Integrin αvß3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity.

Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non-small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvß3 via upregulation of the ß3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvß3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation. SIGNIFICANCE: Upregulation of integrin αvß3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related commentary by Rainero, p. 1543.

A Multidisciplinary Minimally Invasive Approach Is Necessary for the Contemporary Management of Esophageal Diverticula.

Background: Esophageal diverticula were traditionally treated with open surgery, which is associated with significant morbidity and mortality rates. Management has shifted to minimally invasive approaches with several advantages. We examine outcomes in patients with esophageal diverticula treated with minimally invasive techniques by a multidisciplinary surgical team at a single center. Materials and Methods: A retrospective review of a prospectively maintained database was performed for patients who underwent minimally invasive surgery for esophageal diverticula at our institution from June 2010 to December 2022. Primary outcomes were 30-day morbidity and mortality rates. Secondary outcomes were symptom resolution, length of stay (LOS), readmission, and need for reintervention. Results: A total of 28 patients were identified. Twelve patients had pharyngeal diverticula, 7 patients had midesophageal diverticula, and 9 patients had epiphrenic diverticula. Thirty-day morbidity and readmission rates were 10.7% (3 patients), 1 pharyngeal (sepsis), 1 midesophageal (refractory nausea), and 1 epiphrenic (poor oral intake). There were no esophageal leaks. Average LOS was 2.3 days, with the pharyngeal group experiencing a significantly shorter LOS (1.3 days versus 3.4 days for midesophageal, P < .01 versus 2.8 days for epiphrenic, P < .05). Symptom resolution after initial operation was 78.6%. Reintervention rate was 17.9%, and symptom resolution after reintervention was 100%. There were no mortalities. Conclusion: This study demonstrates that esophageal diverticula can be repaired safely and efficiently when performed by a multidisciplinary team utilizing advanced minimally invasive endoscopic and robotic surgical techniques. We advocate for the management of this rare condition at a high-volume center with extensive experience in foregut surgery.

Activation of KrasG12D in Subset of Alveolar Type II Cells Enhances Cellular Plasticity in Lung Adenocarcinoma.

We have previously identified alveolar type II cell as the cell-of-origin of KrasG12D-induced lung adenocarcinoma using cell lineage-specific inducible Cre mouse models. Using gain-of-function and loss-of-function genetic models, we discovered that active Notch signaling and low Sox2 levels dictate the ability of type II cells to proliferate and progress into lung adenocarcinoma upon KrasG12D activation. Here, we examine the phenotype of type II cells after Kras activation and find evidence for proliferation of cells that coexpress type I and type II markers. Three-dimensional organoid culture and transplantation studies determine that these dual-positive cells are highly plastic and tumor initiating in vivo. RNA sequencing analysis reveals that these dual-positive cells are enriched in Ras/MAPK, EGFR, and Notch pathways. Furthermore, the proliferation of these cells requires active Notch signaling and is inhibited by genetic/chemical Sox2 upregulation. Our findings could provide new therapeutic strategies to target KRAS-activated lung adenocarcinomas. SIGNIFICANCE: Identification of progenitor like tumor-initiating cells in KRAS-mutant lung adenocarcinoma may allow development of novel targeted therapeutics.

Tolerability and Feasibility of the Upper Esophageal Sphincter Assist Device in Preventing Acute and Chronic Allograft Rejection Among Lung Transplant Recipients.

GOALS: We aimed to evaluate a novel upper esophageal sphincter (UES) assist device loaner program for the prevention of acute cellular rejection and chronic lung allograft dysfunction among lung transplant (LTx) recipients. BACKGROUND: Laryngopharyngeal reflux can lead to chronic microaspiration and LTx rejection. The UES assist device applies external pressure at the level of UES to decrease reflux. STUDY: We prospectively enrolled and issued UES assist devices to consecutive transplant patients referred for gastrointestinal motility testing from 2016 to 2020. Device tolerability was defined by successful utilization as a bridge to ambulatory pH monitoring and/or antireflux procedure, or as permanent therapy. Incidence of rejection was analyzed before, during, and after device implementation. RESULTS: Twenty-six participants were issued devices (15 pathologic, 5 physiological, 6 unknown reflux status), none of whom developed acute rejection episodes or chronic lung allograft dysfunction while using the device. Thirteen adopted the device promptly after transplantation (mean 1.7 mo) and remained free of rejection episodes over a mean 24.7 months of follow-up. Among those with pathologic reflux, lag time to device adoption strongly correlated with the development of rejection ( r =0.8, P =0.0006). There was no such correlation among those with physiological reflux. Five developed acute rejection after device return. CONCLUSIONS: The device was tolerated by a majority of LTx patients and appears feasible as a barrier measure in the prevention of rejection. Delayed treatment of laryngopharyngeal reflux may lead to early allograft failure; therefore, the UES assist device should be given important consideration in transplant protection.

Racial and ethnic variation in referral times for thoracic oncologic surgery in a major metropolitan area.

OBJECTIVE: The study objective was to understand the impact of race/ethnicity on access to thoracic surgical care for patients undergoing lung resection for cancer. METHODS: We performed a retrospective analysis on 206 consecutive patients who underwent lung resection for cancer (120 female, 86 male; median age 66 years), with respect to how race and ethnicity impact time to referral for thoracic surgery to a major healthcare center. Time between initial radiographic appearance of a lung nodule/mass 1 cm or greater to surgical referral and time from surgical referral to operation were evaluated for 121 White, 30 Asian, 26 Hispanic, 12 African American, and 17 mixed or other race patients. The impact of age, sex, median income of patient's household, national and state Area Deprivation Indices, insurance type, and distance between the patient's domicile and our hospital was evaluated. The influence of the referring physician's practice (hospital-based, hospital-affiliated, or private), internal or external referral, race/ethnicity, and level of specialization was also studied. RESULTS: African American, Asian, Hispanic, and mixed/other race patients had significantly longer wait times between initial radiographic finding of a lung nodule/mass 1 cm or greater and surgical referral compared with White individuals (median days: African American, 78; Asian, 95; Hispanic, 92; mixed or other, 65; White, 35). Multiple linear regression analysis demonstrated that race/ethnicity was the only significant predictor of prolonged time to surgical referral when adjusted for age, sex, median household income level, national and state Area Deprivation Indices, insurance type, and distance between patient's home and our hospital. The referring physician's type of practice and internal versus external referral were not significant. However, the physician's race/ethnicity and level of specialization had an impact on referral times, with nonspecialists referring patients sooner to thoracic surgery compared with specialists who ordered more workup tests. For all patient races/ethnicities, there was no difference in time between surgical referral and day of operation. CONCLUSIONS: Race and ethnicity have a major impact on the time from initial radiographic appearance of a lung nodule/mass 1 cm or greater to referral for surgical resection for cancer. This study suggests the need to develop strategies to reduce minority wait times and improve timely access to surgery for patients with thoracic malignancies. VIDEO ABSTRACT: Discussion of how race and ethnicity impact referral time to thoracic surgery discussed by Dr Moises Hernandez.

The Society of Thoracic Surgeons General Thoracic Surgery Database: 2022 Update on Outcomes and Research.

The Society of Thoracic Surgeons General Thoracic Surgery Database (STS GTSD) remains the largest and most robust thoracic surgical database in the world. Participating sites receive risk-adjusted performance reports for benchmarking and quality improvement initiatives. The GTSD also provides several mechanisms for high-quality clinical research using data from 274 participant sites and 781,000 procedures since its inception in 2002. Participant sites are audited at random annually for completeness and accuracy. Over the last year and a half, the GTSD Task Force continued to refine the data collection process, implementing an updated data collection form in July 2021, ensuring high data fidelity while minimizing data entry burden. In addition, the STS Workforce on National Databases has supported a robust GTSD-based research program, which led to eight scholarly publications in 2021. This report provides an update on volume trends, outcomes, and database initiatives as well as a summary of research productivity resulting from the GTSD over the preceding year.

The Role of Chemotherapy Plus Immune Checkpoint Inhibitors in Oncogenic-Driven NSCLC: A University of California Lung Cancer Consortium Retrospective Study.

Introduction: There is a paucity of data on immune checkpoint inhibitors (ICIs) plus doublet chemotherapy (C) in patients with advanced lung cancer whose tumor harbors an actionable mutation. We sought to provide insight into the role of this combination in relation to chemotherapy alone in this patient population. Methods: We conducted a retrospective study at the five University of California National Cancer Institute-designated Comprehensive Cancer Centers. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS) and significant adverse events. Adverse events in patients who received a tyrosine kinase inhibitor (TKI) post-ICI were also captured. Results: A total of 246 patients were identified, 170 treated with C plus ICI and 76 treated with C alone. Driver alterations included EGFR (54.9%), KRAS (32.9%), ALK (5.3%), HER2/ERBB2 (2.9%), ROS1 (1.2%), MET (1.2%), RET (0.8%), and BRAF non-V600 (0.8%). The overall PFS and OS hazard ratios were not significant at 1.12 (95% confidence interval 0.83-1.51; p = 0.472) and 0.86 (95% confidence interval: 0.60-1.24, p = 0.429), respectively. No significant differences in PFS or OS were observed in the mutational subgroups. Grade 3 or greater adverse events were lower in the C plus ICI group. The multivariate analysis for PFS and OS revealed a performance status (Eastern Cooperative Oncology Group) score of 2, and previous TKI treatment was associated with poorer outcomes with C plus ICI. Conclusions: Our study suggests that patients with oncogenic-driven NSCLC, primarily those with EGFR-driven tumors, treated with a TKI should not subsequently receive C plus ICI. Analysis from prospective clinical trials will provide additional information on the role of ICIs in this group of patients.

NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2022.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

Single-cell chromatin profiling of the primitive gut tube reveals regulatory dynamics underlying lineage fate decisions.

Development of the gastrointestinal system occurs after gut tube closure, guided by spatial and temporal control of gene expression. However, it remains unclear what forces regulate these spatiotemporal gene expression patterns. Here we perform single-cell chromatin profiling of the primitive gut tube to reveal organ-specific chromatin patterns that reflect the anatomical patterns of distinct organs. We generate a comprehensive map of epigenomic changes throughout gut development, demonstrating that dynamic chromatin accessibility patterns associate with lineage-specific transcription factor binding events to regulate organ-specific gene expression. Additionally, we show that loss of Sox2 and Cdx2, foregut and hindgut lineage-specific transcription factors, respectively, leads to fate shifts in epigenomic patterns, linking transcription factor binding, chromatin accessibility, and lineage fate decisions in gut development. Notably, abnormal expression of Sox2 in the pancreas and intestine impairs lineage fate decisions in both development and adult homeostasis. Together, our findings define the chromatin and transcriptional mechanisms of organ identity and lineage plasticity in development and adult homeostasis.

Risk of Acute Lung Injury after Esophagectomy.

To develop a new approach for identifying acute lung injury (ALI) in surgical ward setting and to assess incidence rate, clinical outcomes, and risk factors for ALI cases after esophagectomy. We also compare the degree of lung injury between operative and non-operative sides. Consecutive esophageal cancer patients (n=1022) who underwent esophagectomy from Dec 2012 to Nov 2018 in our hospital were studied. An approach for identifying ALI was proposed that integrated radiographic assessment of lung edema (RALE) score to quantify degree of lung edema. Stepwise logistic regression identified risk factors for postoperative ALI incidence. The degree of bilateral lung injury was compared using the RALE score. The approach for identifying ALI in surgical ward setting was defined as acute onset, PaO2/FiO2≤300 mmHg, bilateral opacities on bedside chest radiograph with a RALE score≥16, and exclusion of cardiogenic pulmonary edema. Incidence rate of ALI was estimated to be 9.7%. ALI diagnosis was associated with multiple clinical complications, prolonged hospital stay, higher medical bills, and higher perioperative mortality. Nine risk factors including BMI, ASA class, DLCO%, duration of surgery, neutrophil percentage, high-density lipoprotein, and electrolyte disorders were identified. The RALE score of the lung lobes of the operative side was higher than the non-operative side. A new approach for identifying ALI in esophageal cancer patients receiving esophagectomy was proposed and several risk factors were identified. ALI is common and has severe outcomes. The lung lobes on the operative side are more likely to be affected than the non-operative side.

Consensus for Thoracoscopic Lower Lobectomy: Essential Components and Targets for Simulation.

BACKGROUND: Despite demonstration of its clear benefits relative to open approaches, a video-assisted thoracic surgery technique for pulmonary lobectomy has not been universally adopted. This study aims to overcome potential barriers by establishing the essential components of the operation and determining which steps are most useful for simulation training. METHODS: After randomly selecting experienced thoracic surgeons to participate, an initial list of components to a lower lobectomy was distributed. Feedback was provided by the participants, and modifications were made based on anonymous responses in a Delphi process. Components were declared essential once at least 80% of participants came to an agreement. The steps were then rated based on cognitive and technical difficulty followed by listing the components most appropriate for simulation. RESULTS: After 3 rounds of voting 18 components were identified as essential to performance of a video-assisted thoracic surgery for lower lobectomy. The components deemed the most difficult were isolation and division of the basilar and superior segmental branches of the pulmonary artery, isolation and division of the lower lobe bronchus, and dissection of lymphovascular tissue to expose the target bronchus. The steps determined to be most amenable for simulation were isolation and division of the branches of the pulmonary artery, the lower lobe bronchus, and the inferior pulmonary vein. CONCLUSIONS: Using a Delphi process a list of essential components for a video-assisted thoracic surgery for lower lobectomy was established. Furthermore 3 components were identified as most appropriate for simulation-based training, providing insights for future simulation development.

Minimally invasive thymectomy for myasthenia gravis favours left-sided approach and low severity class.

OBJECTIVES: Complete thymectomy is a key component of the optimal treatment for myasthenia gravis. Unilateral, minimally invasive approaches are increasingly utilized with debate about the optimal laterality approach. A right-sided approach has a wider field of view, while a left-sided approach accesses potentially more thymic tissue. We aimed to assess the impact of laterality on perioperative and medium-term outcomes, and to identify predictors of a 'good outcome' using standard definitions. METHODS: We performed a multicentre review of 123 patients who underwent a minimally invasive thymectomy for myasthenia gravis between January 2000 and August 2015, with at least 1-year follow-up. The Myasthenia Gravis Foundation of America standards were followed. A 'good outcome' was defined by complete stable remission/pharmacological remission/minimal manifestations 0, and a 'poor outcome' by minimal manifestations 1-3. Univariate and multivariable logistic regression analyses were performed to assess factors associated with a 'good outcome'. RESULTS: Ninety-two percent of thymectomies (113/123) were robotic-assisted. The left-sided approach had a shorter median operating time than a right-sided: 143 (interquartile range, IQR 110-196) vs 184 (IQR 133-228) min, P = 0.012. At a median of 44 (IQR 27-75) months, the left-sided approach achieved a 'good outcome' (46%, 31/68) more frequently than the right-sided (22%, 12/55); P = 0.011. Multivariable analysis identified a left-sided approach and Myasthenia Gravis Foundation of America class I/II to be associated with a 'good outcome'. CONCLUSIONS: A left-sided thymectomy may be preferred over a right-sided approach in patients with myasthenia gravis given the shorter operating times and potential for superior medium-term symptomatic outcomes. A lower severity class is also associated with a 'good outcome'.