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Background Approximately 40% of patients with esophageal cancer present with metastatic disease. Survival with palliative treatment is poor, and the benefit of aggressive focal therapies is unclear. This study aimed to identify a subset of patients with metastatic esophageal cancer with favorable outcomes after curative doses of radiation therapy, esophagectomy, or both. Methods Between 2004 and 2015, the study investigators found 28,101 patients with metastatic esophageal cancer in the National Cancer Database and identified those who underwent chemotherapy and definitive radiation therapy with or without surgery over the study period. The study compared the estimated median overall survival (OS) of all patients with metastatic esophageal cancer with the estimated median OS of patients with metastatic esophageal cancer who underwent radiation therapy with or without surgery. Multivariable analysis was used to examine clinical and pathologic factors associated with OS. Results At a median follow-up of 11.1 months, 3219 patients with a median age of 64 years and a radiation dose of 50.4 Gy were identified. Only 202 (6.2%) patients undergoing definitive-dose radiation therapy underwent esophagectomy, with a median age of 60 years. The median OS durations for all patients, for patients treated with radiation, and for patients treated with radiation therapy in combination with esophagectomy were 6.6, 11.5, and 30.2 months, respectively. Among patients undergoing surgery, median OS after surgery was 23.7 months. Patients with lung, liver, or bone metastases were less likely to undergo esophagectomy. On multivariable analysis, esophagectomy and low tumor grade were associated with higher OS, whereas liver and bone metastases at diagnosis were associated with worse OS. Conclusions This analysis suggests that select subsets of patients with primarily nonvisceral, nonosseous metastatic esophageal cancer have favorable survival and may potentially benefit from aggressive local therapies.

Background/Aims: Peroral endoscopic myotomy (POEM) is a novel procedure for the treatment of achalasia and spastic esophageal disorders. Experience with POEM is limited, but its reported outcomes are excellent. It is deemed safe even for patients with prior interventions. Methods: This retrospective review included patients who underwent POEM at a tertiary US center. POEM was performed in a multidisciplinary approach by advanced endoscopists and foregut surgeons. Clinical success was defined as a post-POEM Eckardt score ≤3. Results: A total of 125 patients were included. Median follow-up period was 18 months (interquartile range, 10-22 months). Clinical success was achieved in 92% of patients and persisted at 12 months in 88% of patients. Mucosal barrier failure (MBF) occurred in 7 patients, 2 of whom required surgical intervention. MBF was more common in patients with prior laparoscopic Heller myotomy (19% vs. 3%, p=0.015). MBF requiring surgical intervention occurred early in the learning curve. Conclusions: POEM is safe and effective in the treatment of achalasia and spastic esophageal disorders even after failed prior interventions. Clin Endosc 2020;53:321-327

Summary Peroral endoscopic myotomy (POEM) in patients with achalasia who are status post bariatric surgery may be technically challenging due to postsurgical scarring and altered anatomy. The aim of the study was to assess the efficacy and safety of POEM for achalasia in patients with prior bariatric surgery. A review of prospectively maintained databases at three tertiary referral centers from January 2015 to January 2021 was performed. The primary outcome of interest was clinical success, defined as a post-treatment Eckardt score ≤ 3 or improvement in Eckardt score by ≥ 1 when the baseline score was

Although cellular transplantation remains a relatively small field compared to solid organ transplantation, the prospects for advancement in basic science and clinical care remain bountiful. In this review, notable historical events and the current landscape of the field of cellular transplantation are reviewed with an emphasis on islets (allo- and xeno-), hepatocytes (including bioartificial liver), adoptive regulatory immunotherapy, and stem cells (SCs, specifically endogenous organ-specific and mesenchymal). Also, the nascent but rapidly evolving field of three-dimensional bioprinting is highlighted, including its major processing steps and latest achievements. To reach its full potential where cellular transplants are a more viable alternative than solid organ transplants, fundamental change in how the field is regulated and advanced is needed. Greater public and private investment in the development of cellular transplantation is required. Furthermore, consistent with the call of multiple national transplant societies for allo-islet transplants, the oversight of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration. Cellular transplantation has the potential to bring profound benefit through progress in bioengineering and regenerative medicine, limiting immunosuppression-related toxicity, and providing markedly reduced surgical morbidity.

Esophagectomy following preoperative chemoradiation provides the best outcomes in the treatment of early stage esophageal carcinoma. The exposure of the mediastinum during transhiatal esophagectomy is limited. We describe our technique of mediastinal dissection during the transhiatal esophagectomy using a newly developed transhiatal retractor.

Background Neoadjuvant chemoradiation therapy (nCRT) has become the standard of care for esophageal cancer patients prior to esophagectomy. However, the optimal timing for surgery after completion of nCRT remains unclear. Methods A retrospective review was performed of patients who underwent esophagectomy with cervical anastomosis for esophageal cancer at a single institution between January 2000 and June 2015. Patients were categorized into 3 cohorts: those who did not receive nCRT prior to esophagectomy (no nCRT), those who underwent esophagectomy within 35 days after nCRT (≤35d), and those who underwent esophagectomy more than 35 days after nCRT (>35d). Results A total of 366 esophagectomies were performed during the study period, and 348 patients met the inclusion criteria. Anastomotic leaks occurred in 11.8% of all patients included in the study (41 of 348). Within each cohort, anastomotic leaks were detected in 14.7% of patients (17 of 116) in the no nCRT cohort, 7.3% (13 of 177) in the ≤35d cohort, and 20.0% (11 of 55) in the >35d cohort (p=0.020). Significant differences in the occurrence of anastomotic leaks were observed between the no nCRT and ≤35d cohorts (p=0.044), and between the ≤35d and >35d cohorts (p=0.007). Conclusion Esophagectomy with cervical anastomosis within 35 days of nCRT resulted in a lower percentage of anastomotic leaks.

BackgroundRegional analgesic techniques such as paravertebral blocks (PVBs) have been popularized for analgesia following video-assisted thoracoscopic surgery (VATS). In this single center retrospective propensity matched cohort of subjects, we investigate the impact of paravertebral blocks on the analgesic and non-analgesic outcomes.MethodsInstitutional database was queried to identify all patients undergoing VATS between January 2013 and July 2019 and these patients were divided into those who received paravertebral blocks in combination with general anesthesia (GA) [PVB group] and those who received GA without paravertebral blocks [GA group]. Propensity score matching based on common patient confounders were used to identify patients in each group. Primary outcomes of the study were average pain scores and opioid consumption in the first 24 hours. Secondary analgesic outcomes included pain scores and opioid requirements at other timepoints over the first 48 hours. Non analgesic outcomes were obtained from STS General Thoracic Surgery Database and included length of hospital stay, need for ICU admission, composite outcome of any complication during the hospital course and 30-day mortality. Exploratory analyses were conducted to investigate the impact of PVB on analgesia following different types of surgery and as to whether any other covariates had a greater influence on the included patient centered outcomes.Main resultsAfter propensity score matching, a total of 520 patients (260 per group) were selected for the study out of 1095 patients. The opioid consumption in terms of oral morphine milligram equivalent (MME) [Median (IQR)] for the first 24 hours was significantly lower with the use of PVB [PVB group– 78.5 (96.75); GA group—127.0 (111.5); pConclusionParavertebral blocks reduced the length of stay and opioid consumption up to 48 hours after VATS without significantly impacting pain scores.

Purpose: This study aimed to investigate the feasibility of stereotactic body radiation therapy (SBRT) as salvage therapy for locally recurrent esophageal cancer. We hypothesized that SBRT would provide durable treated tumor control with minimal associated toxicity in patients with progressive disease after definitive radiation, chemotherapy, and surgical resection. Methods: This single-institution retrospective study assessed outcomes in patients who received SBRT for locoregional failure of esophageal cancer after initial curative-intent treatment. Only patients who had received neoadjuvant chemoradiation (≥41.4 Gy) for esophageal cancer were selected. Subsequent surgical resection was optional but institutional follow-up by an oncologist was required. The primary endpoints of this study were gastrointestinal and constitutional toxicity, scored with the Common Terminology Criteria for Adverse Events v5.0. A secondary outcome, treated-tumor control, was assessed with RECIST v1.1. Results: Nine patients (11 locoregional recurrences) treated with SBRT were reviewed, with a median follow-up time of 10.5 months. Most patients initially presented with T3 (88.9%), N1 (55.6%), moderately differentiated (66.7%) adenocarcinoma (88.9%), and had received a median 50.4 Gy delivered over 28 fractions with concurrent carboplatin/paclitaxel chemotherapy followed by surgical resection. Median time to recurrence was 16.3 months. Median total dose delivered by SBRT was 27.5 Gy (delivered in five fractions). Two patients experienced acute grade 1 fatigue and vomiting. No patient experienced grade 3 or higher toxicity. One patient experienced failure in the SBRT treatment field at 5.8 months after treatment and six patients developed distant failure. The median progression-free survival time for SBRT-treated tumors was 5.0 months, and median overall survival time was 12.9 months. Conclusions: This single-institution study demonstrated the feasibility of SBRT for locoregional recurrence of esophageal cancer with minimal treatment-related toxicity and high rates of treated tumor control. Prospective studies identifying ideal salvage SBRT candidates for locoregional failure as well as validating its safety are needed.

Ferrets are an attractive mammalian model for several diseases, especially those affecting the lungs, liver, brain, and kidneys. Many chronic human diseases have been difficult to model in rodents due to differences in size and cellular anatomy. This is particularly the case for the lung, where ferrets provide an attractive mammalian model of both acute and chronic lung diseases, such as influenza, cystic fibrosis, A1A emphysema, and obliterative bronchiolitis, closely recapitulating disease pathogenesis, as it occurs in humans. As such, ferrets have the potential to be a valuable preclinical model for the evaluation of cell-based therapies for lung regeneration and, likely, for other tissues. Induced pluripotent stem cells (iPSCs) provide a great option for provision of enough autologous cells to make patient-specific cell therapies a reality. Unfortunately, they have not been successfully created from ferrets. In this study, we demonstrate the generation of ferret iPSCs that reflect the primed pluripotent state of human iPSCs. Ferret fetal fibroblasts were reprogrammed and acquired core features of pluripotency, having the capacity for self-renewal, multilineage differentiation, and a high-level expression of the core pluripotency genes and pathways at both the transcriptional and protein level. In conclusion, we have generated ferret pluripotent stem cells that provide an opportunity for advancing our capacity to evaluate autologous cell engraftment in ferrets.

BACKGROUND: The tolerability of adjuvant chemotherapy in esophageal cancer is unclear. PATIENTS AND METHODS: This was a phase II trial of adjuvant paclitaxel in patients with esophageal cancer after trimodality treatment. Patients with residual viable tumor after resection were eligible for study inclusion. Treatment was 80 mg/m(2) paclitaxel intravenously on days 1, 8, and 15 every 28 days for total of two cycles. The primary objective was to determine whether 75% or more of the patients would tolerate 240 mg/m(2) or more of paclitaxel, which corresponded to 50% or more of the total planned dose. RESULTS: Eleven out of the 12 enrolled patients (92%, 95% confidence interval (CI)=62–100%) were able to complete at least 50% of the planned paclitaxel dose. Median progression-free survival was 7 months (95% CI=2–28 months). Median overall survival was 28 months (95% CI=12–36 months). Only one patient experienced a grade 4 adverse event. CONCLUSION: Screening patients with esophageal cancer after trimodality treatment might improve completion of adjuvant trials.

Objective The goal of this post hoc analysis of subjects from a prospective observational study was to identify the predictors of patients developing moderate to severe acute pain (mean numerical rating scale [NRS] ≥4, 0–10) during the first three days after video-assisted thoracoscopic surgery (VATS) from a comprehensive evaluation of demographic, psychosocial, and surgical factors. Methods Results from 82 patients who were enrolled one week before VATS and evaluated during the first three postoperative days are presented. The primary outcome variable of the current study was the presence of moderate to severe acute pain after VATS. Results Fifty-nine percent (95% confidence interval, 47–69%) of study subjects developed moderate to severe acute pain after VATS. Factors univariately associated with the presence of moderate to severe acute pain were greater average expected postoperative pain, greater pain to a suprathreshold cold stimulus, and longer durations of surgery and hospital stay (P Conclusions None of the preoperative psychosocial measures were associated with the moderate to severe acute pain after VATS. Average expected postoperative pain was the only measure associated with the development of moderate to severe acute pain after VATS.

Classical interpretation of cystic fibrosis (CF) lung disease pathogenesis suggests that infection initiates disease progression, leading to an exuberant inflammatory response, excessive mucus, and ultimately bronchiectasis. Although symptomatic antibiotic treatment controls lung infections early in disease, lifelong bacterial residence typically ensues. Processes that control the establishment of persistent bacteria in the CF lung, and the contribution of noninfectious components to disease pathogenesis, are poorly understood.To evaluate whether continuous antibiotic therapy protects the CF lung from disease using a ferret model that rapidly acquires lethal bacterial lung infections in the absence of antibiotics.CFTR (cystic fibrosis transmembrane conductance regulator)-knockout ferrets were treated with three antibiotics from birth to several years of age and lung disease was followed by quantitative computed tomography, BAL, and histopathology. Lung disease was compared with CFTR-knockout ferrets treated symptomatically with antibiotics.Bronchiectasis was quantified from computed tomography images. BAL was evaluated for cellular differential and features of inflammatory cellular activation, bacteria, fungi, and quantitative proteomics. Semiquantitative histopathology was compared across experimental groups. We demonstrate that lifelong antibiotics can protect the CF ferret lung from infections for several years. Surprisingly, CF animals still developed hallmarks of structural bronchiectasis, neutrophil-mediated inflammation, and mucus accumulation, despite the lack of infection. Quantitative proteomics of BAL from CF and non-CF pairs demonstrated a mucoinflammatory signature in the CF lung dominated by Muc5B and neutrophil chemoattractants and products.These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.

Background: Coronary button reimplantation can represent a technical challenge of aortic root reconstruction that can be associated with significant morbidity and mortality. With the goal of simplifying coronary reimplantation and reducing the incidence of related complications, we designed a new Dacron graft with prefabricated coronary branches to minimize coronary artery mobilization and prevent the potential mechanical complications of reattachment to the body of the graft. Methods: Between June 2010 and May 2012, we implanted the graft in eight patients (six males, two females) ranging in age from 42-68 years (mean, 54 years). Six procedures were modified Bentall reconstructions, and two procedures were valve-sparing root replacements using the reimplantation technique. Results: There were no complications and no morbidity or mortality related to coronary reattachment. All patients were alive and doing well at a mean follow-up of 26 months (range, 17-38 months). At an extended mean follow-up of 42 months (range, 25-56 months), one patient died of stroke-related complications. No radiologic or clinical evidence of impairment of coronary perfusion was identified in any patient. Conclusions: The use of this new graft model may simplify the technique of root reconstruction and potentially lower the incidence of mechanical complications related to coronary button reimplantation.

Key Clinical Message Mounier–Kuhn syndrome is a rare clinical disorder characterized by tracheobronchial dilation and recurrent lower respiratory tract infections. While the etiology of the disease remains unknown, histopathological analysis of Mounier–Kuhn airways demonstrates that the disease is, in part, characterized by cellular changes in airway smooth muscle.

We previously reported that delivery of a microRNA-138 mimic or siRNA against SIN3A to cultured cystic fibrosis (ΔF508/ΔF508) airway epithelia partially restored ΔF508-cystic fibrosis transmembrane conductance regulator (CFTR)-mediated cAMP-stimulated Cl− conductance. We hypothesized that dissecting this microRNA-138/SIN3A-regulated gene network would identify individual proteins contributing to the rescue of ΔF508-CFTR function. Among the genes in the network, we rigorously validated candidates using functional CFTR maturation and electrolyte transport assays in polarized airway epithelia. We found that depletion of the ubiquitin ligase SYVN1, the ubiquitin/proteasome system regulator NEDD8, or the F-box protein FBXO2 partially restored ΔF508-CFTR-mediated Cl− transport in primary cultures of human cystic fibrosis airway epithelia. Moreover, knockdown of SYVN1, NEDD8, or FBXO2 in combination with corrector compound 18 further potentiated rescue of ΔF508-CFTR-mediated Cl− conductance. This study provides new knowledge of the CFTR biosynthetic pathway. It suggests that SYVN1 and FBXO2 represent two distinct multiprotein complexes that may degrade ΔF508-CFTR in airway epithelia and identifies a new role for NEDD8 in regulating ΔF508-CFTR ubiquitination.

Chronic lung diseases are a major global health concern—accounting for approximately 13.5% of all deaths world-wide (1). Lung transplantation is an effective therapy for end-stage lung diseases when medical therapies fail.

Pulmonary cystic echinococcosis (CE) is uncommon in non-endemic countries and may be difficult to diagnose and manage. We describe a case of a rupture CE mimicking complicated empyema in a pregnant patient.

Epithelial stem cells reside within multiple regions of the lung where they renew various region-specific cells. In addition, there are multiple routes of regeneration after injury through built-in heterogeneity within stem cell populations and through a capacity for cellular plasticity among differentiated cells. These processes are important facets of respiratory tissue resiliency and organism survival. However, this regenerative capacity is not limitless, and repetitive or chronic injuries, environmental stresses, or underlying factors of disease may ultimately lead to or contribute to tissue remodeling and end-stage lung disease. This chapter will review stem cell heterogeneity among pulmonary epithelia in the lower respiratory system, discuss recent findings that may challenge long-held scientific paradigms, and identify several clinically relevant research opportunities for regenerative medicine.

Obesity is public health problem of epidemic proportions. Esophageal dysmotility including achalasia is more commonly seen in an obese population. Standard therapy for achalasia can be complicated by hepatomegaly and a post-surgical anatomy in a pre- and post-bariatric population. Peroral endoscopic myotomy (POEM) has not been adequately studied in this population. A retrospective review of a prospectively collected database was completed. Patients who had undergone a Roux-en-y gastric bypass (RYGB) prior to or following a POEM were enrolled. Patient demographics, operative information and post-operative course data was collected. Six patients underwent POEM prior to or after RYGB. There were no peri-operative complications with an average length of stay of 1.2 days. Five patients experienced a clinical success with excellent symptom resolution. The one failure was in the setting of type III achalasia, but did have objective evidence of lower esophageal sphincter (LES) relaxation post-operatively. POEM in the setting of bariatric surgery is safe and feasible. The potential increase in GERD following POEM is obviated by RYGB anatomy. In an obese individual, a staged POEM prior to or following a RYGB is an appropriate treatment algorithm for obese and achalasia.

The optimal surgery for resectable pulmonary typical carcinoid (TC), e.g., lobar resection (L-R)The Surveillance, Epidemiology, and End Results (SEER) Program was used to select patients ≥66 years old, and diagnosed between 2000 and 2012 with pulmonary TC. A similar cohort was developed using the SEER-Medicare database (diagnosed from 2000-2007) to identify chemotherapy (CTX) use and co-morbidity. Five-year survival was calculated using univariate and multivariate analysis.A total of 1,506 and 512 patients were identified from SEER and SEER-Medicare, respectively. In the SEER cohort, 49%, 29% and 21% received L-R, SL-R, and no surgery (NS), respectively. Those who received NS were older (P0.001), had a higher stage (P0.001), greater comorbidity (P0.001), and were more likely to receive radiotherapy (XRT) (P0.001) and CTX (P0.001). Relative survival was nearly 100% for those who received L-R or SL-R as opposed to 72% for those who received NS (P0.001). Cox models showed no survival difference for L-RSL-R was better than NS, and similar to L-R in terms of survival. SL-R should be considered over NS if L-R is unfeasible. Role of adjuvant CTX and XRT is unclear as these did not improve survival in this study.

In emphysema airway resistance can exceed collateral airflow resistance, causing air to flow preferentially through collateral pathways. In severe emphysema ventilation through openings directly through the chest wall into the parenchyma (spiracles) could bypass airway obstruction and increase alveolar ventilation via transpleural expiration. During lung transplant operations, spiracles occasionally can occur inadvertently. We observed transpleural expiration via spiracles in three subjects undergoing lung transplant for emphysema. During transpleural spiracle ventilation, inspiratory tidal volumes (TV) were unchanged; however, expiration was entirely transpleural in two patients whereas the expired TV to the ventilator circuit was reduced to 25% of the inspired TV in one. At baseline, mean PCO2 was 61 ± 5 mm Hg, which decreased to a mean PCO2 of 49 ± 5 mm Hg (P = .05) within minutes after transpleural spiracle ventilation and further decreased at 1 to 2 h (36 ± 4 mm Hg; P = .002 compared with baseline) on unchanged ventilator settings. This observation of increased alveolar ventilation supports further studies of spiracles as a possible therapy for advanced emphysema.

Background: Barium swallow is performed following esophagectomy to evaluate the anastomosis for detection of leaks and to assess the emptying of the gastric conduit. The aim of this study was to evaluate the reliability of the barium swallow study in diagnosing anastomotic leaks following esophagectomy. Methods: Patients who underwent esophagectomy from January 2000 to December 2013 at our institution were investigated. Barium swallow was routinely done between days 5–7 to detect a leak. These results were compared to clinically determined leaks (defined by neck wound infection requiring jejunal feeds and or parenteral nutrition) during the postoperative period. The sensitivity and specificity of barium swallow in diagnosing clinically significant anastomotic leaks was determined. Results: A total of 395 esophagectomies were performed (mean age, 62.2 years). The indications for the esophagectomy were as follows: malignancy (n=320), high-grade dysplasia (n=14), perforation (n=27), benign stricture (n=7), achalasia (n=16), and other (n=11). A variety of techniques were used including transhiatal (n=351), McKeown (n=35), and Ivor Lewis (n=9) esophagectomies. Operative mortality was 2.8% (n=11). Three hundred and sixty-eight patients (93%) underwent barium swallow study after esophagectomy. Clinically significant anastomotic leak was identified in 36 patients (9.8%). Barium swallow was able to detect only 13/36 clinically significant leaks. The sensitivity of the swallow in diagnosing a leak was 36% and specificity was 97%. The positive and negative predictive values of barium swallow study in detecting leaks were 59% and 93%, respectively. Conclusion: Barium swallow is an insensitive but specific test for detecting leaks at the cervical anastomotic site after esophagectomy.

Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema, and represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers.

Rationale: Obliterative bronchiolitis (OB) is a major cause of mortality after lung transplantation. Depletion of airway stem cells (SCs) may lead to fibrosis in OB. Objectives: Two major SC compartments in airways are submucosal glands (SMGs) and surface airway p63 (also known as TP63 [tumor protein 63])-positive/K5 (also known as KRT5 [keratin 5])-positive basal cells (BCs). We hypothesized that depletion of these SC compartments occurs in OB. Methods: Ferret orthotopic left lung transplants were used as an experimental model of OB, and findings were corroborated in human lung allografts. Morphometric analysis was performed in ferret and human lungs to evaluate the abundance of SMGs and changes in the expression of phenotypic BC markers in control, lymphocytic bronchiolitis, and OB airways. The abundance and proliferative capacity of proximal and distal airway SCs was assessed using a clonogenic colony-forming efficiency assay. Measurements and Main Results: Ferret allografts revealed significant loss of SMGs with development of OB. A progressive decline in p63(+)/K5(+) and increase in K5(+)/K14(+) and K14(+) BC phenotypes correlated with the severity of allograft rejection in large and small ferret airways. The abundance and proliferative capacity of basal SCs in large allograft airways declined with severity of OB, and there was complete ablation of basal SCs in distal OB airways. Human allografts mirrored phenotypic BC changes observed in the ferret model. Conclusions: SMGs and basal SC compartments are depleted in large and/or small airways of lung allografts, and basal SC proliferative capacity declines with progression of disease and phenotypic changes. Global airway SC depletion may be a mechanism for pulmonary allograft failure.

Summary The mouse trachea is thought to contain two distinct stem cell compartments that contribute to airway repair—basal cells in the surface airway epithelium (SAE) and an unknown submucosal gland (SMG) cell type. Whether a lineage relationship exists between these two stem cell compartments remains unclear. Using lineage tracing of glandular myoepithelial cells (MECs), we demonstrate that MECs can give rise to seven cell types of the SAE and SMGs following severe airway injury. MECs progressively adopted a basal cell phenotype on the SAE and established lasting progenitors capable of further regeneration following reinjury. MECs activate Wnt-regulated transcription factors (Lef-1/TCF7) following injury and Lef-1 induction in cultured MECs promoted transition to a basal cell phenotype. Surprisingly, dose-dependent MEC conditional activation of Lef-1 in vivo promoted self-limited airway regeneration in the absence of injury. Thus, modulating the Lef-1 transcriptional program in MEC-derived progenitors may have regenerative medicine applications for lung diseases.

We appreciate Holm et al.’ s interest in our paper (1). By design, our study was not powered to answer each secondary result. This point was already acknowledged in the limitations section. The primary outcome variable of our study was the incidence of chronic pain, at 6 months, for any patient undergoing thoracic surgery. We tested the primary hypothesis of whether variables from preoperative evaluation can predict chronic pain after thoracic surgery. Based on our data from 99 patients who were followed for 6 months, the answer was no. Acute postsurgical pain was the only covariate associated with the presence of chronic pain.

Lung transplantation is an effective therapy for many patients with end-stage lung disease. Few centers across the United States offer this therapy, as a successful lung transplant program requires significant institutional resources and specialized personnel. Analysis of the United Network of Organ Sharing database reveals that the failure rate of new programs exceeds 40%. These data suggest that an accurate assessment of program viability as well as a strategy to continuously assess defined quality measures is needed. As part of strategic planning, regional availability of recipient and donors should be assessed. Additionally, analysis of institutional expertise at the physician, support staff, financial, and administrative levels is necessary. In May of 2007, we started a new lung transplant program at the University of Iowa Hospitals and Clinics and have performed 101 transplants with an average recipient 1-year survival of 91%, placing our program among the top in the country for the past 5 years. Herein, we review internal and external factors that impact the viability of a new lung transplant program. We discuss the use of four prospectively identified quality measures: volume, recipient outcomes, financial solvency, and academic contribution as one approach to achieve programmatic excellence.

A patient presents with a new bronchogenic carcinoma 5 years after laryngectomy for recurrent laryngeal tumor and 13 years after chemoradiation for concurrent lung cancer with synchronous base-of-tongue tumor. Due to his complex history and perceived limited respiratory reserve, he was felt high risk for the completion pneumonectomy needed for resection of this new tumor. The attending surgeon requested a full cardiopulmonary exercise test for risk assessment prior to surgery. We found that there was no commercially available connector that would allow our CPET equipment to reliably collect respiratory gases from a patient with tracheostomy stoma or tube. We report here a simple coupling devised “in house” that allowed for the performance of an interpretable test leading to a significant change in medical care.

Blunt aortic injuries (BAI) have historically been considered an indication for emergent surgical intervention. Nevertheless, the observation that the outcome of the concomitant traumatic injuries has a major impact on prognosis and the rise of thoracic endovascular aortic repair (TEVAR) as an effective therapy for BAI have significantly changed in recent years the treatment algorithm of this condition. Our objective was to identify findings associated with the aortic injury which would be the best predictor of prognosis, with the objective of guiding the decision-making process for selecting the optimal timing of aortic repair. We reviewed blunt aortic injuries from 3 Level I Trauma Centers from July 2008 to December 2016. We analyzed overall and BAI-related 30-day mortality in relation to: hemodynamics, timing of treatment, TEVAR vs open repair, and aortic injury grade as defined by the Society for Vascular Surgery. Based on computed tomographic angiography (CT scan) imaging, we selected the radiologic aortic findings most indicative of high mortality risk, which we defined as “Radiographic Severe Injury” (RSI): (1) total/partial aortic transection, (2) active contrast extravasation, or (3) the association of 2 of more of the following: contained contrast extravasation > 10 mm, periaortic hematoma, and/or mediastinal hematoma with thickness > 10 mm, or significant left pleural effusion. Of a total of 76 consecutive patients, 50 (66%) underwent immediate repair, 24 (31%) delayed aortic repair, and 2 (3%) died prior to repair. 58 patients (76%) had TEVAR, while 16 (24%) had open repair. Overall mortality was 18% and BAI-related mortality was 13%. In BAI-related mortalities, 70% of patients had RSI. Patients with high risk of overall mortality had hypotension and tachycardia (SBP

Per oral endoscopic myotomy (POEM) has gained increasing popularity for treating achalasia. A multidisciplinary approach may allow safe and early adoption of POEM into clinical practice. We performed a retrospective review of our initial POEM cases. All procedures were performed by a team of interventional gastroenterologist and thoracic surgeon. We analyzed demographics, comorbidities, achalasia subtypes, length of hospital stay, duration of surgery, morbidity, mortality, length of myotomy, preoperative and postoperative Eckardt scores. Thirty-one consecutive patients underwent POEM during the 24-month period from January 2014 to December 2015. Eighteen patients (58%) had prior non-operative interventions. Average duration of follow-up was 9.6 months. Seventeen patients (66.8%) had follow-up of 12 months and longer. Average preoperative Eckardt score was 6.3 (3–10), median 6. Average postoperative Eckardt score was 1.4 (0–8), median 1, in 1 month and an average 2.2, median 1, in 1 year. Patients with type III achalasia were most refractory to treatment, while patients with type II had the best results. Average LOS was 1.3 days (1–5), median 1 day. Average DOS was 106 min (60–148), median 106. Average LOM was 13 cm (10–15), with median of 13 cm. We had one 30-day mortality secondary to coronary artery disease. Four patients had prior Heller myotomies and underwent a posterior myotomy during POEM, with outcomes similar to patients with no prior myotomy. We demonstrated safety and efficiency of a multispecialty approach for achalasia with POEM with a low rate of complications.

Background The goal of this study was to detect the predictors of chronic pain at 6 months after thoracic surgery from a comprehensive evaluation of demographic, psychosocial, and surgical factors. Methods Thoracic surgery patients were enrolled 1 week before surgery and followed up 6 months postsurgery in this prospective, observational study. Comprehensive psychosocial measurements were assessed before surgery. The presence and severity of pain were assessed at 3 and 6 months after surgery. One hundred seven patients were assessed during the first 3 days after surgery, and 99 (30 thoracotomy and 69 video-assisted thoracoscopic surgery, thoracoscopy) patients completed the 6-month follow-up. Patients with versus without chronic pain related to thoracic surgery at 6 months were compared. Results Both incidence (P = 0.37) and severity (P = 0.97) of surgery-related chronic pain at 6 months were similar after thoracotomy (33%; 95% CI, 17 to 53%; 3.3 ± 2.1) and thoracoscopy (25%; 95% CI, 15 to 36%; 3.3 ± 1.7). Both frequentist and Bayesian multivariate models revealed that the severity of acute pain (numerical rating scale, 0 to 10) is the measure associated with chronic pain related to thoracic surgery. Psychosocial factors and quantitative sensory testing were not predictive. Conclusions There was no difference in the incidence and severity of chronic pain at 6 months in patients undergoing thoracotomy versus thoracoscopy. Unlike other postsurgical pain conditions, none of the preoperative psychosocial measurements were associated with chronic pain after thoracic surgery.

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H(2)O(2); however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O(2)(.−) and H(2)O(2) are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H(2)O(2). In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

The choice of the approach for esophagectomy (Ivor Lewis vs McKeown vs transhiatal esophagectomy) depends on the location of the tumor, prior operations, radiation treatment, body habitus, and surgeon’s preference. A transthoracic approach (Ivor Lewis and McKeown) allows dissection of the difficult esophagus under direct vision and may improve extent of lymphadenectomy and radial margin for midesophageal tumors. Cervical anastomosis in the McKeown and transhiatal approach allows for anastomosis healing outside of the radiated field for middle- and lower-third esophageal tumors, but a thoracic anastomosis (Ivor Lewis) puts less tension on the gastric conduit. There is no oncologic survival difference between these approaches. The Ivor Lewis resection combines a thoracic dissection with a thoracic anastomosis and is described in this chapter. This chapter lists the indications, essential steps, variations, and complications of Ivor Lewis esophagectomy. It includes a detailed template operative dictation note.

A transthoracic approach (Ivor Lewis and McKeown) allows dissection of the difficult esophagus under direct vision and may improve extent of lymphadenectomy and radial margin for midesophageal tumors. Cervical anastomosis in the McKeown esophagectomy allows for a greater length of the proximal esophagus to be resected. Thus many surgeons prefer this approach for middle and upper esophageal tumors. This chapter describes indications, essential steps, variations, and complications of this procedure. It provides a detailed template operative note for the procedure.

Cystic fibrosis (CF) is a multiorgan disease caused by loss of a functional cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in many epithelia of the body. Here we report the pathology observed in the gastrointestinal organs of juvenile to adult CFTR-knockout ferrets. CF gastrointestinal manifestations included gastric ulceration, intestinal bacterial overgrowth with villous atrophy, and rectal prolapse. Metagenomic phylogenetic analysis of fecal microbiota by deep sequencing revealed considerable genotype-independent microbial diversity between animals, with the majority of taxa overlapping between CF and non-CF pairs. CF hepatic manifestations were variable, but included steatosis, necrosis, biliary hyperplasia, and biliary fibrosis. Gallbladder cystic mucosal hyperplasia was commonly found in 67% of CF animals. The majority of CF animals (85%) had pancreatic abnormalities, including extensive fibrosis, loss of exocrine pancreas, and islet disorganization. Interestingly, 2 of 13 CF animals retained predominantly normal pancreatic histology (84% to 94%) at time of death. Fecal elastase-1 levels from these CF animals were similar to non-CF controls, whereas all other CF animals evaluated were pancreatic insufficient (

Tracheobronchial submucosal glands (SMGs) are derived from one or more multipotent glandular stem cells that coalesce to form a placode in surface airway epithelium (SAE). Wnt/β-catenin-dependent induction of lymphoid enhancer factor ( Lef-1) gene expression during placode formation is an early event required for SMG morphogenesis. We discovered that Sox2 expression is repressed as Lef-1 is induced within airway SMG placodes. Deletion of Lef-1 did not activate Sox2 expression in SMG placodes, demonstrating that Lef-1 activation does not directly inhibit Sox2 expression. Repression of Sox2 protein in SMG placodes occurred posttranscriptionally, since the activity of its endogenous promoter remained unchanged in SMG placodes. Thus we hypothesized that Sox2 transcriptionally represses Lef-1 expression in the SAE and that suppression of Sox2 in SMG placodes activates Wnt/β-catenin-dependent induction of Lef-1 during SMG morphogenesis. Consistent with this hypothesis, transcriptional reporter assays, ChIP analyses, and DNA-protein binding studies revealed a functional Sox2 DNA binding site in the Lef-1 promoter that is required for suppressing β-catenin-dependent transcription. In polarized primary airway epithelium, Wnt induction enhanced Lef-1 expression while also inhibiting Sox2 expression. Conditional deletion of Sox2 also enhanced Lef-1 expression in polarized primary airway epithelium, but this induction was significantly augmented by Wnt stimulation. Our findings provide the first evidence that Sox2 acts as a repressor to directly modulate Wnt-responsive transcription of the Lef-1 gene promoter. These studies support a model whereby Wnt signals and Sox2 dynamically regulate the expression of Lef-1 in airway epithelia and potentially also during SMG development.

Chronic bacterial lung infections in cystic fibrosis (CF) are caused by defects in the CF transmembrane conductance regulator chloride channel. Previously, we described that newborn CF transmembrane conductance regulator–knockout ferrets rapidly develop lung infections within the first week of life. Here, we report a more slowly progressing lung bacterial colonization phenotype observed in juvenile to adult CF ferrets reared on a layered antibiotic regimen. Even on antibiotics, CF ferrets were still very susceptible to bacterial lung infection. The severity of lung histopathology ranged from mild to severe, and variably included mucus obstruction of the airways and submucosal glands, air trapping, atelectasis, bronchopneumonia, and interstitial pneumonia. In all CF lungs, significant numbers of bacteria were detected and impaired tracheal mucociliary clearance was observed. Although Streptococcus, Staphylococcus, and Enterococcus were observed most frequently in the lungs of CF animals, each animal displayed a predominant bacterial species that accounted for over 50% of the culturable bacteria, with no one bacterial taxon predominating in all animals. Matrix-assisted laser desorption–ionization time-of-flight mass spectrometry fingerprinting was used to quantify lung bacteria in 10 CF animals and demonstrated Streptococcus, Staphylococcus, Enterococcus, or Escherichia as the most abundant genera. Interestingly, there was significant overlap in the types of bacteria observed in the lung and intestine of a given CF animal, including bacterial taxa unique to the lung and gut of each CF animal analyzed. These findings demonstrate that CF ferrets develop lung disease during the juvenile and adult stages that is similar to patients with CF, and suggest that enteric bacterial flora may seed the lung of CF ferrets.