Senescence of Alveolar Type 2 Cells Drives Progressive Pulmonary Fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Accelerated aging, loss of epithelial progenitor cell function and/or numbers, and cellular senescence are implicated in the pathogenies of IPF.Objectives: We sought to investigate the role of alveolar type 2 (AT2) cellular senescence in initiation and/or progression of pulmonary fibrosis and therapeutic potential of targeting senescence-related pathways and senescent cells.Methods: Epithelial cells of 9 control donor proximal and distal lung tissues and 11 IPF fibrotic lung tissues were profiled by single-cell RNA sequencing to assesses the contribution of epithelial cells to the senescent cell fraction for IPF. A novel mouse model of conditional AT2 cell senescence was generated to study the role of cellular senescence in pulmonary fibrosis.Measurements and Main Results: We show that AT2 cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of AT2 cells promotes progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation or senescence block fibrogenesis.Conclusions: Senescence of AT2 cells is sufficient to drive progressive pulmonary fibrosis. Early attenuation of senescence-related pathways and elimination of senescent cells are promising therapeutic approaches to prevent pulmonary fibrosis.

Trends in segmentectomy for the treatment of stage 1A non-small cell lung cancers: Does the robot have an impact?

OBJECTIVES: Lobectomy may unnecessarily resect healthy lung parenchyma in Stage 1A non-small cell lung cancers (NSCLC). Segmentectomies may provide a lung-sparing option. VATS segmentectomies can be technically challenging; robotics may have features that provide advantages in performing segmentectomies. We describe the association of the robot on national trends in segmentectomies. METHODS: The National Cancer Database (2010-2017) was queried for patients with Stage 1A NSCLC who underwent lobectomies and segmentectomies. The proportion of segmentectomies vs. lobectomies and the proportion of robotic vs. VATS segmentectomies was calculated annually. RESULTS: The proportion of segmentectomies increased compared to lobectomies for all surgical approaches but remained constant for minimally-invasive approaches. The proportion of robotic segmentectomies increased over the years compared to VATS segmentectomies. Descriptive statistics are reported as numbers and proportions. Trends in the proportions of lobectomies and segmentectomies were compared using Chi-squared test for categorical variables and unpaired t-test for independent means. A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS Statistics Software version 24 (IBM Corp, Armonk, NY). CONCLUSIONS: We demonstrate an increasing trend and proportion of robotic segmentectomies being performed in comparison to VATS segmentectomies. The robotic platform may facilitate the performance of more segmentectomies for early-stage NSCLC.

Highly sensitive noninvasive early lung cancer detection using DNA methylation topology in sputum-derived epithelial cells.

Objective: Sputum is a source of exfoliated respiratory epithelial cells transformed early in lung carcinogenesis. Malignant cells are hypomethylated and contain less genomic 5-methylcytosine (5mC). Validating a test that recognizes and quantifies aberrantly hypomethylated cells in sputum, we assessed its potential as a screening tool for detecting early-stage non-small cell lung cancer. Methods: Cells extracted from sputum were immunofluorescence labeled with an anti-5-methylcytosine antibody and counterstained with 4',6-diamidino-2-phenylindole (DAPI) delineating global nuclear DNA (gDNA). Via confocal scanning and 3-dimensional image analysis, fluorescence 5mC and DAPI signals were measured in segmented cell nuclei, and a 5mC/DAPI co-distribution map was generated for each imaged cell. Cells were classified as hypomethylated based on 5mC load and 5mC/DAPI co-distribution. The proportion of hypomethylated epithelial cells in the sputum determines whether a patient has lung cancer. Results: A total of 88 subjects were enrolled: 12 healthy subjects; 34 high-risk subjects with benign chronic lung disorders (10 with chronic obstructive pulmonary disease, 24 with idiopathic pulmonary fibrosis), and 43 subjects with non-small cell lung cancer (27 with stage I-II and 16 with stage III-IV). The test identified early-stage non-small cell lung cancer and distinguished it from the high-risk group with 95.8% (95% confidence interval, 78.9-99.9) sensitivity and 41.2% (95% confidence interval, 24.6-59.3) specificity applying only 5mC, 95.8% (95% confidence interval, 78.9-99.9) sensitivity and 26.5% (95% confidence interval, 12.9-44.4) specificity using solely 5mC/DAPI index, and 100% (95% confidence interval, 98.7-100) sensitivity and 26.1% (95% confidence interval, 26.2-27.8) specificity with the combined parameters. Conclusions: We tested and validated a novel, noninvasive, highly sensitive screening test for non-small cell lung cancer. With the use of sputum, our test may impact lung cancer screening, evaluation of pulmonary nodules, and cancer surveillance algorithms.

Robotic navigational bronchoscopy in a thoracic surgery practice: Leveraging technology in the management of pulmonary nodules.

Objectives: Robotic navigational bronchoscopy is increasingly used to improve diagnostic yield for pulmonary nodules compared with the 50% to 60% obtained by standard bronchoscopy; however, safety and efficacy data are limited to small series. The aim of this study was to evaluate diagnostic yield and clinical outcomes in a large multisurgeon single-center cohort. Methods: All patients who underwent robotic navigational bronchoscopy and biopsy from September 2020 to October 2022 were identified from a prospective institutional registry. The primary outcome was diagnostic yield. The secondary outcome was diagnostic yield for molecular testing. Results: A total of 503 nodules were biopsied during the study period. Median nodule size was 2.1 cm. Overall diagnostic yield was 87.9%. Factors associated with increased diagnostic yield were decreased time from date of planning computed tomography to procedure date (odds ratio, 0.98; 95% CI, 0.96-0.99; P = .04) and greater nodule size (odds ratio, 1.03; 95% CI, 1.01-1.07; P = .02) per 0.1-cm increment. Molecular analysis was sent in 101 patients and was sufficient in 90% of cases. Complications occurred in 22 (5%) patients, including 13 (3.1%) with pneumothoraxes (7 patients requiring a chest drain), and 5 (1.2%) patients had bleeding requiring intraprocedural bronchial intervention. A total of 41 patients were consented for biopsy and resection during a single anesthetic event. Four of these cases were stopped at robotic navigational bronchoscopy due to an alternative diagnosis. Mean length of stay was 3.4 ± 1.1 days. There were no major complications. Conclusions: This study suggests robotic navigational bronchoscopy has a high diagnostic yield and obtains adequate tissue for molecular analysis critical for selection of targeted therapies. With careful patient selection robotic navigational bronchoscopy can be combined with surgery to treat lung cancer as a single procedure with low complication rates.

The lasting footprint of COVID-19 on surgical education: A resident and attending perspective on the global pandemic.

BACKGROUND: The COVID-19 pandemic has impacted surgical training nationwide. Our former curricula will likely not return, and training will need to adapt, so we are able to graduate residents of the same caliber as prior to the pandemic. METHODS: A survey evaluating perceptions of changes made in surgical training was conducted on surgery residents and attendings. RESULTS: Disaster medicine training has become more relevant and 85% residents and 75% attendings agreed it should be incorporated into the curriculum. Safety of family was the most significant concern of residents. Virtual curriculum was perceived to be acceptable by 82% residents and only 22% attendings (p < 0.01). Residents (37%) were less concerned than attendings (61%) of falling behind on their overall training (p = 0.04). Both groups agreed operative skills would be adversely affected (56%vs72%; p = 0.37). CONCLUSIONS: To maintain an effective surgical curriculum, programs will need to implement new educational components to better prepare residents to become surgeons of the future.

Consensus for Thoracoscopic Left Upper Lobectomy-Essential Components and Targets for Simulation.

BACKGROUND: Simulation-based training is a valuable component of cardiothoracic surgical education. Effective curriculum development requires consensus on procedural components and focused attention on specific learning objectives. Through use of a Delphi process, we established consensus on the steps of video-assisted thoracoscopic surgery (VATS) left upper lobectomy and identified targets for simulation. METHODS: Experienced thoracic surgeons were randomly selected for participation. Surgeons voted and commented on the necessity of individual steps comprising VATS left upper lobectomy. Steps with greater than 80% of participants in agreement of their necessity were determined to have established "consensus." Participants voted on the physical or cognitive complexity of each, or both, and chose steps most amenable to focused simulation. RESULTS: Thirty thoracic surgeons responded and joined in the voting process. Twenty operative steps were identified, with surgeons reaching consensus on the necessity of 19. Components deemed most difficult and amenable to simulation included those related to dissection and division of the bronchus, artery, and vein. CONCLUSIONS: Through a Delphi process, surgeons with a variety of practice patterns can achieve consensus on the operative steps of left upper lobectomy and agreement on those most appropriate for simulation. This information can be implemented in the development of targeted simulation for VATS lobectomy.

Chromosomal abnormalities and novel disease-related regions in progression from Barrett's esophagus to esophageal adenocarcinoma.

Barrett's esophagus (BE) is a metaplastic condition caused by chronic gastroesophageal reflux which represents an early step in the development of esophageal adenocarcinoma (EAC). Single-nucleotide polymorphism microarray (SNP-chip) analysis is a novel, precise, high-throughput approach to examine genomic alterations in neoplasia. Using 250K SNP-chips, we examined the neoplastic progression of BE to EAC, studying 11 matched sample sets: 6 sets of normal esophagus (NE), BE and EAC, 4 of NE and BE and 1 of NE and EAC. Six (60%) of 10 total BE samples and 4 (57%) of 7 total EAC samples exhibited 1 or more genomic abnormalities comprising deletions, duplications, amplifications and copy-number-neutral loss of heterozygosity (CNN-LOH). Several shared abnormalities were identified, including chromosome 9p CNN-LOH [2 BE samples (20%)], deletion of CDKN2A [4 BE samples (40%)] and amplification of 17q12-21.2 involving the ERBB2, RARA and TOP2A genes [3.1 Mb, 2 EAC (29%)]. Interestingly, 1 BE sample contained a homozygous deletion spanning 9p22.3-p22.2 (1.2 Mb): this region harbors only 1 known gene, basonuclin 2 (BNC2). Real-time PCR analysis confirmed the deletion of this gene and decreased the expression of BNC2 mRNA in the BE sample. Furthermore, transfection and stable expression of BNC2 caused growth arrest of OE33 EAC cells, suggesting that BNC2 functions as a tumor suppressor gene in the esophagus and that deletion of this gene occurs during the development of EAC. Thus, this SNP-chip analysis has identified several early cytogenetic events and novel candidate cancer-related genes that are potentially involved in the evolution of BE to EAC.

Management of Complications in Paraesophageal Hernia Repair.

Paraesophageal hernia repair is a technically challenging operation. Factors that influence morbidity of the operation include the timing of the operation, surgical approach, and patient factors. Medical complications are the most common and usually are respiratory or cardiac related. Perforation, subcutaneous emphysema, pneumothorax, shortened esophagus, and presence of a large hernia all complicate paraesophageal hernia repair. Various strategies of intraoperative management are described. Management of leaks and perforations identified postoperatively are dictated by the clinical status of the patient. Early identification and expeditious intervention are paramount in the overall management of complications.

Outcomes of patients with advanced non-small cell lung cancer and airway obstruction treated with photodynamic therapy and non-photodynamic therapy ablation modalities.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with central airway obstruction (CAO) may have better survival on systemic therapy if the airway patency is successfully restored by bronchoscopic interventions. It remains unclear which therapeutic bronchoscopic modality [laser, stenting, external beam radiation, brachytherapy and photodynamic therapy (PDT)] used for restoring airway patency positively affects outcomes in these patients. We analyzed the effectiveness of PDT in terms of mortality, and time to subsequent treatments in patients with stage III and IV NSCLC. METHODS: Study used Surveillance, Epidemiology, and End Results (SEER) Medicare linked data. We categorized NSCLC patients diagnosed between 2000 and 2011 and with stage III and IV, into three treatment groups: PDT + radiation ± chemotherapy, non-PDT ablation therapy + radiation ± chemotherapy, and radiation + chemotherapy. We analyzed all-cause and cause-specific mortality using Cox proportional hazard models with an inverse probability weighted propensity score adjustment. Time to subsequent treatment was analyzed using GLM model. RESULTS: For the PDT group, hazard for all-cause and cause-specific mortality was comparable to the radiation + chemotherapy group (HR =1.03, 95% CI: 0.73-1.45; and HR =1.04, 95% CI: 0.71-1.51, respectively). The non-PDT ablation group had higher hazard for all-cause (HR =1.22, 95% CI: 1.13-1.33) and cause-specific mortality (HR =1.10, 95% CI: 1.01-1.20), compared to the radiation + chemotherapy group. The PDT group had longer time to follow-up treatment, compared to non-PDT ablation group. CONCLUSIONS: In our exploratory study of stage III and IV NSCLC patients with CAO, addition of PDT demonstrated hazard of mortality comparable to radiation + chemotherapy group. However, addition of non-PDT ablation showed higher mortality compared to the radiation + chemotherapy group. Future studies should investigate the efficacy and effectiveness of multimodal therapy including radiation, chemo, immunotherapy and bronchoscopic interventions.

Disparities in Compliance With National Guidelines for the Treatment of Malignant Pleural Mesothelioma.

BACKGROUND: Current guidelines support cancer-directed surgery, chemotherapy, or active surveillance for clinical stages 1 to 3 of epithelial malignant pleural mesothelioma (MPM). Definitive chemotherapy is recommended for sarcomatoid/biphasic histologies. Our objective is to assess compliance with recommendations, measuring their impact on overall survival. METHODS: The National Cancer Database participant user file (2004 to 2014) was queried for patients diagnosed with MPM clinical stages 1 to 3. Multivariable logistic regression model identified factors independently associated with guideline compliance. Kaplan-Meier analysis and Cox proportional hazards were used for overall survival comparison with histologic subgroup analysis. RESULTS: A total of 3419 patients with clinical stages 1 to 3 met criteria for analysis and comprised epithelial (68.5%), sarcomatoid (17.2%), and biphasic subtypes (14.3%). Cancer-directed surgery was significantly underutilized in epithelial MPM, with 29.3% having no treatment. On multivariable analysis, insurance status and facility type were the strongest predictors of guideline compliance. High-volume hospitals were the most compliant with guidelines (odds ratio 3.58, 95% confidence interval (CI), 2.34 to 5.49, P < .001). Median survival estimates for no treatment, chemotherapy alone, surgery plus chemotherapy, and trimodal therapy were 10.2, 15.4, 21.1, and 21.7 months, respectively (log rank P < .001). In epithelial MPM, a significant increase in overall survival was observed in surgery plus chemotherapy (hazard ratio 0.62, 95% CI, 0.53 to 0.73, P < .001) and trimodality (hazard ratio 0.61, 95% CI, 0.49 to 0.76, P < .001; reference: no treatment). CONCLUSIONS: There is a suboptimal compliance with national guidelines for the treatment of MPM, particularly in low-volume nonacademic settings. Adherence to recommended surgery-based multimodal therapy is associated with an overall survival improvement.

Does the Approach Matter? Comparing Survival in Robotic, Minimally Invasive, and Open Esophagectomies.

BACKGROUND: Our objective was to determine how surgical approach impacts overall survival and postoperative outcomes when comparing robotic-assisted minimally invasive esophagectomy (RAMIE), minimally invasive esophagectomy (MIE), and open esophagectomy (OE). METHODS: The National Cancer Database was queried for patients diagnosed with pathologic Stage 0 to III esophageal cancer from 2010 to 2015. Primary outcome measures evaluated were length of stay, 30-day unplanned readmissions, mortality rates at 30 and 90 days, and overall survival rates. The surgical cohorts underwent 1:1 propensity score matching, and Kaplan-Meier survival estimates were compared by surgical approach. Cox proportional hazards regression was utilized to estimate factors associated with overall survival. RESULTS: Of 5,553 patients that met criteria, 28.4% were MIE, 7.8% RAMIE, and 63.8% OE. From 2010 to 2015, an increasing trend was seen for both minimally invasive approaches, with MIE surpassing the number of OEs. Unplanned 30-day readmissions and 30-day and 90-day mortality rates were not significantly different between the different groups. Median length of stay was significantly shorter in MIE (9 [interquartile range (IQR), 8 to 14] days) and RAMIE (9 [IQR, 7 to 14] days), compared with OE (10 [IQR, 8 to 15] days; p < 0.001). MIE and RAMIE had comparable survival rates compared with OE, with no significant differences in median overall survival estimates after propensity score matching (log-rank p = 0.603), with a trend for increased survival in MIE (adjusted hazard ratio, 0.97; 95% confidence interval, 0.89 to 1.06; p = 0.530) and RAMIE (hazard ratio, 0.81; 95% confidence interval, 0.69 to 0.95; p = 0.012). Both minimally invasive approaches had a significantly higher median lymph node counts (MIE: 15 [IQR, 9 to 22]; RAMIE: 17 [IQR, 11 to 24]; OE: 13 [IQR, 8 to 20]), which may highlight important differences in postoperative upstaging. CONCLUSIONS: Trends in MIE use is surpassing the open approach. Minimally invasive approaches are becoming the preferred approach, with noninferior long-term results compared with OEs. A significantly higher lymph node yield was seen for RAMIE and MIE.

Predictors of Failure to Rescue After Esophagectomy.

BACKGROUND: Failure to rescue (FTR), defined as death after a major complication, is a metric increasingly being used to assess quality of care. Risk factors associated with FTR after esophagectomy have not been previously studied. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent esophagectomy with gastric conduit between 2010 and 2014. Patients with at least one major postoperative complication were grouped according to inhospital mortality (FTR group) and survival to discharge (SUR group). A stepwise logistic regression model was used to identify predictors of FTR. RESULTS: A total of 1,730 patients comprised the study group, with 102 (5.9%) in the FTR group and 1,628 (94.1%) in the SUR group. The FTR patients were older (69.0 versus 64.0 years, p < 0.0001) compared with the SUR patients. There were no differences in sex, body mass index, preoperative weight loss, smoking status, operation type, or surgeon specialty between the two groups. Age greater than 75 years (adjusted odds ratio 2.68, p < 0.0001), black race (adjusted odds ratio 2.75, p = 0.001), American Society of Anesthesiologists class 4 or 5 (adjusted odds ratio 1.82, p = 0.02), and the occurrence of pneumonia, respiratory failure, acute renal failure, sepsis, or acute myocardial infarction were predictive of FTR based on multivariable logistic regression. CONCLUSIONS: Nearly 6% of patients who have a major complication after esophagectomy do not survive to discharge. Age greater than 75 years, black race, American Society of Anesthesiologists class 4 or 5, and complications related to major infection or organ failure predict FTR. Further research is necessary to investigate how these factors affect survival after complications in order to improve rescue efforts.

Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression.

Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.

Current status of research and treatment for non-small cell lung cancer in never-smoking females.

Lung cancer is the leading cause of cancer-related deaths worldwide with over 1 million deaths each year. The overall prognosis of lung cancer patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use. Notably, more than half of the lung cancer cases in women occur in non-smokers. Among non-small-cell lung cancer (NSCLC) cases, cigarette-smokers have a greater association with squamous cell carcinoma than adenocarcinoma, which is more common in non-smokers. These findings imply that specific molecular and pathological features may associate with lung adenocarcinoma arising in non-smoker female patients. Over the past decade, whole genome sequencing and other '-omics' technologies led to the discovery of pathogenic mutations that drive tumor cell formation. These technological developments may enable tailored patient treatments throughout the course of their disease, potentially leading to improved patient outcomes. Some clinical and laboratory studies have shown success outcomes using epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) in patients with EGFR mutations and ALK rearrangements, respectively. In fact, these 2 mutations are predominantly present in female non-smokers with adenocarcinoma. Immunotherapy has also recently emerged as a major therapeutic modality in NSCLC. In this review, we summarize the current understanding of NSCLC biology and new therapeutic molecular targets, focusing on the pathogenesis of non-smoker female NSCLC patients.