The impact of minimally-invasive esophagectomy operative duration on post-operative outcomes

BackgroundEsophagectomy, an esophageal cancer treatment mainstay, is a highly morbid procedure. Prolonged operative time, only partially predetermined by case complexity, may be uniquely harmful to minimally-invasive esophagectomy (MIE) patients for numerous reasons, including anastomotic leak, tenuous conduit perfusion and protracted single-lung ventilation, but the impact is unknown. This multi-center retrospective cohort study sought to characterize the relationship between MIE operative time and post-operative outcomes.MethodsWe abstracted multi-center data on esophageal cancer patients who underwent MIE from 2010 to 2021. Predictor variables included age, sex, comorbidities, body mass index, prior cardiothoracic surgery, stage, and neoadjuvant therapy. Outcomes included complications, readmissions, and mortality. Association analysis evaluated the relationship between predictor variables and operative time. Multivariate logistic regression characterized the influence of potential predictor variables and operative time on post-operative outcomes. Subgroup analysis evaluated the association between MIE >4 h vs. ≤4 h and complications, readmissions and survival.ResultsFor the 297 esophageal cancer patients who underwent MIE between 2010 and 2021, the median operative duration was 4.8 h [IQR: 3.7–6.3]. For patients with anastomotic leak (5.1%) and 1-year mortality, operative duration was elevated above the median at 6.3 h [IQR: 4.8–8.6], p = 0.008) and 5.3 h [IQR: 4.4–6.8], p = 0.04), respectively. In multivariate logistic regression, each additional hour of operative time increased the odds of anastomotic leak and 1-year mortality by 39% and 19%, respectively.ConclusionsEsophageal cancer is a poor prognosis disease, even with optimal treatment. Operative efficiency, a modifiable surgical variable, may be an important target to improve MIE patient outcomes

Development of a Novel miR-3648-Related Gene Signature as a Prognostic Biomarker in Esophageal Adenocarcinoma

Background: Esophageal adenocarcinoma (EA) is a typical immunogenic malignant tumor with a dismal 5-year survival rate lower than 20%. Although miRNA-3648 (miR-3648) is expressed abnormally in EA, its impact on the tumor immune microenvironment remains unknown. In this study, we sought to identify immune-related genes (IRGs) that are targeted by miR-3648 and develop an EA multigene signature. Methods: The gene expression data of 87 EA tumor samples and 67 normal tissue samples from The Cancer Genome Atlas (TCGA) database and the Genotype-Tissue Expression (GTEx) database were downloaded, respectively. Weighted gene co-expression network analysis (WGCNA), the CIBERSORT algorithm, and Cox regression analysis were applied to identify IRGs and to construct a prognostic signature and nomogram. Results: MiR-3648 was expectedly highly expressed in EA tumor tissues (P=2.6e-8), and related to the infiltration of activated natural killer cells (NK cells) and activated CD4 T lymphocytes (CD4 cells). A total of 70 miR-3648-targeted genes related to immune cell infiltration were identified. Among them, 4 genes (C10orf55, DLL4, PANX2, and NKAIN1) were closely related to overall survival (OS), and were thus selected to construct a 4-gene risk score (RS). The RS had a superior capability to predict OS [area under the curve (AUC) =0.740 for 1 year; AUC =0.717 for 3 years; AUC =0.622 for 5 years]. A higher score was indicative of a poorer prognosis than a lower score [hazard ratio (HR) =2.71; 95% confidence interval (CI): 1.45–5.09; P=0.002]. Furthermore, the nomogram formed by combining the RS and the TNM classification of malignant tumors (TNM stage) improved the accuracy of survival prediction [Harrell’s concordance index (C-index) =0.698]. Conclusions: MiR-3648 may play a critical role in EA pathogenesis. The novel 4-gene signature may serve as a prognostic tool to manage patients with EA

nAChRs Mediate Human Embryonic Stem Cell-Derived Endothelial Cells: Proliferation, Apoptosis, and Angiogenesis

Many patients with ischemic heart disease have cardiovascular risk factors such as cigarette smoking. We tested the effect of nicotine (a key component of cigarette smoking) on the therapeutic effects of human embryonic stem cell-derived endothelial cells (hESC-ECs).To induce endothelial cell differentiation, undifferentiated hESCs (H9 line) underwent 4-day floating EB formation and 8-day outgrowth differentiation in EGM-2 media. After 12 days, CD31(+) cells (13.7+/-2.5%) were sorted by FACScan and maintained in EGM-2 media for further differentiation. After isolation, these hESC-ECs expressed endothelial specific markers such as vWF (96.3+/-1.4%), CD31 (97.2+/-2.5%), and VE-cadherin (93.7+/-2.8%), form vascular-like channels, and incorporated DiI-labeled acetylated low-density lipoprotein (DiI-Ac-LDL). Afterward, 5x10(6) hESC-ECs treated for 24 hours with nicotine (10(-8) M) or PBS (as control) were injected into the hearts of mice undergoing LAD ligation followed by administration for two weeks of vehicle or nicotine (100 microg/ml) in the drinking water. Surprisingly, bioluminescence imaging (BLI) showed significant improvement in the survival of transplanted hESC-ECs in the nicotine treated group at 6 weeks. Postmortem analysis confirmed increased presence of small capillaries in the infarcted zones. Finally, in vitro mechanistic analysis suggests activation of the MAPK and Akt pathways following activation of nicotinic acetylcholine receptors (nAChRs).This study shows for the first time that short-term systemic administrations of low dose nicotine can improve the survival of transplanted hESC-ECs, and enhance their angiogenic effects in vivo. Furthermore, activation of nAChRs has anti-apoptotic, angiogenic, and proliferative effects through MAPK and Akt signaling pathways

Mediastinal Envelope Closure in Total Minimally Invasive Ivor Lewis Esophagectomy

Anastomotic leaks of the esophagogastric conduit in minimally invasive esophagectomies (MIE) are associated with increased length of hospital stay, formation of anastomotic strictures, and increased morbidity and mortality rates. The authors’ study has shown that complete closure of the mediastinal envelope over the anastomotic site is associated with decreased rates of postoperative complications, including anastomotic leaks. The method also provides an enhanced recovery and diet regimen for patients, allowing patients to resume oral feeding on postoperative day one without use of a jejunostomy tube. The SurgeryTo begin, the hiatus was dissected in the laparoscopic phase to define the gastroesophageal junction and the stomach was fully mobilized. The gastric conduit was created using tubularization along the lesser curve of the stomach.In the thoracoscopic phase, the mediastinal envelope was dissected. Care was taken to preserve the envelope edge for mediastinal envelope closure later. The esophagus was circumferentially dissected for full mobilization and then divided. Next, the gastric conduit was pulled up into the mediastinum and the esophagogastric anastomosis was formed. The stomach was fully tubularized and the final specimen was removed through a wound protector. The mediastinal envelope was closed from the level of the azygous vein to the hiatus using interrupted sutures. A nasograstric (NG) tube, 28 French chest tube, and 24 French Blake drain were placed.ConclusionClosure of the mediastinal envelope reinforces the anastomotic site and prevents outpouching of the gastric conduit. This minimizes tension on the anastomosis and improves conduit emptying. The authors’ results have shown that closure has been associated with decreased rates of anastomotic leaks, postoperative pyloric dilation, and delayed gastric emptying. It is also associated with shorter length of stay and decreased rates of hospital readmission in 90 days.Closure of the mediastinal envelope also provides benefits in postoperative recovery and diet. Patients can undergo early removal of their NG tube and resume oral feeding on postoperative day one. This quick transition to oral feeding is possible because closure of the mediastinal envelope creates a narrow mechanical feeding pathway that facilitates gastric emptying, allowing patients to resume oral feeding on postoperative day one without use of a jejunostomy tube. Patients can advance to a full liquid diet on postoperative day five and are also given Boost Glucose Control Max supplemental drink to nutritionally support them during recovery. The patient in this video followed this enhanced recovery protocol and is doing well postoperatively.Reference(s)Ashiku SK, Patel AR, Horton BH, Velotta J, Ely S, Avins AL. A refined procedure for esophageal resection using a full minimally invasive approach. J Cardiothorac Surg. 2022;17(1):29. Published 2022 Mar 4. doi:10.1186/s13019-022-01765-2. PMID: 35246177Banks KC, Alcasid NJ, Susai C, Velotta JB. Standardized Operative Approach for Total Minimally Invasive Ivor Lewis Esophagectomy in Hostile Abdomen. March 2023. doi:10.25373/ctsnet.22220854.v1Banks KC, Barnes KE, Wile RK, Hung YY, Santos J, Hsu DS, Choe G, Elmadhun NY, Ashiku SK, Patel AR, Velotta JB. Outcomes of Anastomotic Evaluation Using Indocyanine Green Fluorescence During Minimally Invasive Esophagectomy. Am Surg. 2022 Nov 3:31348221138084. doi: 10.1177/00031348221138084. Epub ahead of print. PMID: 36327490.Ely S, Alabaster A, Dominguez DA, Maxim C, Ashiku SK, Patel AR, Velotta JB. Effect of Thoracic Surgery Regionalization on 1- and 3-Year Survival After Cancer Esophagectomy. Ann Surg. 2023 Feb 1;277(2):e305-e312. doi: 10.1097/SLA.0000000000005076. Epub 2023 Jan 10. PMID: 34261883.Ely S, Alabaster A, Ashiku SK, Patel A, Velotta JB. Regionalization of thoracic surgery improves short-term cancer esophagectomy outcomes. J Thorac Dis. 2019 May;11(5):1867-1878. doi: 10.21037/jtd.2019.05.30. PMID: 31285879; PMCID: PMC6588736.</p

Pediatric pulmonary mucormycosis in a diabetic patient treated with extended pleurectomy and Clagett procedure

Mucor is a ubiquitous fungus that is non-pathogenic in healthy people. In immunocompromised hosts, nonfunctional or absent neutrophils and macrophages result in fungal invasion and infection [1]. Invasive mucor (mucormycosis) most commonly involves the sinuses, brain, or lungs. Pulmonary mucormycosis typically presents in patients with a history of organ transplantation or hematologic malignancy [2], and is rare in patients with diabetes alone. The epidemiology and management of pediatric pulmonary mucormycosis is poorly described. We report an unusual occurrence of this disease, complicated by segmental pulmonary artery thrombus in a 15-year-old with poorly controlled diabetes. His severe, medication-resistant infection was ultimately treated successfully with antifungal medication combined with aggressive surgical debridement. The pulmonary artery segmental thrombus resolved after treatment of the underlying infection without anticoagulation. Keywords: Mucormycosis, Pulmonary mucormycosis, Diabetes, Pneumonectomy, Clagett procedure, Pediatric thoracic surger

Adjuvant Immunotherapy in Curative Intent Esophageal Cancer Resection Patients: Real-World Experience within an Integrated Health System

Background: Adjuvant immunotherapy has been shown in clinical trials to prolong the survival of patients with esophageal cancer. We report our initial experience with immunotherapy within an integrated health system. Methods: A retrospective cohort study was performed reviewing patients undergoing minimally invasive esophagectomy at our institution between 2017 and 2021. The immunotherapy cohort was assessed for completion of treatment, adverse effects, and disease progression, with emphasis on patients who received surgery in 2021 and their eligibility to receive nivolumab. Results: There were 39 patients who received immunotherapy and 137 patients who did not. In logistic regression, immunotherapy was not found to have a statistically significant impact on 1-year overall survival after adjusting for age and receipt of adjuvant chemoradiation. Only seven patients out of 39 who received immunotherapy successfully completed treatment (18%), with the majority failing therapy due to disease progression or side effects. Of the 17 patients eligible for nivolumab, 13 patients received it (76.4%), and three patients completed a full course of treatment. Conclusions: Despite promising findings of adjuvant immunotherapy improving the survival of patients with esophageal cancer, real-life practice varies greatly from clinical trials. We found that the majority of patients were unable to complete immunotherapy regimens with no improvement in overall 1-year survival

Image1_The impact of minimally-invasive esophagectomy operative duration on post-operative outcomes.pdf

BackgroundEsophagectomy, an esophageal cancer treatment mainstay, is a highly morbid procedure. Prolonged operative time, only partially predetermined by case complexity, may be uniquely harmful to minimally-invasive esophagectomy (MIE) patients for numerous reasons, including anastomotic leak, tenuous conduit perfusion and protracted single-lung ventilation, but the impact is unknown. This multi-center retrospective cohort study sought to characterize the relationship between MIE operative time and post-operative outcomes.MethodsWe abstracted multi-center data on esophageal cancer patients who underwent MIE from 2010 to 2021. Predictor variables included age, sex, comorbidities, body mass index, prior cardiothoracic surgery, stage, and neoadjuvant therapy. Outcomes included complications, readmissions, and mortality. Association analysis evaluated the relationship between predictor variables and operative time. Multivariate logistic regression characterized the influence of potential predictor variables and operative time on post-operative outcomes. Subgroup analysis evaluated the association between MIE >4 h vs. ≤4 h and complications, readmissions and survival.ResultsFor the 297 esophageal cancer patients who underwent MIE between 2010 and 2021, the median operative duration was 4.8 h [IQR: 3.7–6.3]. For patients with anastomotic leak (5.1%) and 1-year mortality, operative duration was elevated above the median at 6.3 h [IQR: 4.8–8.6], p = 0.008) and 5.3 h [IQR: 4.4–6.8], p = 0.04), respectively. In multivariate logistic regression, each additional hour of operative time increased the odds of anastomotic leak and 1-year mortality by 39% and 19%, respectively.ConclusionsEsophageal cancer is a poor prognosis disease, even with optimal treatment. Operative efficiency, a modifiable surgical variable, may be an important target to improve MIE patient outcomes.</p