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PDF file - 403K, Supplemental Figure 1. Heat map of 203 metabolites in 21 pairs of CAFs and NFs. Supplemental Figure 2. The distributions of "relative" t-scores for the 203 metabolites categorized into 46 biochemical subgroupings. Supplemental Figure 3. Total LAMP 2A expression in 8 NF/CAF pairs determined by quantitative Western blotting. Supplemental Figure 4: Alteration in glucose concentration has no consistent effect on NF or CAF growth. Supplemental Figure 5. pH calibration curve constructed for rhodamine-fluorescein (R/F)dextran labeled lysosomes in human fibroblasts. Supplemental Figure 6 (A,B,C,D) Rhodamine-fluorescein (R/F) ratios in arbitrary fluorescent units histograms of ROIs of 4 example CAF/NF pairs.

XLSX file - 1691K, Supplemental Table of metabolomic data

ispartof: JOURNAL OF THORACIC DISEASE vol:15 issue:1 pages:204-213 ispartof: location:China status: published

Most patients with non–small cell lung cancer (NSCLC) do not achieve durable clinical responses from immune checkpoint inhibitors, suggesting the existence of additional resistance mechanisms. Nicotinamide adenine dinucleotide (NAD)–induced cell death (NICD) of P2X7 receptor (P2X7R)–expressing T cells regulates immune homeostasis in inflamed tissues. This process is mediated by mono–adenosine 5′-diphosphate (ADP)–ribosyltransferases (ARTs). We found an association between membranous expression of ART1 on tumor cells and reduced CD8 T cell infiltration. Specifically, we observed a reduction in the P2X7R + CD8 T cell subset in human lung adenocarcinomas. In vitro, P2X7R + CD8 T cells were susceptible to ART1-mediated ADP-ribosylation and NICD, which was exacerbated upon blockade of the NAD + -degrading ADP-ribosyl cyclase CD38. Last, in murine NSCLC and melanoma models, we demonstrate that genetic and antibody-mediated ART1 inhibition slowed tumor growth in a CD8 T cell–dependent manner. This was associated with increased infiltration of activated P2X7R + CD8 T cells into tumors. In conclusion, we describe ART1-mediated NICD as a mechanism of immune resistance in NSCLC and provide preclinical evidence that antibody-mediated targeting of ART1 can improve tumor control, supporting pursuit of this approach in clinical studies.

Objective The aim of this study was to report the safety, efficacy, and early results of tracheostomy in patients with COVID-19 and determine whether differences exist between percutaneous and open methods. Summary background data Prolonged respiratory failure is common in symptomatic patients with COVID-19, the disease process caused by infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Tracheostomy, although posing potential risk to the operative team and other healthcare workers, may be beneficial for safe weaning of sedation and ventilator support. However, short- and long-term outcomes remain largely unknown. Methods A prospectively collected database of patients with COVID-19 undergoing tracheostomy at a major medical center in New York City between April 4 and April 30, 2020 was reviewed. The primary endpoint was need for continued mechanical ventilation. Secondary outcomes included complication rates, sedation weaning, and need for intensive care unit (ICU) level of care. Patient characteristics, perioperative conditions, and outcomes between percutaneous and open groups were analyzed. Results During the study period, 67 consecutive patients underwent tracheostomy, including 48 males and 19 females with a median age of 66 years [interquartile range (IQR) 52-72]. Two surgeons alternated techniques, with 35 tracheostomies performed percutaneously and 32 via an open approach. The median time from intubation to tracheostomy was 23 days (IQR 20-26). At a median follow-up of 26 days, 52 patients (78%) no longer required mechanical ventilation and 58 patients (87%) were off continuous sedation. Five patients (7.5%) died of systemic causes. There were 11 total complications (16%) in 10 patients, most of which involved minor bleeding. There were no significant differences in outcomes between percutaneous and open methods. Conclusions Tracheostomy under apneic conditions by either percutaneous or open technique can be safely performed in patients with respiratory failure due to COVID-19. Tracheostomy facilitated weaning from continuous intravenous sedation and mechanical ventilation. Continued follow-up of these patients to ascertain long-term outcome data is ongoing.

Background Stapling across lung parenchyma may lead to tissue granulation, which could be confused radiographically with recurrence. We sought to define the time course and radiographic characteristics of such thickening and to determine their association with recurrence. Methods Patients who underwent limited resection for non-small cell lung cancer were included. Surveillance computed tomography scans were reviewed to characterize the morphology and size of staple line granulation tissue. Radiological and clinical findings were analyzed and univariate predictors of recurrence were examined. Results We characterized 78 patients for tissue granulation a total of 314 times in serial scans. On initial postoperative scans, 3.8% (n = 3) of staple lines showed no thickening and 17.9% (n = 14) showed thickening less than 2 mm, whereas 78.2% (n = 61) showed thickening 2 mm or greater. Of the 75 staple lines with thickening, soft tissue was characterized as linear in 32.0% (n = 24), focal along the pleura, hilum, or parenchyma in 24.0% (n = 18), and nodular in 44.0% (n = 33). Subsequent scans revealed that 25.3% of these areas (n = 19) did not change in shape or size over time, 58.7% (n = 44) showed regressive changes, and 16.0% (n = 12) showed progressive changes, the thickening of which in all 12 of these patients showed an increase in the largest dimension by 2 mm or greater. Among the 78 patients, 7.7% (n = 6) had biopsy-proven recurrence along the staple line. An increase in the largest dimension by 2 mm or greater (83.3% versus 9.7%; P = .001) and radiologic concern for malignancy (66.7% versus 11.1%; P = .001) predicted staple line recurrence. Conclusions Staple line thickening is a frequent occurrence after pulmonary limited resection, but rarely indicative of recurrence. The characteristics and initial size of granulation tissue do not predict recurrence. Increases in tissue 2 mm or greater at the staple line over time predict local recurrence, which typically occurs after a prolonged time interval.

In this report, we describe the use of custom-designed 3D-printed titanium implants to reconstruct the anterior chest wall, including the sternum and adjacent ribs, in two patients. These cases are the first to be reported in the United States, and they are among a handful performed around the world.

MINI In patients with esophageal cancer who received neoadjuvant chemoradiation, the total number of resected nodes is a significant determinant of improved survival regardless of clinical nodal status. OBJECTIVES The aim of this study was to explore the potential value of extended nodal-dissection following neoadjuvant chemoradiation (CRT), by analyzing data from the National Cancer Database (NCDB). BACKGROUND A CROSS-trial post-hoc analysis showed that the number of dissected lymph nodes was associated with improved survival in patients undergoing upfront surgery but not in those treated with neoadjuvant CRT. METHODS The NCDB was queried (2004-2014) for patients who underwent esophagectomy following induction CRT. Predictors of overall survival (OS) were assessed. The optimal number of dissected LNs associated with highest survival benefit was determined by multiple regression analyses and receiver-operating characteristic curve analysis. The whole cohort was divided into 2 groups based on the predefined cutoff number. The two groups were propensity-matched (PMs). RESULTS Esophagectomy following induction-CRT was performed in 14,503 patients. The number of resected nodes was associated with improved OS in the multivariable analysis (hazard ratio for every 10 nodes: 0.95 (95% confidence interval: 0.93-0.98). The cutoff number of resected LNs that was associated with the highest survival benefit was 20 nodes. In the PM groups, patients in the "≥20 LNs" group had a 14% relative-increase in OS (P = 0.002), despite having more advanced pathological stages (stage II-IV: 76% vs 72%, P < 0.001), and higher number of positive nodes (0-2 vs 0-1, P < 0.001). CONCLUSIONS The total number of resected nodes is a significant determinant of improved survival following induction CRT in patients with either node negative or node positive disease. In the matched groups, patients with higher number of resected lymph nodes had higher OS rate, despite having more advanced pathological disease and higher number of resected positive lymph nodes.

Cullin (CUL) 4A and 4B ubiquitin ligases are often highly accumulated in human malignant neoplasms and are believed to possess oncogenic properties. However, the underlying mechanisms by which CUL4A and CUL4B promote pulmonary tumorigenesis remain largely elusive. This study reports that CUL4A and CUL4B are highly expressed in patients with non–small cell lung cancer (NSCLC), and their high expression is associated with disease progression, chemotherapy resistance, and poor survival in adenocarcinomas. Depletion of CUL4A (CUL4A(k/d)) or CUL4B (CUL4B(k/d)) leads to cell cycle arrest at G(1) and loss of proliferation and viability of NSCLC cells in culture and in a lung cancer xenograft model, suggesting that CUL4A and 4B are oncoproteins required for tumor maintenance of certain NSCLCs. Mechanistically, increased accumulation of the cell cycle–dependent kinase inhibitor p21/Cip1/WAF1 was observed in lung cancer cells on CUL4 silencing. Knockdown of p21 rescued the G(1) arrest of CUL4A(k/d) or CUL4B(k/d) NSCLC cells, and allowed proliferation to resume. These findings reveal that p21 is the primary downstream effector of lung adenocarcinoma dependence on CUL4, highlight the notion that not all substrates respond equally to abrogation of the CUL4 ubiquitin ligase in NSCLCs, and imply that CUL4A(high)/CUL4B(high) may serve as a prognostic marker and therapeutic target for patients with NSCLC.

The influence of SARS-CoV-2 on surgery for non-small cell lung cancer needs to be understood to inform clinical decision making during and after the COVID-19 pandemic.This study reports on the 90-day rate of infection as well as the morbidity and mortality of lung surgery for cancer in a tertiary care hospital located in a pandemic epicenter.We conducted a retrospective review of a prospective database to identify consecutive patients who underwent lung cancer resection before (January 1, 2020-March 10, 2020, group 1; 57 patients) and during the COVID-19 pandemic (March 11, 2020-June 10, 2020, group 2; 41 patients). The primary end point was the occurrence of SARS-CoV-2 infection during the first 90-days after surgery. The secondary outcome measure was 90-day perioperative morbidity and mortality.Patient characteristics were not significantly different between the groups. Ninety-day COVID-19 infection rates was 7.3% (3 out of 41) for patients undergoing an operation during the pandemic and 3.5% (2 out of 57) in patients operated on immediately before the pandemic. All patients tested positive 10 to 62 days after the index surgical procedure following hospital discharge. Four COVID-19-positive patients were symptomatic and 4 out of 5 patients required hospitalization, were men, previous or current smokers with hyperlipidemia, and underwent a sublobar resection. Univariate analysis did not identify any differences in postoperative complications before or during the COVID-19 pandemic. Ninety-day mortality was 5% (2 out of 41) for lung cancer surgery performed during the pandemic, with all deaths occurring due to COVID-19, compared with 0% (0 out of 57) mortality in patients who underwent an operation before the pandemic.During the COVID-19 pandemic, COVID-19 infections occurred in 7.3% of patients who underwent surgery for non-small cell lung cancer. In this series all infections occurred after hospital discharge. Our results suggest that COVID-19 infections occurring within 90 days of surgery portend a 40% mortality, warranting close postoperative surveillance.

OBJECTIVE Report long-term tracheostomy outcomes in patients with COVID-19. STUDY DESIGN Review of prospectively collected data. METHODS Prospectively collected data were extracted for adults with COVID-19 undergoing percutaneous or open tracheostomy between April 4, 2020 and June 2, 2020 at a major medical center in New York City. The primary endpoint was weaning from mechanical ventilation. Secondary outcomes included sedation weaning, decannulation, and discharge. RESULTS One hundred one patients underwent tracheostomy, including 48 percutaneous (48%) and 53 open (52%), after a median intubation time of 24 days (IQR 20, 31). The most common complication was minor bleeding (n = 18, 18%). The all-cause mortality rate was 15% and no deaths were attributable to the tracheostomy. Eighty-three patients (82%) were weaned off mechanical ventilation, 88 patients (87%) were weaned off sedation, and 72 patients (71%) were decannulated. Censored median times from tracheostomy to sedation and ventilator weaning were 8 (95% CI 6-11) and 18 (95% CI 14-22) days, respectively (uncensored: 7 and 15 days). Median time from tracheostomy to decannulation was 36 (95% CI 32-47) days (uncensored: 32 days). Of those decannulated, 82% were decannulated during their index admission. There were no differences in outcomes or complication rates between percutaneous and open tracheostomy. Likelihood of discharge from the ICU was inversely related to intubation time, though the clinical relevance of this was small (HR 0.97, 95% CI 0.943-0.998; P = .037). CONCLUSION Tracheostomy by either percutaneous or open technique facilitated sedation and ventilator weaning in patients with COVID-19 after prolonged intubation. Additional study on the optimal timing of tracheostomy in patients with COVID-19 is warranted. LEVEL OF EVIDENCE 3 Laryngoscope, 131:E2849-E2856, 2021.

Because of recent lung cancer screening recommendations and corresponding insurance coverage, it is expected that more early stage cases will be identified that require thoracic surgery. However, these services may not be equally available in all regions. Our objective is to describe the availability of thoracic surgeons by examining geographic variation, rural-urban differences, and temporal changes before and after screening recommendation and insurance coverage policy changes.We examined the U.S. thoracic surgery workforce using the 2010 and 2014 Area Health Resource Files. We calculated the density of thoracic surgeons per 100,000 persons for each year at the state and county level. We performed descriptive statistics and developed maps highlighting changes over time and geographic regions.Despite an overall increase in thoracic surgeons from 2010 to 2014, we observed declining density nationwide (1.5% change) and in sparsely populated states. The difference in thoracic surgeon density widened slightly between 2010 from 0.80 per 100,000 compared with 0.84 per 100,000 in 2014 in all rural counties compared with urban counties (P.001 for both years). The difference in thoracic surgeon density was most pronounced between small adjacent rural and urban counties (0.95 and 0.96 per 100,000 for 2010 and 2014, respectively; P.001 for both years). The Northeast held a disproportionate share of the thoracic surgery workforce.Limited access to thoracic surgeons in rural areas is a concern, given an older and retiring surgical workforce, the higher burden of lung cancer in rural areas, and recent policy changes for screening reimbursement.

OBJECTIVES Sublobar resection (SLR) is an alternative to lobectomy for non-small-cell lung cancer (NSCLC). Outcomes following SLR for tumours >2 cm are not well described. We sought to determine the utilization of SLR for stage I tumours >2–5 cm in size and to determine predictors of outcome. METHODS We utilized the Surveillance, Epidemiology and End Results Program (SEER)-Medicare database to identify NSCLC patients with primary lung cancer ≥66 years old with stage I cancers >2–5 cm in size. We evaluated overall survival and cancer-specific survival among cohorts undergoing lobectomy versus SLR. Propensity score matching was performed. We compared patient characteristics and survival between groups. RESULTS For the study time period (2007–2012), among patients with tumours >2 cm and ≤5 cm (n = 4582), 3890 lobectomies (85%) and 692 SLR (15%) were performed. Patients undergoing SLR were older, had smaller tumours and more comorbidities. Patients undergoing lobectomy were much more likely to have any lymph nodes removed (95.6% vs 65.6%, P 10 nodes removed (29.6% vs 7.5%, P CONCLUSIONS In pathologically staged patients, SLR appears inferior to lobectomy for stage I NSCLC 2–5 cm in size. SLR is associated with less extensive lymphadenectomy and with worse survival than lobectomy in this cohort of patients. However, the 76.5% 3-year cancer-specific survival in patients undergoing SLR may exceed that of other localized treatment options for NSCLC. As such, SLR may be an appropriate option for high-risk patients with carefully staged 2–5 cm N0 tumours.

OBJECTIVES: Despite the recent increased rate of adoption of robotic approaches for the resection of thymic tumours, their use is still limited to large-volume academic centres. To date, a large-scale analysis of the robotic approach has not been performed. We assessed the recent trends and outcomes of robotic thymectomies in the United States compared to those of open and video-assisted thoracoscopic surgical (VATS) approaches. METHODS: The National Cancer Database was queried for patients who underwent resection for thymic tumours (2010–2014). Predictors of using the robotic approach were estimated by logistic regression analysis. Propensity matching analysis (robotic versus open and robotic versus VATS) was done (1:1—caliper 0.05), controlling for age, gender, comorbidity index, induction treatment, tumour size and tumour extension. RESULTS: A total of 2558 thymectomies were performed (robotic = 300, VATS = 280, open = 1978). The use of a robotic approach increased from 6% (2010) to 14% (2014). The number of hospitals performing at least 1 robotic thymectomy increased from 22 (2010) to 52 (2014). Independent predictors influencing the choice of a robotic approach included an academic research/integrated cancer programme [odds ratio (OR) 1.66, confidence interval (CI) 1.22–2.27], later year of diagnosis (2014; OR 2.23, CI 1.31–3.80) and a patient’s race (Asian) (OR 1.68, CI 1.05–2.69). A robotic approach was less likely to be utilized in midwestern hospitals (OR 0.65, CI 0.42–0.99), in larger tumours (cm) (OR 0.85, CI 0.80–0.90), with invasion of adjacent organs (OR 0.55, CI 0.37–0.82), thymic carcinoma (OR 0.62, CI 0.40–0.97) and following induction chemotherapy (OR 0.22, CI 0.08–0.61). In a propensity-matched analysis, there were no differences in the incidence of positive margins, nodal dissection, 30-day readmission rates and 30-/90-day mortality rates between the groups. However, a robotic approach was associated with fewer conversions compared to VATS, with a trend towards a shorter length of stay compared to an open approach. There were no differences in the 5-year overall survival rate between the matched groups (robotic 93% vs VATS 94%; P = 0.571; robotic 91% vs open 80%; P = 0.094). CONCLUSIONS: Over a 4-year study period, there was a significant increase in robotic utilization for thymectomies and an increase in the number of hospitals performing the procedure. In a matched analysis, a robotic approach was comparable to a VATS or an open approach. Current trends demonstrate increased robotic utilization for small thymomas with excellent perioperative results.

Background: There is a paucity of data regarding the role of wedge resection (WR) in the management of bronchial carcinoid (BC) tumors. In this study, we queried the Surveillance, Epidemiology, and End Results (SEER) database to compare the oncologic outcomes of patients with BC tumors treated with WR or anatomic resection. Methods: The SEER database was retrospectively reviewed for patients with BC treated with surgical resection between 1973–2013. Patients who underwent WR were compared to those who underwent lobectomy or segmentectomy (Lob/Seg). Patients with multiple primaries and those who underwent pneumonectomy or have an unspecified surgical procedure were excluded. Differences in demographics and clinicopathological data were compared using Chi (χ 2 ) test or Mann Whitney U test. Overall and cancer specific survival (OS, CSS) were estimated using Kaplan-Meier method and differences were compared using log-rank test. Cox-regression multivariable analysis (MVA) was performed to explore factors associated with worse CSS. Propensity-score matching analysis was done to compare survival differences between WR and Lob/Seg. Results: A total of 22,350 patients with BC were identified, of them 4,450 met our inclusion criteria (3,511 Lob/Seg, vs. 939 WR). The median age was 59.0 years [interquartile range (IQR) =49.0–68.0], 67.6% were females and the median tumor size was 2 cm (1.5–3 cm). 4,119 patients had typical carcinoid (TC) and 331 had atypical carcinoid (AC). WR was performed more frequently in elderly patients, females, lower lobe tumors, TC’s and in earlier stage disease. For patients with TC, there was no difference in CSS between WR and Lob/Seg in both the entire cohort (P=0.654) and in the propensity matched groups (P=0.900). However, for patients with AC, Lob/Seg was associated with better CSS compared to WR both in the entire cohort (P

Fine needle aspiration cytology (FNAC) of mediastinal masses allows for rapid on-site evaluation and the triaging of material for ancillary studies. However, surgical pathology is often considered to be the gold standard for diagnosis. This study examines the sensitivity and specificity of FNAC compared to a concurrent or subsequent surgical pathology specimen in 77 mediastinal lesions. The overall sensitivity for mediastinal mass FNAC was 78% and the overall specificity was 98%. For individual categories the sensitivity and specificity of FNAC was respectively as follows: inflammatory/infectious (33%, 99%), metastatic carcinoma (93%, 100%), lymphoma (84%, 97%), cysts (25%, 100%), soft tissue tumors (100%, 100%), paraganglioma (50%, 100%), germ cell tumor (100%, 99%), thymoma (87%, 94%), thymic carcinoma (60%, 100%), benign thymus (0%, 100%), and indeterminate (100%, 90%). For different locations within the mediastinum the sensitivity and specificity of FNAC was respectively as follows: anterosuperior mediastinum (80%, 98%), posterior mediastinum (33%, 95%), middle mediastinum (100%, 100%), and mediastinum, NOS (79%, 99%). Thus, mediastinal FNAC is fairly sensitive, very specific, and is a valuable technique in the diagnosis of mediastinal masses.

OBJECTIVES: Minimum volume standards for thoracic surgical procedures have been advocated to improve outcomes. However, such standards are controversial within the thoracic surgery literature, and the methodology to determine cut points between high- and low-volume hospitals has been criticized. Furthermore, while multiple studies have examined hospital volume and its relationship with outcomes, there have been very few attempts to study this issue from the perspective of the individual thoracic surgeon. The aim of this study was to determine if surgeon volume is associated with differences in outcomes using a large state-wide database. METHODS: The study utilized the New York State Department of Health Statewide Planning and Research Cooperative (SPARCS) data for analysis. Patients who underwent major lung resections including sublobar resection, lobectomy and pneumonectomy from 1995 to 2014 were included and were categorized into 3 subgroups based on the extent of resection. Patient characteristics included age, gender, race, insurance and comorbidities. Surgeon information was obtained by using a unique identifier. Average annual surgical volumes of sublobar resection, lobectomy and pneumonectomy were calculated separately and grouped into 3 categories based on the tertiles. Demographic data and comorbidities were compared between the various volume groups to analyse the resulting complications. Primary outcomes were in-hospital mortality and 30-day readmission. RESULTS: There were a total of 99 576 major lung resections performed between 1995 and 2014 in the SPARCS database. Among these, the majority were wedge or segmental resections (n = 54 953, 55.2%) followed by lobectomy (n = 40 421, 40.6%) and pneumonectomy (n = 4202, 4.2%). In-hospital mortality was significantly greater for low-volume surgeons compared to high-volume surgeons for all resection groups. Additionally, low-volume surgeons had higher 30-day readmission rates for patients undergoing lobectomy and pneumonectomy. However, low-volume surgeons as a group were more likely to operate on black patients and patients with Medicaid, and black race was an independent predictor of mortality across all resection groups. The vast majority of surgeons performing lobectomy (89.5%) were in the low-volume group. CONCLUSIONS: Low-volume surgeons had higher rates of in-hospital mortality compared to their high-volume counterparts. However, the vast majority of surgeons performing lobectomy (89.5%) were in the low-volume group, and low-volume surgeons operated on higher percentages of black patients. These findings suggest that minimal volume standards would significantly impact the current delivery of thoracic surgery in the US.

Routine mutation profiling for resected lung cancers is not widespread despite an increasing array of targeted therapies. We report the incidence of epidermal growth factor receptor mutations (EGFRmu+) in resected lung adenocarcinomas and their outcomes at a large North American cancer center to characterize this population now eligible for targeted adjuvant therapy.Among 1036 pulmonary resections performed between 2015 and 2019, 647 patients (62%) had adenocarcinomas that underwent molecular profiling by next-generation sequencing. Clinical and pathologic characteristics, along with survival, were analyzed.EGFRmu+ were identified in 238 patients (37%). Patients with EGFRmu+ were more likely to be Asian than those with EGFR wild-type (79/238 [33%] vs 37/409 [9%], respectively; P.001) and more likely to be never-smokers (115/238 [48%] vs 73/409 [18%], P.001). However, most patients with EGFRmu+ in our cohort were White (45%) and had a history of smoking (52%). A statistically nonsignificant trend was observed toward improved 3-year overall survival for pathologic stage IB to III cancers with EGFRmu+ (91% vs 77%, P = .09). Patients with pathologic stage IB lung cancers with EGFRmu+ had a 97% rate of 3-year disease-free survival, with only 1 recurrence in the first 3 years of follow-up. EGFR mutation subtype was not associated with survival differences.Although Asians and never-smokers comprised a disproportionately large group of patients with lung adenocarcinomas with EGFRmu+, most EGFR mutations within our cohort were found in patients who were White or with a smoking history, supporting a routine rather than selective approach to mutation profiling. Patients with surgically resected stage IA and IB lung adenocarcinomas enjoy excellent survival regardless of their mutational status.

Sublobar resection is frequently offered to patients with small, peripheral lung cancers, despite the lack of outcome data from ongoing randomized clinical trials. Sublobar resection may be a particularly attractive surgical strategy for screen-detected lung cancers, which have been suggested to be less biologically aggressive than cancers detected by other means. Using prospective data collected from patients undergoing surgery in the National Lung Screening Trial, we sought to determine whether extent of resection affected survival for patients with screen-detected lung cancer.The National Lung Screening Trial database was queried for patients who underwent surgical resection for confirmed lung cancer. Propensity score matching analysis (lobectomy vs sublobar resection) was done (nearest neighbor, 1:1, matching with no replacement, caliper 0.2). Demographics, clinicopathologic and perioperative outcomes, and long-term survival were compared in the entire cohort and in the propensity-matched groups. Multivariable logistic regression analysis was done to identify factors associated with increased postoperative morbidity or mortality.We identified 1029 patients who underwent resection for lung cancer in the National Lung Screening Trial, including 821 patients (80%) who had lobectomy and 166 patients (16%) who had sublobar resection, predominantly wedge resection (n = 114, 69% of sublobar resection). Patients who underwent sublobar resection were more likely to be female (53% vs 41%, P = .004) and had smaller tumors (1.5 cm vs 2 cm, P .001). The sublobar resection group had fewer postoperative complications (22% vs 32%, P = .010) and fewer cardiac complications (4% vs 9%, P = .033). For stage I patients undergoing sublobar resection, there was no difference in 5-year overall survival (77% for both groups, P = .89) or cancer-specific survival (83% for both groups, P = .96) compared with patients undergoing lobectomy. On multivariable logistic regression analysis, sublobar resection was the only factor associated with lower postoperative morbidity/mortality (odds ratio, 0.63; 95% confidence interval, 0.40-0.98). To compare surgical strategies in balanced patient populations, we propensity matched 127 patients from each group undergoing sublobar resection and lobectomy. There were no differences in demographics or clinical and tumor characteristics among matched groups. There was again no difference in 5-year overall survival (71% vs 65%, P = .40) or cancer-specific survival (75% vs 73%, P = .89) for patients undergoing lobectomy and sublobar resection, respectively.For patients with screen-detected lung cancer, sublobar resection confers survival similar to lobectomy. By decreasing perioperative complications and potentially preserving lung function, sublobar resection may provide distinct advantages in a screened patient cohort.

Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab.We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual.Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported.Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial.AstraZeneca.

In an increasingly connected world, healthcare is rapidly evolving to meet the needs of a growing patient population seeking information online. In the past few years, social media has erupted as a means of dissemination of health-related information between patients and healthcare providers alike. Patients online have access to communities and expert-opinion previously inaccessible. Cancer patients especially are empowered through online knowledge acquisition and interactions with support groups or advocacy groups. As patients continue seeking information online, social media has increasingly been recognized as an important potential physician-patient interface. Healthcare provider's presence on social media is growing to meet this need. Providers can utilize social media to easily reach patients to promote health-related information, guide important conversations like the importance of cancer screening and even improve health-related behaviors. Social media can also aid in conducting research through cultivation of networking, patient recruitment, and promotion of rapid dissemination of new results. Whether through "Tweet chats" or conference hashtags, the most up to date information is easily accessible and rapidly transmissible. Social media is positioned to bridge a gap of communication and accessibility between 21st century patients and physicians.

OBJECTIVES Oesophagectomy following induction chemoradiation therapy (CRT) is technically challenging. To date, little data exist to describe the feasibility of a robotic approach in this setting. In this study, we assessed national trends and outcomes of robotic oesophagectomy following induction CRT compared to the traditional open approach. METHODS The National Cancer Database was queried for patients who underwent oesophagectomy following induction CRT (2010–2014). Trends of robotic utilization were assessed by a Mantel–Haenszel test of trend. Propensity matching controlled for differences in age, gender, comorbidity, stage, histology and tumour location between the robotic and open groups. Overall survival was estimated by Kaplan–Meier analysis and compared by a log-rank test RESULTS Oesophagectomy following induction CRT was performed in 6958 patients. Of them, 555 patients (8%) underwent robotic surgery (5% converted to an open approach). Between 2010 and 2014, utilization of a robotic approach increased from 3% to 11% (Mantel–Haenszel, P CONCLUSIONS Robotic oesophagectomy after induction CRT is feasible and associated with shorter hospitalization compared to an open approach, and does not compromise the adequacy of oncological resection, perioperative outcomes or long-term survival.

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.

PURPOSE To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with locally advanced esophageal cancer. METHODS ASCO convened an Expert Panel to conduct a systematic review of the more recently published literature (1999-2019) on therapy options for patients with locally advanced esophageal cancer and provide recommended care options for this patient population. RESULTS Seventeen randomized controlled trials met the inclusion criteria. Where possible, data were extracted separately for squamous cell carcinoma and adenocarcinoma. RECOMMENDATIONS Multimodality therapy for patients with locally advanced esophageal carcinoma is recommended. For the subgroup of patients with adenocarcinoma, preoperative chemoradiotherapy or perioperative chemotherapy should be offered. For the subgroup of patients with squamous cell carcinoma, preoperative chemoradiotherapy or chemoradiotherapy without surgery should be offered. Additional subgroup considerations are provided to assist with implementation of these recommendations. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Three-field lymph node dissection for squamous cell cancer of the esophagus was pioneered by Japanese surgeons. With such an extended resection, 25–40% of patients will be found to have occult metastases to the recurrent laryngeal and deep cervical nodes. The Western experience with this technique, where adenocarcinoma is the predominant cell type, is limited to only a handful of centers. The prevalence of occult nodal metastases to the recurrent laryngeal and/or cervical nodes in esophageal adenocarcinoma may be as high as 20–30% and can be predicted by tumor location, depth of invasion, and by nodal metastatic burden. In experienced hands, three-field lymph node dissection can be performed safely with a hospital mortality of less than 5% and with only slightly increased overall morbidity compared to two-field dissections, although the risk of recurrent laryngeal nerve palsy is certainly higher. In the absence of adequately powered randomized trials comparing two- and three-field dissection, the existing retrospective data suggest that dissection of the third field, the recurrent laryngeal and/or cervical nodes, may improve staging and local control in patients with esophageal adenocarcinoma. We therefore recommend dissection of the third field in patients with T2 or deeper tumors above the lower third of the esophagus and in all patients with proven nodal disease along the lower esophagus.

It is evident that the frequency of nodal metastasis in part-solid lung adenocarcinoma is significantly low. For those cases, the prognostic impact of the lymph node dissection (LND) is highly controversial.We reviewed 462 clinical stage I radiologic part-solid lung adenocarcinoma patients who underwent lobectomy or segmentectomy with lymphadenectomy. Consolidation tumor ratio was evaluated for all patients. Extent of LND was classified into systematic/lobe-specific mediastinal LND (m-LND) and hilar LND only (h-LND). Prognostic significance of LND was assessed by a multivariable analysis using propensity score matching. Survival was calculated by the Kaplan-Meier method using the log rank test.The m-LND was performed in 314 patients (68%), and h-LND in 148 (32%). Overall survival (OS) was not significantly different between m-LND and h-LND (5-year OS, 94.2% versus 92.8%, p = 0.585), as shown in 92 matched pairs (5-year OS, 94.0% versus 93.2%, p = 0.845). Cox proportional hazards model revealed maximum standardized uptake value as an independently significant oncologic prognosticator (p = 0.003), but extent of LND was not (p = 0.997). Nodal involvement was found in 16 patients, and was exclusive in solid-dominant lesions (ie, 0.5 less than consolidation tumor ratio of 1.0 or less; 4.9%). Multivariable analysis revealed carcinoembryonic antigen and maximum standardized uptake value as significant predictors of nodal metastasis among solid-dominant lesions (0.001, 0.002). For 329 solid-dominant lesions (71%), however, survival was similar between m-LND and h-LND (5-year OS, 93.2% versus 87.1%, p = 0.097), and was proven in 58 matched pairs (5-year OS, 82.9% versus 82.9%, p = 0.822).Extent of LND was not associated with survival outcome of part-solid lung adenocarcinoma. Furthermore, it had no influence on the prognosis even for solid-dominant lesions by propensity score analysis, which could be selectively omitted based on both preoperative variables including carcinoembryonic antigen or maximum standardized uptake value.

Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on treatment with stereotactic body radiotherapy (SBRT) for patients with early-stage non–small-cell lung cancer. ASCO has a policy and set of procedures for endorsing and/or adapting clinical practice guidelines that have been developed by other professional organizations. Methods The ASTRO Evidence-Based Guideline for Stereotactic Body Radiotherapy for Early-Stage Non–Small-Cell Lung Cancer was reviewed for developmental rigor by methodologists. An ASCO Expert Panel updated the literature search and reviewed the guideline content and recommendations. Results The ASCO Expert Panel determined that the recommendations from the ASTRO guideline, published in 2017, are clear, thorough, and based on the most relevant scientific evidence. ASCO statements and minor modifications were added to enhance the applicability of the ASTRO guideline for the broader ASCO audience. Recommendations For standard operative risk patients with stage I NSCLC, SBRT is not recommended outside of a clinical trial. Lobectomy with systematic lymph node evaluation remains the recommended treatment, although a sublobar resection may be considered in select clinical scenarios. Recommendations are provided regarding the use of SBRT in high operative risk patients and for inoperative patients, including in challenging scenarios where tumors are: centrally located, > 5 cm in diameter, lacking tissue diagnosis, synchronous primary or multifocal, second primary after pneumonectomy, proximal to or involved with mediastinal structures, abutting the chest wall, or recurring after previous treatment. Qualifying statements are included to provide further guidance for implementation, and the importance of a discussion of treatment options among members of the multidisciplinary cancer care team is emphasized. Additional information is available at: www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .

Background Recurrent esophageal carcinoma (EC) has a dismal prognosis. However, prior studies showed that selected patients with isolated recurrence may benefit from definitive therapy. The aim of this study was to identify the predictors of postrecurrence survival (PRS) in patients with isolated EC recurrence who were treated with curative intent. Methods A retrospective review of a prospective database (1988 to 2015) was performed to identify all recurrent EC patients after curative esophagectomy. Demographic and clinicopathologic data were reviewed. The probability of PRS was estimated with the Kaplan-Meier method. Predictors of PRS after definitive therapy for isolated EC recurrence were determined by the multivariable Cox proportional hazards model. Results Of the 640 curative esophagectomies, 241 patients (37.7%) experienced recurrences (median follow-up 50 months). Fifty-six patients (9%) received definitive treatment of isolated EC recurrence (31 were treated surgically with or without chemotherapy-radiotherapy [CTRT] and 25 received definitive CTRT alone). Median time to recurrence (TTR) was 19 months. The 1- and 3-year PRSs were 78% and 38% (median survival 26 months). On multivariable analysis; TTR was the only significant independent predictor for survival after recurrence (hazards ratio 0.98, 95% confidence interval: 0.96 to 0.99, p = 0.034). No pronounced difference was found in disease-free survival or in PRS between recurrent patients treated with operation with or without CTRT and patients who received definitive CTRT. Conclusions A select subgroup of patients with isolated EC recurrence can be treated with curative intent. TTR was the best predictor for PRS.

OBJECTIVES Pulmonary sarcomatoid carcinoma (PSC) is a rare malignant neoplasm that accounts for a small percentage of non-small-cell lung carcinoma (NSCLC). At least 10% of PSCs has a spindle and/or giant cell component, which is often associated with a poor prognosis. We reviewed the Surveillance, Epidemiology, and End Results (SEER) database for the clinicopathological characteristics and surgical outcomes of PSCs. METHODS The SEER database (1973-2013) was queried for PSC. A comparison between PSC and other NSCLC patients was performed. Cox regression for overall survival (OS) and logistic regression for node-positive predictors were performed. A propensity-matched (1:2) analysis (including age, gender, grade and stage) among surgically treated cases was done to compare OS in PSC versus other NSCLCs. RESULTS A total of 955 899 NSCLC patients were identified; of these, 4987 patients had been diagnosed with PSC (0.52%). Men represented 60.9% of cases, with a median age of 68 years. The median size of the tumour was 5 cm and 3.5 cm in PSCs and NSCLCs, respectively (P

254 Background: Quality improvement (QI) in cancer care delivery requires understanding the setting, clearly defining problem(s), and identifying targeted solutions. The Association of Community Cancer Centers (ACCC) conducted a national project to identify and provide guidance on key issues in care for patients with stage III/IV non-small cell lung cancer (NSCLC). We report the problems and solutions identified after a mixed-methods baseline data evaluation. Methods: The multi-phase ACCC QI initiative was guided by an expert steering committee. A request for applications was advertised to all ACCC programs, with committee members ranking each site in pre-specified categories (ex., replicability, practice champion engagement). After selection of sites, baseline data assessed programs’ patient populations, current care delivery practices, processes of care, and biomarker testing rates. A full-day workshop was conducted with multidisciplinary team members and expert faculty to review baseline data, refine problem statements, and identify site-specific QI solutions. Results: The 6 participating US sites were regionally diverse with a rural/urban mix. In baseline data, median patient ages were 65-72 years and patients treated were 50% stage III/50% stage IV. Biomarker testing practices, use of multidisciplinary tumor board, and clinical care pathways varied across sites. Five key QI areas were identified: 1.Management of immune related adverse events (irAE), 2.Biomarker testing, 3.Emergency visit management (EVM), 4.Access to clinical trials, and 5.Smoking cessation. Two sites identified problems with irAE management during immunotherapy (IT). The first identified needs for proactive symptom identification, assessment, and management. Solutions included: 1. a patient questionnaire to identify early signs of irAEs and 2. pilot testing a nurse-administered questionnaire. A second site identified that front-line clinicians may not be properly identifying possible irAEs. Solutions included: 1. form an IT toxicity working group and 2. educate front-line clinicians about irAEs. Two sites focused on biomarker testing. The first problem identified was inefficient tracking of testing results. Solutions were: 1. assign a nurse navigator to track, enter, and communicate test results and 2. proactively coordinate appointments for patients with positive test results. The second site identified delayed care when inadequate tissue was obtained. Solutions included: 1. pathology-driven reflex testing and 2. liquid biopsy order at diagnosis. Similar problems/solutions were developed for EVM, clinical trial access, and smoking cessation. Conclusions: Challenges in lung cancer care delivery can be identified and addressed using an intentional QI approach. Clearly defining the problem and identifying potential solution(s) are critical steps and should occur before implementation.

OBJECTIVES We sought to examine changes over time in the proportion of never smokers among surgical lung cancer patients and to determine whether smoking history affected survival. METHODS We performed a retrospective review of a prospective database. Among never smokers and smokers, demographic and pathological data were compared. Disease-free survival (DFS) and cancer-specific survival (CSS) were analysed. Propensity matching was performed for further comparison of survival in a matched cohort. RESULTS Among 3232 patients, we identified 718 never smokers (22%), 993 smokers with

Background Despite the relatively high sensitivity of fluorodeoxyglucose-positron emission tomography (PET) and computed tomography (CT) scans used for staging of non-small cell lung cancer (NSCLC), a subset of patients with peripherally located clinical T1a N0 will be upstaged due to pathologic nodal disease. It is important to study this risk of upstaging, especially if local treatments, such as wedge resection or stereotactic body radiation therapy, are potential treatment modalities. Our aim was to determine the rate of pathologic N1/N2 disease in peripherally located clinical T1a N0 NSCLC and predictive factors for nodal metastasis. Methods A retrospective review of a prospective database (2000 to 2015) identified 1,342 patients with clinical T1a N0 NSCLC, and 914 (68%) underwent lobectomy. Among this group, 449 patients had peripherally located tumors and were deemed node negative by fluorodeoxyglucose-PET/CT scan. The relationship between clinicopathologic features and the PET maximal-standardized uptake value (SUVmax) of the primary tumor was investigated. Predictors for nodal metastasis were determined by multivariable logistic regression analysis. The receiver operating characteristic curve was used to assess the cutoff value of PET-SUVmax on the incidence of nodal metastasis. Results Nodal metastasis was detected in 9.6% (43 of 449) of the patients: 4.5% (n = 20) had pN1 and 5.1% (n = 23) had pN2 metastasis. The relationship between SUVmax and development of pathologic nodal metastasis was calculated using the receiver operating characteristic curve with cutoff point at SUVmax of 3.3. In multivariable analysis, PET-SUVmax exceeding 3.3 was the only independent predictor for N1/N2 metastasis ( p = 0.016). Disease-free survival showed a trend of poor survival for patients with nodal metastasis ( p = 0.068). Conclusions High PET-SUVmax of the primary tumor is associated with elevated risk of nodal disease for peripheral T1a N0 NSCLC patients. Further diagnostic procedures, such as endobronchial ultrasound, may be required, especially if wedge resection or stereotactic body radiation therapy are being considered.

Reduced PTEN protein is linked to tumorigenesis. Here, Chen et al. show that the nuclear transport receptor Importin-11 separates PTEN from degradation machinery. IPO11 mutant mice exhibit PTEN degradation, lung adenocarcinoma, and prostate neoplasia. In human prostatectomy patients, IPO11 status predicts disease recurrence and metastasis., Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, is a limiting factor for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele.