngeal myotomy(CM) is considered standard of care for Zenker's diverticulum(ZD). Trans-oral CM has been described using a rigid stapling device for two decades; however, this remains problematic for severely kyphotic patients. This problem can be overcome with flexible endoscopy utilizing an electrosurgical needle knife. We sought to compare clinical outcomes between these techniques to stratify patient selection. METHODS: Patients undergoing ZD treatment from 1992 to 2015 were reviewed. Demographics, diverticulum size, post-operative complications, and length of stay (LOS) were compared between open cricopharyngeal myotomy (OpenCM), rigid trans-oral stapling myotomy (RigidCM), and flexible endoscopic myotomy (FlexCM). Dysphagia scores (DS, 0:best-4:worst) and pneumonia incidence were assessed pre-operatively and post-operatively. RESULTS: 62 patients underwent OpenCM (39/62(63 %)) or endoscopic CM (23/62(37 %) (8 RigidCM/15 FlexCM)). CM significantly reduced dysphagia for all approaches [OpenCM:2(2-3)-0(0-0); RigidCM:2(2-2)-0(0-0); FlexCM:3(3-3)-0(0-0)]. FlexCM patients had significantly worse pre-operative DS. Endoscopic CM was attempted and completed in 23/35(66 %) patients. Reasons for OpenCM conversion included inability to position the diverticular retractor due to patient body habitus (RigidCM), and the inability to position the overtube due to small ZD (FlexCM). Major post-operative complications were rare and similar in all groups. Medium-to-long-term post-myotomy pneumonia was comparable between groups. LOS (days) was reduced for FlexCM (1(1-2)) versus RigidCM (3(2-6)) and OpenCM (4(3-7)). CONCLUSIONS: CM is highly effective for treating ZD. Open and endoscopic approaches offer comparable outcomes and dysphagia resolution. FlexCM is efficacious for large ZD and can be performed in most patients irrespective of body habitus. FlexCM represents an excellent approach for large ZD, while OpenCM should be reserved for small ZD for which an overtube cannot be positioned.

Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation.

Surgery is required for the curative treatment of lung cancer but is associated with high rates of postoperative pneumonias predominantly caused by gram negative bacteria. Recent evidence suggests that these severe infectious complications may decrease long term survival after hospital discharge via cancer recurrence, but the mechanism is unclear. Lung cancer cells have recently been demonstrated to express Toll-like receptors (TLR) that mediate pathogen recognition. We hypothesized that incubation of non-small cell lung cancer (NSCLC) cells with heat-inactivated Escherichia coli can augment cancer cell adhesion, migration and metastasis via TLR4 signaling. Incubation of murine and human NSCLC cells with E. coli increased in vitro cell adhesion to collagen I, collagen IV and fibronectin, and enhanced in vitro migration. Using hepatic intravital microscopy, we demonstrated that NSCLC cells have increased in vivo adhesion to hepatic sinusoids after coincubation with gram negative bacteria. These enhanced cell adhesion and migration phenotypes following incubation with E. coli were attenuated at three levels: inhibition of TLR4 (Eritoran), p38 MAPK (BIRB0796) and ERK1/2 phosphorylation (PD184352). Incubation of murine NSCLC cells in vitro with E. coli prior to intrasplenic injection significantly augmented formation of in vivo hepatic metastases 2 weeks later. This increase was abrogated by NSCLC TLR4 blockade using Eritoran. TLR4 represents a potential therapeutic target to help prevent severe postoperative infection driven cancer metastasis.

Routine contrast esophagram has minimal impact on the postoperative management of patients undergoing esophagectomy for esophageal cancer.

BACKGROUND: Routine contrast esophagram is frequently performed after esophagectomy in order to detect occult anastomotic leak (AL). This modality has a low sensitivity, and its routine use has been called into question. Accordingly, we sought to demonstrate the clinical impact of routine contrast esophagography in the management of patients undergoing esophagectomy for malignant disease. METHODS: All patients undergoing esophagectomy from 2005 to 2011 for malignancy at a North American University hospital were identified from a prospectively collected database. Barium esophagram (BE) was performed within the first week postoperatively. Patients were dichotomized according to whether they had an AL, and the sensitivity and specificity of BE was determined. The clinical impact of the BE result, defined as cessation of enteral feeding, additional interventions, or delay in discharge, was determined. RESULTS: Overall, 221 patients underwent esophagectomy. Thirty (13.6 %) developed an AL, of which 10 (30 %) had a positive BE, 12 (40 %) had a negative BE, and 8 (26.7 %) had no BE and were diagnosed clinically (1/8), by computed tomography (CT) (3/8), endoscopically (3/8), or at reoperation (1/7). AL in patients with a negative BE was confirmed clinically (4/12), by CT (6/12), endoscopically (1/12), or at reoperation (1/12). The sensitivity and specificity of BE was 45.5 and 97.8 %, respectively. BE altered postoperative management in 8/221 (3.6 %) patients, with 5/221 (2.3 %) undergoing therapeutic intervention. Conversely, 3/221 (1.4 %) patients demonstrated clinically insignificant AL, delaying discharge and feeding without intervention. CONCLUSION: Contrast esophagram is not an effective screening modality for AL when employed routinely following esophagectomy.

Long-term Symptom Control After Laparoscopic Heller Myotomy and Dor Fundoplication for Achalasia.

BACKGROUND: Achalasia is a primary esophageal motility disorder in which there is incomplete relaxation of the lower esophageal sphincter and absence of peristalsis in the lower two thirds of the esophagus. A favored treatment is laparoscopic modified Heller myotomy with Dor fundoplication (LHMDor) with more than 90% immediate beneficial effect. The short-term outcomes of LHMDor are well documented, but stability and durability of postoperative symptom control over time is less understood. METHODS: Between 2004 and 2016, 54 patients with achalasia underwent LHMDor (single center). Using validated questionnaires, patients rated their symptoms in five domains: pain, gastroesophageal reflux disease (GERD), dysphagia, regurgitation, and quality of life. Symptom ratings were done preoperatively, 4 weeks postoperatively, 6 months postoperatively, and yearly after the operation. RESULTS: As expected, patients reported marked improvement in dysphagia, odynophagia, regurgitation, GERD, and quality of life after the operation (P < .001). From then on, the symptom control remained durable with respect to absence of pain, regurgitation, and odynophagia; however, we observed a recurrence of GERD symptoms beginning 3 to 5 years postoperatively (P = .001 and P = .04, respectively), with associated increased antireflux medication use. After initial LHMDor, 5 patients required endoscopic dilatation an average of 1.5 years postoperatively, and no patient required reoperation. Patients reported preserved improved quality of life to 11 years after the operation (P = .001). CONCLUSIONS: These results demonstrate the durability of LHMDor in the definitive management of achalasia, offering consistent symptomatic relief and significant improvement in quality of life over the decade after surgery, despite some increase in GERD symptoms and antireflux medication use.

Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis.

While emerging data suggest nucleotide oligomerization domain receptor 1 (NOD1), a cytoplasmic pattern recognition receptor, may play an important and complementary role in the immune response to bacterial infection, its role in cancer metastasis is entirely unknown. Hence, we sought to determine the effects of NOD1 on metastasis. NOD1 expression in paired human primary colon cancer, human and murine colon cancer cells were determined using immunohistochemistry and immunoblotting (WB). Clinical significance of NOD1 was assessed using TCGA survival data. A series of in vitro and in vivo functional assays, including adhesion, migration, and metastasis, was conducted to assess the effect of NOD1. C12-iE-DAP, a highly selective NOD1 ligand derived from gram-negative bacteria, was used to activate NOD1. ML130, a specific NOD1 inhibitor, was used to block C12-iE-DAP stimulation. Stable knockdown (KD) of NOD1 in human colon cancer cells (HT29) was constructed with shRNA lentiviral transduction and the functional assays were thus repeated. Lastly, the predominant signaling pathway of NOD1-activation was identified using WB and functional assays in the presence of specific kinase inhibitors. Our data demonstrate that NOD1 is highly expressed in human colorectal cancer (CRC) and human and murine CRC cell lines. Clinically, we demonstrate that this increased NOD1 expression negatively impacts survival in patients with CRC. Subsequently, we identify NOD1 activation by C12-iE-DAP augments CRC cell adhesion, migration and metastasis. These effects are predominantly mediated via the p38 mitogen activated protein kinase (MAPK) pathway. This is the first study implicating NOD1 in cancer metastasis, and thus identifying this receptor as a putative therapeutic target.

Gram-Negative Pneumonia Augments Non-Small Cell Lung Cancer Metastasis through Host Toll-like Receptor 4 Activation.

INTRODUCTION: Surgery is essential for cure of early-stage non-small cell lung cancer (NSCLC). Rates of postoperative bacterial pneumonias, however, remain high, and clinical data suggests that post-operative infectious complications confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory response to infection by recognizing evolutionarily conserved bacterial structures at the surface of numerous pulmonary cell types; yet, little is known about how host TLR activation influences NSCLC metastasis. TLR4 recognizes gram-negative bacterium lipopolysaccharide activating the innate immune system. METHODS: C57BL/6 and TLR4 knockout murine airways were inoculated with Escherichia coli or lipopolysaccharide. Hepatic metastasis assays and intravital microscopy were performed. Bronchoepithelial conditioned media was generated through coincubation of bronchoepithelial cells with TLR4 activating Escherichia coli or lipopolysaccharide. Subsequently, H59 NSCLC were stimulated with conditioned media and subject to various adhesion assays. RESULTS: We demonstrate that gram-negative Escherichia coli pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through TLR4 activation. Additionally, infected C57BL/6 mice demonstrate increased H59 NSCLC in vivo hepatic sinusoidal adhesion compared with negative controls, a response that is significantly diminished in TLR4 knockout mice. Similarly, intratracheal injection of purified TLR4 activating lipopolysaccharide increases in vivo adhesion of H59 cells to murine hepatic sinusoids. Furthermore, H59 cells incubated with bronchoepithelial conditioned medium show increased cell adhesion to in vitro extracellular matrix proteins and in vivo hepatic sinusoids through a mechanism dependent on bronchoepithelial TLR4 activation and interleukin-6 secretion. CONCLUSION: TLR4 is a viable therapeutic target for NSCLC metastasis augmented by gram-negative pneumonia.

A review and analysis of strategies for prediction, prevention and management of post-operative atrial fibrillation after non-cardiac thoracic surgery.

Atrial fibrillation (AF) is the most common sustained arrhythmia after non-cardiac thoracic surgery and is associated with a significant increase in perioperative morbidity, intensive care unit (ICU) admission, and mortality. Practical guidance is needed to assist clinicians in managing this critical issue and direct further research. Here we aim to provide a synoptic review and analysis of the literature to distil practical recommendations for prediction, prevention and management of post-operative atrial fibrillation (POAF) suitable for clinical application and further evaluation. To predict POAF, risk factors including age, gender, elevated pre-operative heart rate and extent of surgical resection have been reproducibly identified and integrated into scoring systems. To prevent POAF, prophylactic therapy with beta-blockers, amiodarone, or magnesium have demonstrated to be effective, but need further trials in high-risk populations. To manage unstable POAF that precipitates hypotension and hypoperfusion, although rare, requires immediate electrocardioversion to restore cardiac output and adequate oxygen delivery. For hemodynamically stable patients, rate control and prevention of adverse events are the objectives. We propose an individualized approach aimed at rate control using initial incremental low dose beta-blocker or calcium channel blocker (CCB) therapy with close monitoring of a patient's response, and continuation of the drug that they respond to, along with simultaneous identification and reduction of triggers of AF, in order for spontaneous return to sinus rhythm. For patients who persistently fail to respond to rate control therapy, rhythm control may be considered using an agent selected based on the patient's comorbidities and the medications' side effect profile. While controversial and requiring further study, anticoagulation therapy is recommended in patients with risk factors for thromboembolic events after 48 hours of persistent AF. We recommend continuous prospective monitoring of incidence and severity of POAF to track the impact of protocols to predict, prevent and manage POAF.

Adult colo-colonic intussusception caused by congenital bands: A case report and literature review.

INTRODUCTION: Intussusception refers to the telescoping of a segment of bowel into the lumen of an adjacent segment. While pediatric intussusception is common and generally idiopathic, adult intussusception is exceedingly rare and is usually attributable to a pathologic lead point. PRESENTATION OF CASE: 37-year-old man who presented with abdominal pain, and was preoperatively diagnosed with a colo-colonic intussusception. Intraoperatively, the lead point was found to be congenital bands, and there was no evidence of underlying malignancy. He underwent a laparoscopic-assisted extended right hemicolectomy with side-to-side ileo-colic anastomosis. DISCUSSION: Colo-colonic intussusception is a rare cause of intestinal obstruction in adults. Patients generally present with subacute abdominal pain and obstructive symptoms, rendering the clinical diagnosis challenging. Computed tomography has been shown to be the most accurate diagnostic imaging modality. Due to the high incidence of underlying malignancy in adult colo-colonic intussusception, en-bloc resection of the involved bowel segment remains the standard of care. CONCLUSION: Congenital bands can serve as a lead point in colo-colonic intussusception, particularly in younger adults. Prompt surgical intervention remains paramount to limit morbidity.

Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis.

The majority of patients with cancer undergo at least one surgical procedure as part of their treatment. Severe postsurgical infection is associated with adverse oncologic outcomes; however, the mechanisms underlying this phenomenon are unclear. Emerging evidence suggests that neutrophils, which function as the first line of defense during infections, facilitate cancer progression. Neutrophil extracellular traps (NETs) are extracellular neutrophil-derived DNA webs released in response to inflammatory cues that trap and kill invading pathogens. The role of NETs in cancer progression is entirely unknown. We report that circulating tumor cells become trapped within NETs in vitro under static and dynamic conditions. In a murine model of infection using cecal ligation and puncture, we demonstrated microvascular NET deposition and consequent trapping of circulating lung carcinoma cells within DNA webs. NET trapping was associated with increased formation of hepatic micrometastases at 48 hours and gross metastatic disease burden at 2 weeks following tumor cell injection. These effects were abrogated by NET inhibition with DNAse or a neutrophil elastase inhibitor. These findings implicate NETs in the process of cancer metastasis in the context of systemic infection and identify NETs as potential therapeutic targets.