Omission of intraoperative pyloric procedures in minimally invasive esophagectomy: assessing the impact on patients.

Pyloroplasty or pyloromyotomy is often undertaken during esophagectomy to aid gastric emptying postoperatively. Minimally invasive esophagectomy (MIE) frequently omits a pyloric procedure. The impact on perioperative outcomes and the need for subsequent interventions is unclear. This study assesses the requirements for endoscopic balloon dilation of the pylorus (EPD) following MIE. Patients undergoing MIE from 2016 to 2020 were reviewed. Patients undergoing open resection, or an intraoperative pyloric procedure were excluded. Demographic, clinical and pathological data were reviewed. Univariable and multivariable analysis were performed as appropriate. In total, 171 patients underwent MIE. There were no differences in age (median 65 vs. 65 years, P = 0.6), pathological stage (P = 0.10) or ASA status (P = 0.52) between those requiring and not requiring endoscopic pyloric dilation (EPD). Forty-three patients (25%) required EPD, with a total of 71 procedures. Twenty-seven patients (16%) had EPD on their index admission. Seventy-five patients (43%) had a postoperative complication. Higher ASA status was associated with increased requirement for EPD (odds ratio 10.8, P = 0.03). On multivariable analysis, there was no association between the need for a pyloric procedure and overall survival (P = 0.14). Eight patients (5%) required insertion of a feeding jejunostomy in the postoperative period, with no difference between those with or without EPD (P = 0.11). Two patients required subsequent surgical pyloromyotomy for delayed gastric emptying. Although pyloroplasty or pyloromyotomy can safely be excluded during MIE, a quarter of patients will require postoperative EPD procedures. The impact of excluding pyloric procedures on gastric emptying requires further study.

Utility of bile acids in large airway bronchial wash versus bronchoalveolar lavage as biomarkers of microaspiration in lung transplant recipients: a retrospective cohort study.

BACKGROUND: Bronchoalveolar lavage (BAL) is a key tool in respiratory medicine for sampling the distal airways. BAL bile acids are putative biomarkers of pulmonary microaspiration, which is associated with poor outcomes after lung transplantation. Compared to BAL, large airway bronchial wash (LABW) samples the tracheobronchial space where bile acids may be measurable at more clinically relevant levels. We assessed whether LABW bile acids, compared to BAL bile acids, are more strongly associated with poor clinical outcomes in lung transplant recipients. METHODS: Concurrently obtained BAL and LABW at 3 months post-transplant from a retrospective cohort of 61 lung transplant recipients were analyzed for taurocholic acid (TCA), glycocholic acid (GCA), and cholic acid by mass spectrometry and 10 inflammatory proteins by multiplex immunoassay. Associations between bile acids with inflammatory proteins and acute lung allograft dysfunction were assessed using Spearman correlation and logistic regression, respectively. Time to chronic lung allograft dysfunction and death were evaluated using multivariable Cox proportional hazards and Kaplan-Meier methods. RESULTS: Most bile acids and inflammatory proteins were higher in LABW than in BAL. LABW bile acids correlated with inflammatory proteins within and between sample type. LABW TCA and GCA were associated with acute lung allograft dysfunction (OR = 1.368; 95%CI = 1.036-1.806; P = 0.027, OR = 1.064; 95%CI = 1.009-1.122; P = 0.022, respectively). No bile acids were associated with chronic lung allograft dysfunction. Adjusted for risk factors, LABW TCA and GCA predicted death (HR = 1.513; 95%CI = 1.014-2.256; P = 0.042, HR = 1.597; 95%CI = 1.078-2.366; P = 0.020, respectively). Patients with LABW TCA in the highest tertile had worse survival compared to all others. CONCLUSIONS: LABW bile acids are more strongly associated than BAL bile acids with inflammation, acute lung allograft dysfunction, and death in lung transplant recipients. Collection of LABW may be useful in the evaluation of microaspiration in lung transplantation and other respiratory diseases.

Preoperative and Postoperative Approaches to Gastroesophageal Cancer: What is All the Fuss About.

Gastroesophageal cancers carry poor prognoses, and are a leading cause of cancer-related morbidity and mortality worldwide. Even in those with resectable disease, more than half of patients treated with surgery alone experience disease recurrence. Multimodality approaches using preoperative and postoperative chemotherapy and/or radiotherapy have been established, resulting in incremental improvements in outcomes. Globally, there is no standardized approach, and treatment varies with geographic location. The question remains of how to select the optimal perioperative treatment that will maximize benefit for patients while avoiding toxicities from unnecessary therapies. This article reviews currently available evidence supporting preoperative and postoperative therapy in gastroesophageal cancers, with an emphasis on recent practice-changing trials and ongoing areas of investigation, including the role of immune checkpoint inhibition and biomarker-guided treatment.

Predicting donor lung acceptance for transplant during ex vivo lung perfusion: The EX vivo lung PerfusIon pREdiction (EXPIRE).

Ex vivo lung perfusion (EVLP) has being increasingly used for the pretransplant assessment of extended-criteria donor lungs. Mathematical models to predict lung acceptance during EVLP have not been reported so far. Thus, we hypothesized that predictors of lung acceptance could be identified and used to develop a mathematical model describing the clinical decision-making process used in our institution. Donor lungs characteristics and EVLP physiologic parameters included in our EVLP registry were examined (derivation cohort). Multivariable logistic regression analysis was performed to identify predictors independently associated with lung acceptance. A mathematical model (EX vivo lung PerfusIon pREdiction [EXPIRE] model) for each hour of EVLP was developed and validated using a new cohort (validation cohort). Two hundred eighty donor lungs were assessed with EVLP. Of these, 186 (66%) were accepted for transplantation. ΔPO2 and static compliance/total lung capacity were identified as independent predictors of lung acceptance and their respective cut-off values were determined. The EXPIRE model showed a low discriminative power at the first hour of EVLP assessment (AUC: 0.69 [95% CI: 0.62-0.77]), which progressively improved up to the fourth hour (AUC: 0.87 [95% CI: 0.83-0.92]). In a validation cohort, the EXPIRE model demonstrated good discriminative power, peaking at the fourth hour (AUC: 0.85 [95% CI: 0.76-0.94]). The EXPIRE model may help to standardize lung assessment in centers using the Toronto EVLP technique and improve overall transplant rates.

Lung donation after medical assistance in dying at home.

Organ donation after medical assistance in dying (MAID) has only been possible for patients having the MAID procedure performed at a hospital facility due to prohibitive warm ischemic times. Herein, we describe a protocol for lung donation following MAID at home and demonstrate excellent postoperative outcomes. Lung donation following MAID at home is possible and should be considered by transplant programs.

Transcriptomic investigation reveals donor-specific gene signatures in human lung transplants.

INTRODUCTION: Transplantation of lungs from donation after circulatory death (DCD) in addition to donation after brain death (DBD) became routine worldwide to address the global organ shortage. The development of ex vivo lung perfusion (EVLP) for donor lung assessment and repair contributed to the increased use of DCD lungs. We hypothesise that a better understanding of the differences between lungs from DBD and DCD donors, and between EVLP and directly transplanted (non-EVLP) lungs, will lead to the discovery of the injury-specific targets for donor lung repair and reconditioning. METHODS: Tissue biopsies from human DBD (n=177) and DCD (n=65) donor lungs, assessed with or without EVLP, were collected at the end of cold ischaemic time. All samples were processed with microarray assays. Gene expression, network and pathway analyses were performed using R, Ingenuity Pathway Analysis and STRING. Results were validated with protein assays, multiple logistic regression and 10-fold cross-validation. RESULTS: Our analyses showed that lungs from DBD donors have upregulation of inflammatory cytokines and pathways. In contrast, DCD lungs display a transcriptome signature of pathways associated with cell death, apoptosis and necrosis. Network centrality revealed specific drug targets to rehabilitate DBD lungs. Moreover, in DBD lungs, tumour necrosis factor receptor-1/2 signalling pathways and macrophage migration inhibitory factor-associated pathways were activated in the EVLP group. A panel of genes that differentiate the EVLP from the non-EVLP group in DBD lungs was identified. CONCLUSION: The examination of gene expression profiling indicates that DBD and DCD lungs have distinguishable biological transcriptome signatures.

Prognostic Impact of CXCR7 and CXCL12 Expression in Patients with Esophageal Adenocarcinoma.

BACKGROUND: Chemokines are major regulators of cell trafficking and adhesion. The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, have been reported as biomarkers in various cancers, including esophageal cancer; however, there are few studies in esophageal adenocarcinoma (EAC). In this study, we investigated the relationship between expression of CXCL12, CXCR4, and CXCR7, and prognosis in patients with EAC. METHODS: This study examined 55 patients with EAC who were treated in Toronto General Hospital from 2001 to 2010. Tissue microarray immunohistochemistry was used to evaluate the expression of CXCL12, CXCR4, and CXCR7. Evaluation of immunohistochemistry was performed by a pathologist without knowledge of patients' information and results were compared with the patients' clinicopathological features and survival. RESULTS: High CXCR7 expression was significantly associated with lymphatic invasion (present vs absent, P = 0.005) and higher number of lymph node metastases (pN0-1 vs pN2-3, P = 0.0014). Patients with high CXCR7 expression (n = 23) were associated with worse overall (OS) and disease-free survival (DFS) (P = 0.0221, P = 0.0090, respectively), and patients with high CXCL12 (n = 24) tended to have worse OS and DFS (P = 0.1091, P = 0.1477, respectively). High expression of both CXCR7 and CXCL12 was an independent prognostic factor for OS and DFS on multivariate analysis (HR = 0.3, 95% CI: 0.1-0.9, P = 0.0246, HR = 0.3, 95% CI: 0.1-0.8, P = 0.0134, respectively). CONCLUSIONS: High CXCR7 expression was associated with poor prognosis in patients with EAC, and high expression of CXCR7 with its ligand CXCL12 had a stronger association with prognosis. Further study of this potential biomarker using whole tissue samples and a larger sample size is warranted.

[Lung transplant with ex vivo lung perfusion, Chilean and Latin American first experience]. / Trasplante pulmonar ex vivo . Primera experiencia en Chile y Latinoamérica.

BACKGROUND: The number of patients waiting for a lung transplant worldwide greatly exceeds the number of available donors. Ex vivo lung perfusion is a useful tool that allows marginal donor lungs to be evaluated and reconditioned for a successful lung transplantation. AIM: To describe the first Chilean and Latin American experience in ex vivo lung perfusion for marginal donor lungs before transplantation. MATERIAL AND METHODS: Descriptive analysis of all ex vivo lung perfusion conducted for marginal donor lungs at a private clinic, from April 2019 to October 2020. High risk donor lungs and rejected lungs from other transplantation centers were included. The "Toronto Protocol" was used for ex vivo lung perfusion. Donor lung characteristics and recipient outcomes were studied. RESULTS: During the study period, five ex vivo lung perfusions were performed. All lungs were reconditioned and transplanted. No complications were associated. There were no primary graft dysfunctions and only one chronic allograft dysfunction. There was no mortality during the first year. The median arterial oxygen partial pressure/fractional inspired oxygen ratio increased from 266 mm Hg in the donor lung to 419 after 3 hours of ex vivo lung perfusion (p = 0.043). CONCLUSIONS: ex vivo lung perfusion is a safe and useful tool that allows marginal donor lungs to be reconditioned and successfully transplanted.

How Many Nodes Need to be Removed to Make Esophagectomy an Adequate Cancer Operation, and Does the Number Change When a Patient has Chemoradiotherapy Before Surgery?

INTRODUCTION AND DESIGN: Node dissection during esophagectomy is an important aspect of esophageal cancer staging. Controversy remains as to how many nodes need to be resected in order to properly stage a patient and whether the removal of more nodes carries a stage-independent survival benefit. A review of the literature performed by a group of experts in the subject may help define a minimum accepted number of lymph nodes to be resected in both primary surgery and post-induction therapy scenarios. RESULTS AND CONCLUSIONS: The existing evidence generally supports the goal of obtaining a minimum of 15 lymph nodes for pathological examination in both primary surgery and post-induction therapy scenarios.

Towards donor lung recovery-gene expression changes during ex vivo lung perfusion of human lungs.

We and others have demonstrated that acellular normothermic ex vivo lung perfusion of high-risk donor lungs can result in posttransplant outcomes equivalent to that of contemporaneous lung transplantation using standard donor lungs. However, the mechanism of this effect remains unclear. Given the restoration of cellular metabolic activity during normothermic perfusion, one possibility is that of lung healing via natural innate recovery mechanisms. We explored this by examining the gene expression changes occurring in human lungs during ex vivo lung perfusion. Human lungs clinically rejected for transplantation were perfused for 12 hours of EVLP with biopsies taken at the start, at 1 hour, at 3 hours, and then every 3 hours thereafter to 12 hours. Temporal changes were identified in 2585 genes using the Short Time-series Expression Miner and used for pathway analysis. Despite increases in endothelial markers of inflammation, circulating leukocyte cell-specific gene expression fell over 12 hours of ex vivo lung perfusion (EVLP), suggesting an interrupted inflammation response secondary to washout of circulating leukocytes. Analysis of these gene changes suggests lung recovery follows specific stages: cellular death, cellular preservation, cellular reorganization, and cellular invasion. EVLP may improve posttransplant lung function by washout of leukocytes and facilitating innate mechanisms of repair.

Ex-vivo lung perfusion: the model for the organ reconditioning hub.

PURPOSE OF REVIEW: Lung evaluation and reconditioning by ex-vivo lung perfusion (EVLP) is becoming increasingly established. We review strategies for broader implementation of this technology to transplant centers worldwide. RECENT FINDINGS: The organ reconditioning hub model is a viable strategy for disseminating EVLP to small and large transplant centers given the well tolerated prolongation of preservation time afforded by EVLP. Regulatory and process issues remain hurdles to be overcome. SUMMARY: EVLP demonstrates promise to increase lung utilization. Organ reconditioning hubs appear to be an efficient method of delivering this promise to all transplant centers, not necessarily only the largest ones. Organ allocation processes will need to adapt to this new paradigm of organ preservation and evaluation. Moreover, regulatory issues will need to be deliberated by the transplant community.

Protein expression profiling predicts graft performance in clinical ex vivo lung perfusion.

OBJECTIVES: To study the impact of ex vivo lung perfusion (EVLP) on cytokines, chemokines, and growth factors and their correlation with graft performance either during perfusion or after transplantation. BACKGROUND: EVLP is a modern technique that preserves lungs on normothermia in a metabolically active state. The identification of biomarkers during clinical EVLP can contribute to the safe expansion of the donor pool. METHODS: High-risk brain death donors and donors after cardiac death underwent 4 to 6 hours EVLP. Using a multiplex magnetic bead array assay, we evaluated analytes in perfusate samples collected at 1 hour and 4 hours of EVLP. Donor lungs were divided into 3 groups: (I) Control: bilateral transplantation with good early outcome [absence of primary graft dysfunction- (PGD) grade 3]; (II) PGD3: bilateral transplantation with PGD grade 3 anytime within 72 hours; (III) Declined: lungs unsuitable for transplantation after EVLP. RESULTS: Of 50 cases included in this study, 27 were in Control group, 7 in PGD3, and 16 in Declined. From a total of 51 analytes, 34 were measurable in perfusates. The best marker to differentiate declined lungs from control lungs was stem cell growth factor -ß [P < 0.001, AUC (area under the curve) = 0.86] at 1 hour. The best markers to differentiate PGD3 cases from controls were interleukin-8 (P < 0.001, AUC = 0.93) and growth-regulated oncogene-α (P = 0.001, AUC = 0.89) at 4 hours of EVLP. CONCLUSIONS: Perfusate protein expression during EVLP can differentiate lungs with good outcome from lungs PGD3 after transplantation. These perfusate biomarkers can be potentially used for more precise donor lung selection improving the outcomes of transplantation.

Normothermic ex vivo lung perfusion in clinical lung transplantation.

BACKGROUND: More than 80% of donor lungs are potentially injured and therefore not considered suitable for transplantation. With the use of normothermic ex vivo lung perfusion (EVLP), the retrieved donor lung can be perfused in an ex vivo circuit, providing an opportunity to reassess its function before transplantation. In this study, we examined the feasibility of transplanting high-risk donor lungs that have undergone EVLP. METHODS: In this prospective, nonrandomized clinical trial, we subjected lungs considered to be high risk for transplantation to 4 hours of EVLP. High-risk donor lungs were defined by specific criteria, including pulmonary edema and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (PO(2):FIO(2)) less than 300 mm Hg. Lungs with acceptable function were subsequently transplanted. Lungs that were transplanted without EVLP during the same period were used as controls. The primary end point was primary graft dysfunction 72 hours after transplantation. Secondary end points were 30-day mortality, bronchial complications, duration of mechanical ventilation, and length of stay in the intensive care unit and hospital. RESULTS: During the study period, 136 lungs were transplanted. Lungs from 23 donors met the inclusion criteria for EVLP; in 20 of these lungs, physiological function remained stable during EVLP and the median PO(2):FIO(2) ratio increased from 335 mm Hg in the donor lung to 414 and 443 mm Hg at 1 hour and 4 hours of perfusion, respectively (P<0.001). These 20 lungs were transplanted; the other 116 lungs constituted the control group. The incidence of primary graft dysfunction 72 hours after transplantation was 15% in the EVLP group and 30% in the control group (P=0.11). No significant differences were observed for any secondary end points, and no severe adverse events were directly attributable to EVLP. CONCLUSIONS: Transplantation of high-risk donor lungs that were physiologically stable during 4 hours of ex vivo perfusion led to results similar to those obtained with conventionally selected lungs. (Funded by Vitrolife; ClinicalTrials.gov number, NCT01190059.).

Impact of telehealth postoperative care on early outcomes following esophagectomy.

OBJECTIVES: To address the short-term clinical outcomes of patients postesophagectomy who underwent telehealth care following surgery. The primary objective was to compare the frequency of emergency department admission between telehealth and in-person cohorts. Secondary objectives included comparing the frequency of endoscopies and clinic visits, as well as reasons for emergency department admission. METHODS: We conducted a retrospective cohort study to assess the clinical outcomes of patients who underwent esophagectomy between March 2018 and May 2022. Patients attending telehealth (phone or video call) surgical follow-up visits, largely due to the COVID-19 pandemic, were compared with a pre-COVID cohort of patients attending standard in-person care. Demographic data, clinical and disease characteristics, and hospital visit data within 6 months of operation were collected. This included surgical clinic visits, endoscopies, and emergency department admissions. RESULTS: There were 168 patients who underwent esophagectomy and had follow-up care between March 2018 and May 2022; 76 telehealth and 92 in-person. Patients attending telehealth appointments had significantly fewer emergency department admissions (0.45 vs 0.79, P = .037) and more endoscopy visits (1.37 vs 0.91, P = .020) compared with patients attending in-person visits. The number of follow-up surgical clinic visits did not differ between the groups. The most frequent reasons for emergency visits for the telehealth cohort included dysphagia, feeding-tube problems, and failure to thrive. For the in-person cohort, feeding-tube complications, inflammation/infection, and failure to thrive were the most common reasons. CONCLUSIONS: A program of virtual follow-up, with integrated in person visits and endoscopy as required, is feasible and safe for following patients postesophagectomy.

A radiographic score for human donor lungs on ex vivo lung perfusion predicts transplant outcomes.

BACKGROUND: Ex vivo lung perfusion (EVLP) is an advanced platform for isolated lung assessment and treatment. Radiographs acquired during EVLP provide a unique opportunity to assess lung injury. The purpose of our study was to define and evaluate EVLP radiographic findings and their association with lung transplant outcomes. METHODS: We retrospectively evaluated 113 EVLP cases from 2020-21. Radiographs were scored by a thoracic radiologist blinded to outcome. Six lung regions were scored for 5 radiographic features (consolidation, infiltrates, atelectasis, nodules, and interstitial lines) on a scale of 0 to 3 to derive a score. Spearman's correlation was used to correlate radiographic scores to biomarkers of lung injury. Machine learning models were developed using radiographic features and EVLP functional data. Predictive performance was assessed using the area under the curve. RESULTS: Consolidation and infiltrates were the most frequent findings at 1 hour EVLP (radiographic lung score 2.6 (3.3) and 4.6 (4.3)). Consolidation (r = -0.536 and -0.608, p < 0.0001) and infiltrates (r = -0.492 and -0.616, p < 0.0001) were inversely correlated with oxygenation (∆pO2) at 1 hour and 3 hours of EVLP. First-hour consolidation and infiltrate lung scores predicted transplant suitability with an area under the curve of 87% and 88%, respectively. Prediction of transplant outcomes using a machine learning model yielded an area under the curve of 80% in the validation set. CONCLUSIONS: EVLP radiographs provide valuable insight into donor lungs being assessed for transplantation. Consolidation and infiltrates were the most common abnormalities observed in EVLP lungs, and radiographic lung scores predicted the suitability of donor lungs for transplant.

Airway pepsinogen A4 identifies lung transplant recipients with microaspiration and predicts chronic lung allograft dysfunction.

BACKGROUND: Aspiration is a known risk factor for adverse outcomes post-lung transplantation. Airway bile acids are the gold-standard biomarker of aspiration; however, they are released into the duodenum and likely reflect concurrent gastrointestinal dysmotility. Previous studies investigating total airway pepsin have found conflicting results on its relationship with adverse outcomes post-lung transplantation. These studies measured total pepsin and pepsinogen in the airways. Certain pepsinogens are constitutively expressed in the lungs, while others, such as pepsinogen A4 (PGA4), are not. We sought to evaluate the utility of measuring airway PGA4 as a biomarker of aspiration and predictor of adverse outcomes in lung transplant recipients (LTRs) early post-transplant. METHODS: Expression of PGA4 was compared to other pepsinogens in lung tissue. Total pepsin and PGA4 were measured in large airway bronchial washings and compared to preexisting markers of aspiration. Two independent cohorts of LTRs were used to assess the relationship between airway PGA4 and chronic lung allograft dysfunction (CLAD). Changes to airway PGA4 after antireflux surgery were assessed in a third cohort of LTRs. RESULTS: PGA4 was expressed in healthy human stomach but not lung. Airway PGA4, but not total pepsin, was associated with aspiration. Airway PGA4 was associated with an increased risk of CLAD in two independent cohorts of LTRs. Antireflux surgery was associated with reduced airway PGA4. CONCLUSIONS: Airway PGA4 is a marker of aspiration that predicts CLAD in LTRs. Measuring PGA4 at surveillance bronchoscopies can help triage high-risk LTRs for anti-reflux surgery.