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Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7–43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6–61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129.)

For extrathoracic malignant neoplasms that have metastasized to the lungs, previous investigations have demonstrated both oncologic and survival benefits after pulmonary and repeated metastasectomy. Little is known about the feasibility of incrementally increasing numbers of subsequent metastasectomy procedures.We conducted a retrospective review of patients who underwent ≥3 pulmonary resection procedures for recurrent, metachronous metastatic disease of nonlung primary malignant neoplasms at a single institution between 1992 and 2020. Primary outcomes collected pertained to safety and feasibility, including estimated blood loss (EBL), hospital length of stay, and details of postoperative complications.There were 117 patients who met inclusion criteria, having undergone at least 3 metastasectomy operations, with 55 (47.1%) undergoing a fourth operation and 20 (17.1%) undergoing a fifth operation. EBL did not differ between first and second operations (106.6 mL vs 102.5 mL; P = .76). It was, however, significantly greater at third operations (102.5 mL vs 238.7 mL; P = .000016). We noted an increase in wound complications between the second and third operations (0.9% vs 6.8%; P = .02) and incremental increases in likelihood of prolonged air leak with each subsequent operation. The need for reoperation was low for all and similar between operations. Importantly, hospital length of stay was similar for all procedures, as were the frequencies of hospital readmission.Third-time redo pulmonary metastasectomy can be performed safely and feasibly in select patients. Further repeated resection should remain a therapeutic option for patients, although risks for potentially longer operating time, greater EBL, and prolonged air leaks may be anticipated.

Background The assumption that increased [18F] fluoro-2-deoxy-d-glucose (FDG) uptake in hilar nodes on PET/CT imaging is indicative of distant metastasis can result in palliative rather than curative care in patients with esophageal cancer. This study aims to determine the significance of increased FDG uptake in hilar nodes in patients with potentially curable, locally advanced disease at initial staging. Methods We included patients with biopsy-proven esophageal carcinoma who had pretreatment FDG-PET/CT at initial staging, and follow-up imaging >1 year. We excluded patients with distant hematogeneous metastases. Hilar nodes were considered concerning for metastatic disease when SUV max was >2.5 or FDG uptake was visually > mediastinal background were examined. Results We reviewed FDG-PET CT scans from 806 patients treated for esophageal cancer from 2010-2018 and identified 42 patients with FDG avid hilar adenopathy. Thirteen patients underwent histological assessment and 29 were followed with imaging. None of the 42 patients were found to have distant metastatic disease on initial work up and all were treated curatively. In follow up, 2/42 patients eventually manifested hilar nodal metastases after treatment; one who had a biopsy-negative hilar node at initial staging and another who did not have a biopsy of the hilar node. Conclusions Increased FDG uptake in hilar nodes in patients with localized esophageal cancer was not indicative of non-regional nodal metastasis. Patients in these situations should be approached with curative intent. The need for biopsy of FDG avid hilar nodes in this cohort should be carefully considered due to the low diagnostic utility.

The lung represents a frequent site of spread for metastatic melanoma, which has historically been managed with surgical resection achieving promising outcomes. We hypothesized that the role of surgery in the management of melanoma pulmonary metastases (MPM) is evolving among the development of less invasive diagnostic and novel systemic therapeutic strategies.A single-center thoracic surgery database was reviewed and patients who underwent surgical resection of MPM between 1998 and 2019 were identified. Demographic, clinicopathologic, and surgical data were collected and analyzed, as were the annual volumes and indications for surgical resection. A Cochran-Armitage test was used to assess the trend in surgical indication.Three hundred and seventy seven surgical procedures for MPM were performed during the years of study in the care of 347 patients. Patients were predominantly male, with a mean age of 59.3 y. The mean number of annual resections was 17 and while this number initially increased from six in 1998 to a peak of 39 cases in 2008, a decline was subsequently observed. Diagnostic resection decreased from 22% in 1998-1999 to 5% at the peak of procedures in 2008-2009 and to 0 in 2018-2019 (P = 0.02). Curative resection increased from 44% in 1998-1999 to 73% in 2008-2009 (P 0.001) and remained the dominant reason for surgery in later years.Surgical indications in the management of MPM have transformed in conjunction with systemic modalities, and the volume of resections has decreased in the modern era. Despite innovations in systemic management and shifting goals of operative interventions, surgeons continue to play a vital role in caring for these patients with an advanced disease.

Background Although smokers are at an increased risk for postoperative pulmonary complications after thoracic surgery, the relationship between cessation timing and postoperative pulmonary complications has not been explored in an era of enhanced recovery protocols and active tobacco cessation programs. Because a strong preference exists among thoracic surgeons to delay surgery to continued smokers, we sought to evaluate this relationship in a modern era. Methods Patients undergoing lung resection for a diagnosis of non-small cell lung cancer from 2012 to 2017 were identified. Multivariable logistic regression was used to evaluate preoperative tobacco cessation timing to determine the impact on postoperative pulmonary complications. Results In all, 1038 ever smokers were identified. Patients were current smokers in 30 (3%) instances, and among former smokers, the preoperative cessation interval was 0 to 14 days in 10% (104), more than 14 days to 1 month in 6% (62), more than 1 month to 1 year in 18% (189), more than 1 to 5 years in 10% (107), and more than 5 years in 53% (546). Pulmonary complications occurred in 269 patients (26%). Multivariable analysis revealed that no group of recent or long-term quitters had superior outcomes in terms of pulmonary complications when evaluating various periods of abstinence in comparison with continued smokers and active quitters. Conclusions In an era of enhanced recovery protocols, minimally invasive surgery, and active tobacco cessation programs that may help patients to cut back, our data do not support the practice of delaying or denying surgery to patients who have difficulty quitting completely. Perioperative cessation counseling should be aimed at long-term benefits, including reduction of disease recurrence and secondary malignancies.

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Supplementary Data from Immunohistochemical Expression of Estrogen and Progesterone Receptors Identifies a Subset of NSCLCs and Correlates with EGFR Mutation

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Purpose:Nintedanib enhances the activity of chemotherapy in metastatic non–small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint.Patients and Methods:Eligible patients had stage IB (≥4 cm)–IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%.Results:Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%–32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%–54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%–93%) and 91% (95% CI, 79%–100%), respectively. Most frequent treatment-related grade 3–4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018).Conclusions:Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies.See related commentary by Blakely and McCoach, p. 3499

Purpose: We performed a study to determine if a fluorescence in situ hybridization (FISH)–based assay using isolated peripheral blood mononuclear cells (PBMCs) with DNA probes targeting specific sites on chromosomes known to have abnormalities in non–small cell lung cancer (NSCLC) cases could detect circulating genetically abnormal cells (CACs).Experimental Design: We evaluated 59 NSCLC cases with stage I through IV disease and 24 controls. PBMCs and matched tumors were hybridized with 2 two-color [3p22.1/CEP3 and 10q22.3 (SP-A)/CEP10) and 2 four-color [CEP3, CEP7, CEP17, and 9p21.3 (URO); and EGFR, c-MYC, 6p11-q11, and 5p15.2 (LAV)] FISH probes. Percentages of cytogenetically abnormal cells (CACs) in peripheral blood and in matched tumor specimens were quantified by using an automated fluorescent scanner. Numbers of CACs were calculated based on the percentage of CACs (defined as PBMCs with genetic abnormalities) per milliliter of blood and expressed per microliter of blood.Results: Patients with NSCLC had significantly higher numbers of CACs than controls. Mean number of CACs ranged from 7.23 ± 1.32/μL for deletions of 10q22.3/CEP10 to 45.52 ± 7.49/μL for deletions of 3p22.1/CEP3. Numbers of CACs with deletions of 3p22.1, 10q22.3, and 9p21.3, and gains of URO, increased significantly from early to advanced stage of disease.Conclusions: We have developed a sensitive and quantitative antigen-independent FISH-based test for detecting CACs in peripheral blood of patients with NSCLC, which showed a significant correlation with the presence of cancer. If this pilot study can be validated in a larger study, CACs may have a role in the management of patients with NSCLC. Clin Cancer Res; 16(15); 3976–87. ©2010 AACR.

OBJECTIVES To assess the impact of intraoperative dexmedetomidine and ketamine on postoperative pain and opioid consumption within an ERAS program in thoracic pulmonary oncologic surgery. DESIGN Retrospective, propensity-score matched analysis SETTING: Enhanced Recovery After Surgery (ERAS) program. PARTICIPANTS Patients undergoing thoracic pulmonary oncologic surgery between March 2016 and April 2020. INTERVENTIONS Continuous infusion of dexmedetomidine and ketamine. MEASUREMENTS & MAIN RESULTS The authors initially analyzed data of 1,630 patients undergoing thoracic pulmonary oncologic surgery within their ERAS program. In total, 117 matched pairs were included in this analysis. Patients in the intraoperative dexmedetomidine + ketamine group were more likely to be opioid-free (76.6% vs 60.9%, P

Summary Background A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND). Methods This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0–2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov , NCT02357992 . Findings Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9–5·8). Overall survival was 91% (95% CI 85–98) at 3 years and 87% (79–95) at 5 years. SABR was tolerated well, with no grade 4–5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85–98) at 3 years and 84% (76–93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45–1·65], p=0·65) from a multivariable analysis. Interpretation Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended. Funding Varian Medical Systems and US National Cancer Institute (National Institutes of Health).

Objective Minimally invasive procedures coupled with enhanced recovery pathways enable faster postoperative recovery and shorter hospitalizations. However, patients may experience unexpected concerns after return home, prompting after-hours calls. We aimed to characterize concerns prompting after-hours calls to improve discharge strategies. Methods A single-institution, retrospective review was conducted of thoracic surgical patients from 11/4/2019 to 6/14/2020. Records were reviewed and elements of patient demographics, surgical procedures, postoperative courses, reasons for calls, and outcome of calls were collected. We compared characteristics of patients who made after-hours calls to those who did not, and performed multivariable analysis to identify characteristics associated with making an after-hours call. Results During the study period, 379 patients underwent thoracic surgical procedures, among whom 88 (23.2%) initiated after-hours calls. Of these, 62 (70%) addressed patient symptoms, while 26 (30%) addressed patient questions including drain management, medications, and hospital policy questions. Patients making after-hours calls more frequently had undergone complex operations (26.1% vs 8.2%, P = 0.001), and were less likely to have received a standardized, clinician-initiated post-discharge telephone follow-up (29.5% vs 54.3%, P < 0.001). Complex operations increased likelihood of after-hours calls (OR: 3.33, 95% CI: 1.69-6.57, P < 0.001), while receipt of clinician-initiated telephone follow-up decreased likelihood of after-hours calls (OR: 0.38, 95% CI: 0.22-0.64, P < 0.001). There were no differences in emergency visits between the 2 groups (11% vs 8%, P = 0.370). Conclusions Despite efforts to optimize patient symptoms and knowledge prior to discharge, a substantial number of patients still have concerns after discharge. Many after-hours calls are related to knowledge gaps that may be addressed with improved predischarge education. Moreover, clinician-initiated telephone follow-up shows benefit in reducing after-hours calls.

Patients with esophageal cancer undergoing esophagectomy have an improved survival over time, however adverse events associated with the use of a gastric conduit are increasingly being reported. Delayed gastric emptying (DGE) is an esophagectomy-related complication which can decreased quality of life by causing debilitating gastrointestinal symptoms and malnutrition. The aim of our study was to evaluate the effect of endoscopic intrapyloric botulinum (BT) injection in combination with pyloric balloon dilation in patients with DGE following distal esophagectomy at our tertiary cancer center. Patients with a prior history of distal esophagectomy who had also undergone endoscopic BT injection with pyloric balloon dilation by a single endoscopist between 2007 and 2017 were included in the study. One hundred units of BT were injected endoscopically into the pylorus in four quadrants using an injection needle. Following BT injection, a standard through-the-scope balloon was passed to the pylorus and inflated to a maximum diameter of 12–20 mm. For patients who underwent repeat procedures, the symptomatic outcomes were assessed and documented by the endoscopist; for the other patients, the electronic medical records were reviewed. A total of 21 patients undergoing 44 endoscopic intrapyloric botox injections combined with balloon dilatations were identified. The patients underwent the procedures at a median of 22 months (range, 1–108 months) after esophagectomy. The procedures were performed only once in 43% of the patients; 43% patients underwent the procedure twice, while 14% had it multiple times (>2). Overall, intrapyloric BT injection coupled with balloon dilation was a safe procedure, without any major immediate or delayed (1 month) procedure-related adverse events. Eighteen patients (85%) reported a significant overall improvement in symptoms from the initial presentation. One patient (5%) showed no improvement, whereas in two (10%) patients responses were not available. In our particular cohort of patients, the interventions of endoscopic intrapyloric BT injection with pyloric balloon dilation proved to be very beneficial, leading to significant symptomatic improvement. The balloon dilation after BT injection might have resulted in better diffusion of the BT into the pyloric sphincter complex, possibly increasing its therapeutic effects. Further prospective studies are needed to validate these results.

Objectives Although colorectal cancer bowel segment location has been shown to independently predict the outcomes in early stage disease, it has not been previously studied in the setting of pulmonary metastases. We sought to determine whether colorectal cancer location affects survival after pulmonary metastasectomy. Methods Patients who had undergone pulmonary metastasectomy for colorectal cancer at a single institution from 2011 to 2018 were reviewed. Univariable and multivariable Cox regression analyses were performed to identify predictors of overall survival and disease-free survival. The Kaplan-Meier survival method was used to determine differences between groups. Results A total of 194 patients were evaluated. The median follow-up, survival time, and 5-year survival rate were 36.8 months, 75.8 months, and 57%, respectively, and 122 patients (63%) had experienced disease recurrence at any location. On univariable analysis, age, primary tumor location, pulmonary nodule size, ≥3 pulmonary nodules, and intrathoracic nodal disease were associated with overall survival. On multivariable analysis, patients with left-sided tumors experienced a survival benefit (hazard ratio, 0.31; P = .036). Kaplan-Meier analysis revealed a median survival time of 90 months (95% confidence interval, 82 months to not reached) compared with 55 months (95% confidence interval, 49 months to not reached) for patients with left-sided and rectal tumors, respectively, after metastasectomy (P = .078). Location was not associated with disease-free survival on Cox multivariable regression. Conclusions We found that left-sided colorectal cancer is associated with prolonged survival after pulmonary metastasectomy. Future investigations are required to determine the validity of such findings, including the effect of location in the prognostication for patients who are candidates for pulmonary metastasectomy.

Study Design: Retrospective case series. Objective: To determine predictive factors of overall survival (OS) and local recurrence (LR), report complications, and assess the impact of complications on survival, recurrence, and function in patients undergoing en bloc resection of sacral chordoma. Methods: This retrospective case series was obtained from a prospective database (1995-2016). All patients underwent en bloc resection of sacral chordoma. Demographic, perioperative, and complication data were collected. Outcomes included: overall survival(OS), local recurrence(LR), and complications. Survival analysis with multivariable cox regression was performed. Results: Among 50 patients, median follow-up was 5.3 years (range = 1.3-17.2). The majority (82%) underwent a negative margin resection. Survival: 17 patients died (34%) with a median OS of 10.0 years (range = 1.3-17.2). Multivariable cox regression revealed that a negative margin resection was not significantly associated with improved survival (HR = 3.35, 95%CI 0.87-12.80, P = .078). Recurrence: 20 patients (40%) experienced LR with a median time of 6.2 years (range = 0-16.9). Multivariable cox regression revealed that a negative margin resection was associated with a significant decreased risk of LR (HR = 4.96, 95%CI 1.84-13.34, P = 0.002,). A 62% overall complication rate was seen (42% major), with 26% reoperation rate. Of the reoperations, 54% were delayed (>6 weeks after the index surgery). Multivariable cox regression demonstrated that neither major complication nor reoperation significantly impacted OS (HR = 0.62, 95%CI 0.22-1.79, P = 0.380), LR (HR = 1.28, 95%CI 0.49-3.36, P = 0.611), or functional outcomes (OR = 2.94, 95%CI 0.25-34.8, P = 0.393). Conclusions: Negative margin resection was associated with decreased LR. Neither major complication nor reoperation significantly impacted OS, LR, or functional outcome. Though additional studies are needed, it appears that despite the morbidity associated with sacral chordoma resection, the long-term clinical outcomes are favorable.

BACKGROUND: For patients with bilateral pulmonary metastases, staged resections have historically been the preferred surgical intervention. During the spring of 2020, the COVID-19 pandemic made patient travel to the hospital challenging and necessitated reduction in operative volume so that resources could be conserved. We report our experience with synchronous bilateral metastasectomies for the treatment of disease in both lungs. METHODS: Patients with bilateral pulmonary metastases who underwent simultaneous bilateral resections were compared with a cohort of patients who underwent staged resections. We used nearest-neighbor propensity score (1:1) matching to adjust for confounders. Perioperative outcomes were compared between groups using paired statistical analysis techniques. RESULTS: Between 1998 and 2020, 36 patients underwent bilateral simultaneous metastasectomies. We matched 31 pairs of patients. The length of stay was significantly shorter in patients undergoing simultaneous resection (median 3 vs. 8 days, p < .001) and operative time was shorter (156 vs. 235.5 min, p < .001) when compared to the sum of both procedures in the staged group. The groups did not significantly differ with regard to postoperative complications. CONCLUSION: In a carefully selected patient population, simultaneous bilateral metastasectomy is a safe option. A single procedure confers benefits for both the patient as well as the hospital resource system.

Websites are primary sources of information for prospective trainees. However, little is known regarding the information deemed most important to cardiothoracic (CT) surgery interviewees when evaluating a program. The objectives of this study were to (1) report informational content important to CT surgery interviewees on a fellowship website and (2) improve the quality of a specific program's website.Study investigators conducted a survey of interviewees at a traditional 2-year CT surgery fellowship program. Questions were asked to elicit what information interviewees considered important to include in a program website and to identify gaps in the website's content. After administering the survey to 2018 fellowship interviewees, the website was redesigned, and the survey was readministered to 2019 fellowship interviewees.A total of 49 interviewees completed the survey (response rate, 90.7%); 45 (91.8%) of these interviewees had previously visited the program's website. Interviewees reported that the most important information they sought when accessing fellowship websites included faculty profiles (n = 47), rotation schedules (n = 33), current fellows' profiles (n = 29), and past fellows' profiles (n = 26). The website was revamped to include content across each of these domains. After website redesign, there was significant improvement in interviewees reporting that they found the information they sought (mean score, 3.56 to 4.64; P.001) and that the website was useful (mean score, 3.67 to 4.77; P.001) compared with the previous year.CT surgery fellowship websites are accessed by the majority of interviewees and are a critical source of program information. Optimizing website design and content on the basis of survey feedback objectively improved the usefulness of the program website to interviewees.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC. Neoadjuvant treatment with nivolumab plus ipilimumab is well tolerated and demonstrates clinical efficacy in patients with early stage lung cancer.

Most patients undergoing esophagectomy will experience intermittent reflux of gastric and biliary content into the remnant esophagus postoperatively. The incidence of new or recurrent intestinal metaplasia following chemoradiation and surgery has not been well-described. Furthermore, post-resection guidelines do not exist regarding surveillance for metaplasia in the esophageal remnant. Patients undergoing Ivor Lewis esophagectomy after concurrent chemoradiation for a diagnosis of esophageal adenocarcinoma from 2006 to 2018 were identified. Pathology records were reviewed for the presence of intestinal metaplasia on pretreatment biopsies, surgical specimen, or post-resection biopsies. In total, 619 patients met inclusion criteria, including 267 (43%) who had intestinal metaplasia noted either prior to or at the time of esophagectomy. The median duration of metaplastic disease prior to resection was 4.4 months. During a median follow-up time of 28 months (interquartile range, 12–60), intestinal metaplasia was noted in the remnant esophagus in 12 (2%) patients, 7 of whom had a prior history of metaplasia. Local recurrence of adenocarcinoma was also uncommon, and occurred in 37/577 (6%) of patients with complete resections, with similar event rates among those with and without a prior history of metaplasia (14/249 [6%] vs. 23/328 [7%], p = 0.614). Our findings suggest that despite several factors predisposing to mucosal damage following esophagectomy, occurrence of new intestinal metaplasia after trimodality therapy in our patient population appears to be rare, even among patient with a previous history of this pathologic finding, which may have significant implications for surveillance and cost-savings after resection.

Enhanced recovery after surgery protocols are known to accelerate immediate postoperative recovery and to facilitate healing. Our purpose was to further characterize benefits after discharge from the hospital.An institutional database was queried to identify patients with clinical stage I non-small cell lung cancer who were classified as Eastern Cooperative Oncology Group performance status 0 and received a lobectomy between January 1, 2000, and August 31, 2020. The presence or absence of symptoms (ie, pain, shortness of breath, fatigue, among others) and performance status were recorded by clinic staff at the time of follow-up. Cox proportional hazards regression was used to identify factors associated with postdischarge recovery, which was defined as a return to Eastern Cooperative Oncology Group performance status 0 in the follow-up clinic.A total of 935 patients were identified (pre-enhanced recovery after surgery, 523; transition period, 222; enhanced recovery after surgery, 190). Outpatient performance status data were recorded in 774 of 935 patients (83%). The number of patients reporting symptoms at the 1-month follow-up appointment decreased from the pre-enhanced recovery after surgery to transition to the enhanced recovery after surgery period (60%, 50%, and 33%, respectively, P .001), predominately due to less pain reported (43%, 35%, and 23%, respectively, P = .001). At 6-month follow-up, these differences were no longer statistically significant. Surgery during the enhanced recovery after surgery period was independently associated with significant improvements in postdischarge recovery (hazard ratio, 1.60, 95% confidence interval, 1.29-2.00), and the presence of coronary artery disease (hazard ratio, 0.69, P = .006) and receipt of thoracotomy (hazard ratio, 0.84, P = .036) were independently associated with delayed postdischarge recovery.Enhanced recovery is associated with significant improvements in postdischarge recovery of performance status.

BACKGROUND: Mutations in the serine-threonine kinase LKB1/STK11 have been implicated in mediating resistance to checkpoint blockade among patients with advanced lung adenocarcinoma. We sought to examine the associations between clinicopathologic characteristics, tumor LKB1 expression, features of the immune microenvironment, and postoperative prognosis among patients with early-stage lung adenocarcinoma undergoing surgical therapy. METHODS: Formalin-fixed, paraffin-embedded specimens of patients undergoing resection of stage I-III, chemotherapy-naïve adenocarcinomas (1997–2008) were analyzed using tissue microarray sectioning. Sublobar resections were excluded. Intratumoral LKB1/STK11 expression was quantified as H-score. In a subset, tumor associated immune cell populations were quantified using whole tumor sections in peritumoral and intratumoral compartments. RESULTS: 104 patients met inclusion criteria. LKB1/STK11 expression (median H-score 102.9) was higher in women (median 123.3) than men (100.0, p=0.004) and in never-smokers (median 145.0) than former/current smokers (100.0, p=0.002). LKB1/STK11 expression was positively correlated with intratumoral infiltration of CD3(+) (r=0.351, P=0.005), CD4(+) (r=0.436, P

Purpose: Nintedanib enhances the activity of chemotherapy in metastatic non–small cell lung cancer (NSCLC). In this phase I/II study, we assessed safety and efficacy of nintedanib plus neoadjuvant chemotherapy, using major pathologic response (MPR) as primary endpoint. Patients and Methods: Eligible patients had stage IB (≥4 cm)–IIIA resectable NSCLC. A safety run-in phase was followed by an expansion phase with nintedanib 200 mg orally twice a day (28 days), followed by three cycles of cisplatin (75 mg/m2), docetaxel (75 mg/m2) every 21 days plus nintedanib, followed by surgery. With 33 planned patients, the study had 90% power to detect an MPR increase from 15% to 35%. Results: Twenty-one patients (stages I/II/III, N = 1/8/12) were treated. One of 15 patients treated with nintedanib 200 mg achieved MPR [7%, 95% confidence interval (CI), 0.2%–32%]. Best ORR in 20 evaluable patients was 30% (6/20, 95% CI, 12%–54%). Twelve-month recurrence-free survival and overall survival were 66% (95% CI, 47%–93%) and 91% (95% CI, 79%–100%), respectively. Most frequent treatment-related grade 3–4 toxicities were transaminitis and electrolyte abnormalities. On the basis of an interim analysis the study was discontinued for futility. Higher levels of CD3+ and cytotoxic CD3+CD8+ T cells were found in treated tumors of patients who were alive than in those who died (652.8 vs. 213.4 cells/mm2, P = 0.048; 142.3 vs. 35.6 cells/mm2, P = 0.018). Conclusions: Although tolerated, neoadjuvant nintedanib plus chemotherapy did not increase MPR rate compared with chemotherapy historical controls. Additional studies of the combination in this setting are not recommended. Posttreatment levels of tumor-infiltrating T cells were associated with patient survival. Use of MPR facilitates the rapid evaluation of neoadjuvant therapies. See related commentary by Blakely and McCoach, p. 3499

Introduction The standard of care for stage IIIA (N2) non–small-cell lung cancer (NSCLC) includes concurrent definitive chemoradiation (dCRT) followed by durvalumab, thus challenging the role of surgery in resectable patients. We assessed locoregional disease control and survival in patients with surgically resected and unresected stage IIIA (N2) NSCLC disease. Patients and Methods We conducted a retrospective analysis from prospectively collected databases at MD Anderson Cancer Center. Patients undergoing neoadjuvant chemotherapy and surgery or dCRT for clinical stage IIIA (N2) disease (2004-2014) were evaluated. Primary outcomes included locoregional disease control, disease-free survival (DFS), and overall survival (OS). Kaplan-Meier outcome analyses were performed. Results Of the 159 resected patients, the majority had lobectomy (82.4%), followed by pneumonectomy (11.9%) and sublobar resection (5.7%). The 30- and 90-day mortality rates were 0.6% and 1.3%, respectively. At median follow-up of 52.8 months, recurrence was 55.3%, with 44.0% having distant and 15.1% locoregional recurrence. At 5 years, OS was 50.8% and DFS was 33.1% Median OS was 61.2 months. A total of 366 patients underwent dCRT, with intensity-modulated radiation in 64.5%, proton therapy in 26.0%, and 3-dimensional conformal radiotherapy in 9.6%. The mean dose was 68.1 Gy. At median follow-up of 20.8 months, recurrence was 53.6%, with distant and locoregional recurrence of 40.7% and 30.3%, respectively. At 5 years, OS was 29.2% and DFS was 20.5%. Median OS was 27.5 months. Conclusion Stage IIIA (N2) NSCLC continues to be a heterogeneous disease, and patients with surgically resected and unresected disease represent different risk populations. Ongoing immunotherapy trials may further redefine treatment algorithms in this complex patient population.

Background and objectives It is unclear if a specific strategy for simultaneous treatment of primary thymic neoplasms and pleural metastases confers benefit for Masaoka stage IVA disease. We reviewed our experience with thymic neoplasms with concurrent pleural metastases to identify factors influencing outcomes. Methods Records of patients who presented with stage IVA thymic neoplasms from 2000 to 2018 were assessed. Multivariate Cox proportional hazards analyses were completed to determine predictors of progression-free and overall survival. Results Forty-eight patients were identified, including 34 (71%) who underwent surgery. Median overall and progression-free survival were 123 and 21 months, respectively. The extent of resection varied, and was most commonly thymectomy plus partial pleurectomy (22, 65%). Median progression-free survival for patients who underwent surgical resection versus those who had not was 24 versus 12 months (P = .018). Following surgical resection, mediastinal recurrence was uncommon (2, 6%, vs 7, 50% nonoperatively). Five-year survival rates in these groups were suggestive of possible benefit to surgery (87% vs 68%). Conclusions Thymic neoplasms with pleural dissemination represents a treatment challenge. As part of a multidisciplinary approach, surgery appears to be associated with more favorable long-term results, although selection bias may account for some of the survival differences observed.

Objective To summarize the multi-specialty strategy and initial guidelines of a Case Review Committee in triaging oncologic surgery procedures in a large Comprehensive Cancer Center and to outline current steps moving forward after the initial wave. Summary of background data The impetus for strategic rescheduling of operations is multifactorial and includes our societal responsibility to minimize COVID-19 exposure risk and propagation among patients, the healthcare workforce, and our community at large. Strategic rescheduling is also driven by the need to preserve limited resources. As many states have already or are considering to re-open and relax stay-at-home orders, there remains a continued need for careful surgical scheduling because we must face the reality that we will need to co-exist with COVID-19 for months, if not years. Methods The quality officers, chairs, and leadership of the 9 surgical departments in our Division of Surgery provide specialty-specific approaches to appropriately triage patients. Results We present the strategic approach for surgical rescheduling during and immediately after the COVID-19 first wave for the 9 departments in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, Texas. Conclusions Cancer surgeons should continue to use their oncologic knowledge to determine the window of opportunity for each surgical procedure, based on tumor biology, preoperative treatment sequencing, and response to systemic therapy, to safely guide patients through this cautious recovery phase.

Background The improvement in the management of lung cancer have the potential to improve survival in patients undergoing resection for early-stage (stage I and II) non-small cell lung cancer (NSCLC), but few studies have evaluated time trends and identified predictors of overall survival (OS). Methods We identified surgically resected early-stage NSCLC between 1998 and 2016. The 3-year OS (1998-2014) and 5-year OS (1998-2012) rates were calculated for each year. Joinpoint regression was used to calculate annual percentage changes (APC) and to test time trends in OS. Multivariable Cox regression was used to identify predictors of OS. Results There was a significant upward trend in the 3-year (1998, 56%; 2014, 83%; APC = 1.8) and 5-year (1998, 47%; 2012, 76%; APC = 3.1) OS. Older age; male sex; history of diabetes, coronary artery disease, and chronic obstructive pulmonary disease; high ASA score; smoking pack-years; high-grade tumor; pneumonectomy; thoracotomy; neoadjuvant therapy; nodal disease; and positive tumor margin were predictors of poor OS. Conclusion The upward time trend in OS suggests that improved staging, patient selection, and management have conferred a survival benefit in early-stage NSCLC patients. The prediction model of OS could be used to refine selection criteria for resection and improve survival outcomes.

Background Approximately one third of needle biopsies that are performed to rule out malignancy of indeterminate pulmonary nodules detected radiologically during lung cancer screening are negative, thus exposing cancer-free patients to risks of pneumothorax, bleeding, and infection. A noninvasive confirmatory tool (eg, liquid biopsy) is urgently needed in the lung cancer diagnosis setting to stratify patients who should receive biopsy versus those who should be monitored. Methods A novel antigen-independent, 4-color fluorescence in situ hybridization (FISH)-based method was developed to detect circulating tumor cells (CTCs) with abnormalities in gene copy numbers in mononuclear cell-enriched peripheral blood samples from patients with (n = 107) and without (n = 100) lung cancer. Results Identification of CTCs using FISH probes at 10q22.3/CEP10 and 3p22.1/3q29 detected lung cancer cases with 94.2% accuracy, 89% sensitivity, and 100% specificity compared with biopsy. Conclusion The high accuracy of this liquid biopsy method suggests that it may be used as a noninvasive decision tool to reduce the frequency of unnecessary needle biopsy in patients with benign pulmonary lesions.

BACKGROUND: We previously reported that post-discharge nursing telephone assessments identified a frequent number of patient complaints. Our aim was to determine if telephone assessments can identify patients at risk for emergency room (ER) visits or hospital readmissions. METHODS: A single-institution, retrospective review was performed on all patients undergoing pulmonary resection over a 12-month period. Standardized nursing telephone calls were conducted and records were reviewed to determine postoperative issues. ER visits and readmissions within 30 and 90 days were recorded. RESULTS: In total, 521 patients underwent pulmonary resection and 245 (47%) were reached for telephone assessment. ER visits within 30/90 days were 8.1% (n=42) and 12.1% (n=63). Readmissions within 30/90 days were 3.1% (n=16) and 6% (n=31). For those reached by telephone assessment, patients with major issue demonstrated increased 30-day ER visits: 22.6% (n=7) vs. 8.0% (n=17), P=0.019. For all patients, those with 90-day ER visit and/or readmission were more likely to have pulmonary complications during initial admission (43.8% vs. 21.2%, P

Background Opioids represent the mainstay for treating postsurgical pain but can cause significant morbidity in addition to dependency. The aim of the study was to determine the incidence of persistent opioid use after lung surgery. Methods Patients who underwent lung resection from 2008 to 2013 for non-small cell lung cancer were identified in the Surveillance, Epidemiology and End Results-Medicare database. Patients were categorized as being chronic, intermittent, or naive preoperative opioid users using information obtained from part D records. Persistent opioid use was defined as having a filled opioid prescription between 3 and 6 months after lung resection. Results A total of 6948 patients were identified, among whom 3946 (56.8%) were opioid naive, 2017 (29.0%) were intermittent opioid users, and 985 (14.2%) were chronic opioid users preoperatively. Persistent opioid use (3-6 months) after lung resection was high (31%), even among opioid-naive patients (17%). Among those who were previously opioid naive, independent predictors of persistent opioid use were receipt of adjuvant radiation or chemotherapy, less than 70 years of age, Charlson comorbidity score of 1 or 2, and residence in zip codes associated with lower education. Conversely, patients who underwent minimally invasive surgery were less likely to have persistent opioid use. Those with persistent opioid use after surgery did not show any trend toward returning to preoperative opioid utilization for at least the first postoperative year. Conclusions Opioid dependence after lung resection in the population over 65 years of age is high but was significantly lower among those who received minimally invasive surgery, in addition to other factors.

400 Background: The management of esophageal cancer (EC) and gastroesophageal junction (GEJ) adenocarcinoma has focused on perioperative approaches that aim to increase pathological complete response (pathCR) rates, decrease or delay metastases, improve resectability, and enhance overall survival. Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1, and B7-1, both of which function as inhibitory receptors expressed on T-cells. Therapeutic binding of PD-L1 by atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T-cell responses, resulting in improved anti-tumor activity. The use of immunotherapy in combination with chemotherapy in the perioperative setting may improve the response rate in patients with localized EC and GEJ adenocarcinoma. Methods: We conducted a phase I study evaluating the efficacy and safety of atezolizumab in combination with oxaliplatin and 5-fluorouracil (modified FOLFOX) therapy in the perioperative setting. Patients with T1N1 or T2-3 (any N) localized EC and GEJ type I or II adenocarcinoma were included. Treatment consisted of oxaliplatin (85 mg/m2 over 2 hours on days 1 and 15) and 5-fluorouracil (2.4g/m2 (over 48 hours) via infusion pump on days 1 and 15) followed by atezolizumab (840 mg via IV on days 1 and 15) of each 28-day cycle for a total of 6 doses followed by surgery and subsequently postoperative atezolizumab 1200 mg IV on Day 1 of each 21-day cycle for 8 more doses. Results: From April 2019 to November 2020, 20 patients were enrolled with a median age of 61 years old and baseline TNM staging: T2-3N0 (n=8), T3N1-N2 (n=10), and T3N3-NX (n=2). Eighteen patients underwent surgery; two patients (11%, 95% credible interval = 1-28%) achieved the primary efficacy objective (pathCR defined as pathological T0N0), and two additional patients (11%) had near complete pathCR with

BACKGROUND: Surgical outcomes for non-small cell lung cancer after neoadjuvant immune checkpoint inhibitors continue to be debated. We assessed perioperative outcomes of patients treated with Nivolumab or Nivolumab plus Ipilimumab (NEOSTAR) and compared them with patients treated with chemotherapy or previously untreated patients with stage I-IIIA non-small cell lung cancer. METHODS: Forty-four patients with stage I to IIIA non-small cell lung cancer (American Joint Committee on Cancer Staging Manual, seventh edition) were randomized to nivolumab (N; 3 mg/kg intravenously on days 1, 15, and 29; n = 23) or nivolumab with ipilimumab (NI; I, 1 mg/kg intravenously on day 1; n = 21). Curative-intent operations were planned between 3 and 6 weeks after the last dose of neoadjuvant N. Patients who completed resection upfront or after chemotherapy from the same time period were used as comparison. RESULTS: In the N arm, 21 (91%) were resected on-trial, 1 underwent surgery off-trial, and one was not resected (toxicity-related). In the NI arm, 16 (76%) resections were performed on-trial, one off-trial, and 4 were not resected (none toxicity-related). Median time to operation was 31 days, and consisted of 2 (5%) pneumonectomies, 33 (89%) lobectomies, and 1 (3%) each of segmentectomy and wedge resection. The approach was 27 (73%) thoracotomy, 7 (19%) thoracoscopy, and 3 (8%) robotic-assisted. Conversion occurred in 17% (n = 2/12) of minimally invasive cases. All 37 achieved Ro resection. Pulmonary, cardiac, enteric, neurologic, and wound complications occurred in 9 (24%), 4 (11%), 2 (5%), 1 (3%), and 1 (3%) patient, respectively. The 30- and 90-day mortality rate was 0% and 2.7% (n = 1), respectively. Postoperative complication rates were comparable with lung resection upfront or after chemotherapy. CONCLUSIONS: Operating after neoadjuvant N or NI is overall safe and effective and yields perioperative outcomes similar to those achieved after chemotherapy or upfront resection.

The multimodal management of operable non-small cell lung cancer (NSCLC) continues to evolve rapidly. The immune milieu allowing for immunotherapeutic benefit can be affected by multiple parameters including clinicopathologic and genetic. Surgery induced physiological changes has received attention for modulating and affecting post-operative oncotaxis and immunosuppression. Here, we sought to investigate how surgical stress influences phenotype of peripheral blood mononuclear cells (PBMCs) in patients with NSCLC who underwent lobectomy.Blood was prospectively collected from patients with Stage IA-IIIA NSCLC undergoing lung resection between 2016 and 2018. Samples were obtained pre-operatively, 24 h and 4 weeks after surgery. PBMCs were isolated and subject to high-dimensional flow cytometry, analyzing a total of 115 cell populations with a focus on myeloid cells, T cell activation, and T cell trafficking. We further evaluated how surgical approach influenced post-operative PBMC changes, whether the operation was conducted in an open fashion with thoracotomy, or with minimally invasive Video Assisted Thoracoscopic Surgery (VATS).A total of 76 patients met the inclusion criteria (Open n = 55, VATS n = 21). Surgical resection coincided with a decrease in T lymphocyte populations, including total CD3+ T cells, CD8+ T cells, and T effector memory cells, as well as an increase in monocytic myeloid-derived suppressor cells (mMDSC). Post-operative changes in PBMC populations were resolved after 4 weeks. Surgical-induced changes in immune populations were equivalent in patients undergoing open thoracotomy and VATS.Surgical stress resulted in transient reduction in T cells and T effector memory cells, and increase of mMDSC following resection in NSCLC patients. The immune profile modulation was similar regardless of surgical approach. These findings suggest that surgical approach does not seem to affect mononuclear cell lines obtained from peripheral blood. Thus, the decision regarding surgical approach should be patient centered, rather than based on post-operative treatment response optimization.

Goal-directed fluid therapy (GDFT) has been proposed as a cornerstone for enhanced recovery after surgery (ERAS) programs, particularly among high-risk patients undergoing high-risk surgery. However, because of the increased advocacy of euvolemia before surgery, the utility of GDFT in the context of ERAS is being questioned. Our primary objective was to determine whether GDFT has any impact on daily postoperative renal outcomes of high-risk patients undergoing thoracic surgery in an ERAS program.All patients included in this study were at high risk with a baseline glomerular filtration rate (GFR) below 90 mL/min per 1.73 mIn total, 451 matched pairs were included in this analysis. Both groups had similar demographic and clinical characteristics. Patients treated with GDFT received more ephedrine (5 [0-15] mg vs 0 [0-15] mg; P = .03) and less volume of fluids (1163 ± 484 mL vs 1246 ± 626 mL; P = .03) compared with those in the standard group. The incidence of acute kidney injury was similar in both groups (5.1% in the GDFT group vs 7.1% in the non-GDFT group; P = .57). Mixed effect analysis showed no significant differences in the trajectory of postoperative GFRs between groups (P = .59).GDFT does not have an impact on postoperative renal function compared with standard of care among high-risk patients in an ERAS program for thoracic pulmonary surgery.

Enhanced Recovery After Surgery programs have been shown to effectively reduce opioid prescriptions at discharge after their implementation in several institutions, but little is known regarding the sustainability of this effect. Understanding opioid prescribing patterns after long-term implementation of Enhanced Recovery After Surgery initiatives may help guide further opioid prescription reduction and improvements. Our group aimed to determine whether reductions in opioid prescriptions at discharge are sustained in an Enhanced Recovery After Surgery program for thoracic surgery.This retrospective cohort included 2,081 patients undergoing thoracic surgery within a 4-year Enhanced Recovery After Surgery program from March 2016 through April 2020. Our Enhanced Recovery After Surgery protocol included a standardized multimodal analgesic regimen (ie, preoperative gabapentin, tramadol, intercostal nerve block with liposomal bupivacaine, and intraoperative acetaminophen, and ketorolac) and the rest of the interventions recommended by the Enhanced Recovery After Surgery society guidelines. Our primary outcomes were the presence of opioid prescriptions at discharge (hydrocodone, hydromorphone, and oxycodone) and the total opioid amount prescribed (morphine equivalent daily dose). Multilevel generalized linear models were used to account for surgeon variabilities and types of thoracic resection.Over the study period, the rate of opioid prescriptions at discharge reduced from 35% (Mar 2016) to 25% (Apr 2020), and the amount of opioid prescribed declined from 184 ± 321 morphine equivalent daily dose to 94 ± 251 morphine equivalent daily dose. In multilevel generalized linear models, there was a sustained downward trend in opioid prescriptions over the study period (β -11.8 morphine equivalent daily dose per year, P = .048), which was also directly correlated with the use of minimally invasive surgery (β -84.9 morphine equivalent daily dose for video-assisted thoracoscopic surgery, P.001; β -139.2 morphine equivalent daily dose for robotic-assisted thoracic surgery, P.001), intraoperative opioid administration (β -1.4 morphine equivalent daily dose per 1 morphine equivalent dose, P = .026), and the amount of postoperative acetaminophen (β -18.2 morphine equivalent daily dose per 1 g, P = .026). The sustained reduction of opioid prescriptions at discharge did not impact hospital readmission rates within 30 days (odds ratio 1.17, 95% confidence interval 0.86-1.59, P = .306). Subgroup analysis showed a significant, sustained decrease in hydromorphone (β -10.9 morphine equivalent daily dose per year, P = .004), but not for hydrocodone prescriptions (β -5.7 morphine equivalent daily dose per year, P = .168) or oxycodone (β +4.78 morphine equivalent daily dose per year, P = .183).Our Enhanced Recovery After Surgery program for thoracic surgery contributed to a sustained reduction of opioid prescriptions at discharge, which positively correlated with the duration of its implementation and the use of minimally invasive surgical techniques but was negatively impacted by the amount of intraoperative opioid administration.

Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non–small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown. Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC. Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis. Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared “two-hit” alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1). Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.

Background Adenocarcinoma of the gastroesophageal junction (AEG) poses a management challenge, as preoperative prediction of occult mediastinal nodal metastasis is difficult. We sought to identify factors predictive of mediastinal involvement among patients undergoing trimodality therapy. Methods Patients undergoing trimodality therapy for Siewert II and III AEG at a single institution between 2000 and 2015 were identified. Mediastinal involvement was defined as pathologic nodal involvement after neoadjuvant chemoradiation (ypN+) in mediastinal stations or mediastinal recurrence 2 years or less after resection. Maximal χ2 analysis and Youden's J index were used to identify the pretreatment proximal tumor extent that best discriminated mediastinal involvement. Results In all, 204 patients (151 [74%] AEG II, 53 [26%] AEG III) were included, of whom 47 (23%) had clinical evidence of thoracic nodal disease. Thirty-one of the 204 patients (15%) met criteria for mediastinal involvement (24 of 31 ypN+, 10 of 31 mediastinal recurrence). Patients with mediastinal involvement had greater proximal tumor extent (median 2 cm [interquartile range, 1.0 to 3.0 cm] vs 1.4 cm [interquartile range, 0.7 to 3.0 cm], P = .030), were more frequently Siewert II lesions (27 of 31 [87.1%] vs 124 of 173 [71.7%], P = .071), and were more often observed to have clinical thoracic nodal metastasis (cN) evidence (13 of 31 [42%] vs 34 of 173 [20%], P = .007) than patients who did not. On multivariable analysis of patients with intrathoracic cN0, esophageal extent of 1.5 cm or greater was independently predictive of mediastinal involvement (odds ratio 5.46, P = .011), whereas Siewert classification was not (Siewert II odds ratio 3.48, P = .116). Conclusions Pretreatment proximal tumor extent, rather than Siewert classification, is an independent predictor of mediastinal involvement among AEG II/III patients without clinical evidence of mediastinal metastasis and should be considered during treatment planning.

Objective Trimodality therapy may prolong survival for patients with resectable malignant pleural mesothelioma. However, many patients are unable to complete therapy. We sought to identify risk factors for failing to complete adjuvant intensity-modulated radiation therapy after cytoreduction for malignant pleural mesothelioma. Methods We performed a single-institution review of those who received an extrapleural pneumonectomy or pleurectomy/decortication for malignant pleural mesothelioma from 2004 to 2017. Multivariable logistic regression was used to assess preoperative or intraoperative risk factors associated with failing to complete adjuvant intensity-modulated radiation therapy. Results A total of 160 patients were identified, among whom 94 (59%) received an extrapleural pneumonectomy and 66 (41%) received a pleurectomy/decortication. Adjuvant intensity-modulated radiation therapy was completed among 105 patients (66%). Reasons for failing to complete adjuvant intensity-modulated radiation therapy included mortality (19), dose constraints (21), postoperative morbidity or delayed recovery (11), and refused or unknown status (4). On multivariable analysis, American Society of Anesthesiologists 3+ classification (P = .002) and smoking history (P = .022) were associated with failure to complete adjuvant intensity-modulated radiation therapy, whereas forced expiratory volume in 1 second 70% or less of predicted and pStage 4 (T4) were significant on univariable analysis only. Other factors, including extrapleural pneumonectomy or pleurectomy/decortication, margin status, age, and histology, were not associated with receiving adjuvant intensity-modulated radiation therapy. Conclusions Many patients are unable to complete adjuvant intensity-modulated radiation therapy after cytoreduction. Failure to complete adjuvant intensity-modulated radiation therapy was associated with worse preoperative comorbidity, but not the type of surgery or margin status.