Publications by authors named "Matthew J Bott"

39 Publications

A Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma.

JAMA Surg 2021 Feb 10;156(2):e205601. Epub 2021 Feb 10.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence.

Objective: To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system.

Design, Setting, And Participants: This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018.

Main Outcomes And Measures: The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model.

Results: Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation.

Conclusions And Relevance: The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.
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http://dx.doi.org/10.1001/jamasurg.2020.5601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758824PMC
February 2021

A More Extensive Lymphadenectomy Enhances Survival Following Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Adenocarcinoma.

Ann Surg 2020 Nov 12. Epub 2020 Nov 12.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Objective: We sought to determine the extent of lymphadenectomy that optimizes staging and survival in patients with locally advanced esophageal adenocarcinoma (EAC) treated with neoadjuvant chemoradiotherapy followed by esophagectomy.

Summary Background Data: Several studies have found that a more extensive lymphadenectomy leads to better disease-specific survival in patients treated with surgery alone. Few studies, however, have investigated whether this association exists for patients treated with neoadjuvant chemoradiotherapy.

Methods: We examined our prospective database and identified patients with EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy between 1995 and 2017. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier methods, and a multivariable Cox proportional hazards model was used to identify independent predictors of OS and DFS. The relationship between the total number of nodes removed and 5-year OS or DFS was plotted using restricted cubic spline functions.

Results: In total, 778 patients met the inclusion criteria. The median number of excised nodes was 21 (interquartile range, 16-27). A lower number of excised lymph nodes was independently associated with worse OS and DFS (OS: hazard ratio [HR], 0.98; confidence interval [CI], 0.97-1.00; P = 0.013; DFS: HR, 0.99; CI, 0.98-1.00; P = 0.028). Removing 25 to 30 lymph nodes was associated with a 10% risk of missing a positive lymph node. Both OS and DFS improved with up to 20 to 25 lymph nodes removed, regardless of treatment response.

Conclusions: The optimal extent of lymphadenectomy to enhance both staging and survival following chemoradiotherapy, regardless of treatment response, is approximately 25 lymph nodes.
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http://dx.doi.org/10.1097/SLA.0000000000004479DOI Listing
November 2020

Two-Year Quality of Life Outcomes After Robotic-Assisted Minimally Invasive and Open Esophagectomy.

Ann Thorac Surg 2020 Nov 3. Epub 2020 Nov 3.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Background: Robotic-assisted minimally invasive esophagectomy (RAMIE) is a safe alternative to open esophagectomy (OE). However, differences in quality of life (QOL) after these procedures remain unclear. We previously reported on short-term QOL outcomes after RAMIE and OE and describe here our results from two years of follow-up.

Methods: We conducted a prospective, nonrandomized trial of patients with esophageal cancer undergoing transthoracic resection via RAMIE or OE at a single institution. The primary outcomes were patient-reported QOL, measured by the Functional Assessment of Cancer Therapy-Esophageal (FACT-E), and pain, measured by the Brief Pain Inventory (BPI). Generalized linear models were used to assess the relationship between QOL outcomes and surgery cohort. P values were adjusted (p-adj) within each model using the false discovery rate correction.

Results: In total, 170 patients underwent esophagectomy (106 OE and 64 RAMIE). The groups did not differ significantly by any measured clinicopathologic variables. After covariates were controlled for, FACT-E scores were higher in the RAMIE cohort than in the OE cohort (parameter estimate [PE], 6.13; p-adj=0.051). RAMIE was associated with higher esophageal cancer subscale (PE, 2.72; p-adj=0.022) and emotional well-being (PE, 1.25; p-adj=0.016) scores. BPI pain severity scores were lower in the RAMIE cohort than in the OE cohort (PE, -0.56; p-adj=0.005), but pain interference scores did not differ significantly between groups (p-adj=0.11).

Conclusions: During 2 years of follow-up, RAMIE was associated with improved patient-reported QOL, including esophageal symptoms and emotional well-being, and decreased pain, compared with OE.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.027DOI Listing
November 2020

Multiplanar 3D fluoroscopy redefines tool-lesion relationship during robotic-assisted bronchoscopy.

Respirology 2021 Jan 2;26(1):120-123. Epub 2020 Nov 2.

Section of Interventional Pulmonology, Pulmonary Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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http://dx.doi.org/10.1111/resp.13966DOI Listing
January 2021

Is routine chest radiography necessary after endobronchial ultrasound-guided fine needle aspiration?

Ann Thorac Surg 2020 Oct 20. Epub 2020 Oct 20.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065. Electronic address:

Background: Chest radiography (CXR) is routinely performed after endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) to detect clinically occult pneumothorax. As the established rate of postprocedure pneumothorax is low, we sought to determine whether this practice can be safely eliminated and to determine potential cost reduction with omission of routine chest radiography.

Methods: Patients who underwent EBUS-FNA between January 1, 2017, and December 31, 2018 were retrospectively identified. Patient factors were summarized using descriptive statistics. Outcomes were compared using χ, Fisher's exact, and ANOVA tests. Univariate regression analysis was used to identify factors predictive of postprocedure pneumothorax.

Results: 757 patients were included for study. 72.4% (548/757) underwent routine CXR in the postanesthesia care unit (PACU). 1.5% (11/757) developed clinically relevant or radiographically evident pneumothorax. Of patients who underwent CXR, 0.5% (3/548) required unplanned admission for postprocedure pneumothorax, and 0.2% (1/548) required tube thoracostomy. Of 209 patients who did not undergo CXR, none developed a clinically evident pneumothorax. In total, only 1 patient (0.1%) experienced symptomatic pneumothorax. The pneumothorax event rate was so low that no association with demographic or clinical factors and no predictive factors could be identified. The number of patients needed to be screened by CXR to identify 1 patient requiring deviation from routine management is 183. The potential total cost reduction if routine CXR were eliminated was $33,950.

Conclusions: The extremely low rate of postprocedure pneumothorax precluded informative statistical analysis. Routine CXR following EBUS-FNA may not be necessary, and omission of routine CXR may confer a cost savings.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.033DOI Listing
October 2020

How Effective Is Neoadjuvant Therapy Followed by Surgery for Pathologic Single-Station N2 Non-Small Cell Lung Cancer?

Semin Thorac Cardiovasc Surg 2021 Spring;33(1):206-216. Epub 2020 Aug 25.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

The optimal treatment strategy for pathologic single-station N2 (pN2a1) non-small cell lung cancer (NSCLC)-surgery first followed by adjuvant treatment (SF) or neoadjuvant therapy followed by surgery (NS)-remains unclear. We compared disease-free survival (DFS) and overall survival (OS) after NS versus SF for pN2a1 NSCLC. We retrospectively identified patients with pN2a1 NSCLC resected between 2000 and 2018. Patients in the SF group had cN0 disease and were treated with surgery before adjuvant chemotherapy; patients in the NS group had known preoperative nodal disease, cN2 disease, and were treated with neoadjuvant therapy before surgery. The matching-weights procedure was applied to generate a cohort with similar characteristics between groups. DFS and OS were calculated using the Kaplan-Meier approach and compared between groups using weighted log-rank test and Cox proportional hazards models. We identified 227 patients with pN2a1 disease: 121 treated with SF and 106 with NS. After the matching-weights procedure, 5- and 10-year DFS were 45% and 27% for SF versus 26% and 21% for NS (log-rank P = 0.056; hazard ratio [HR], 1.61; 95% confidence interval [CI], 0.98-2.65); 5- and 10-year OS were 49% and 30% for SF versus 43% and 20% for NS (log-rank P = 0.428; HR, 1.24; 95% CI, 0.67-2.28). SF and NS for pN2a1 NSCLC resulted in similar survival. A study comparing SF for known preresectional pN2a1 with occult pN2a1 disease could be a next step. Further investigation of SF for known N2a1 versus occult pN2a1 disease could power a clinical trial focused on N2a NSCLC.
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http://dx.doi.org/10.1053/j.semtcvs.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904958PMC
August 2020

The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.

J Thorac Oncol 2020 12 10;15(12):1844-1856. Epub 2020 Aug 10.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Introduction: The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD).

Methods: We identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection.

Results: MIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049).

Conclusions: These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
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http://dx.doi.org/10.1016/j.jtho.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704768PMC
December 2020

Perioperative considerations for neoadjuvant immunotherapy in non-small cell lung cancer.

J Thorac Cardiovasc Surg 2020 Nov 5;160(5):1376-1382. Epub 2020 Jul 5.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1016/j.jtcvs.2020.05.119DOI Listing
November 2020

Intentional Segmentectomy for Clinical T1 N0 Non-small Cell Lung Cancer: Survival Differs by Segment.

Ann Thorac Surg 2021 03 31;111(3):1028-1035. Epub 2020 Jul 31.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: Outcomes after segmentectomy compare favorably with those after lobectomy in patients with stage I non-small cell lung cancer (NSCLC). Whether long-term outcomes vary by segmentectomy location is unclear. We investigated whether disease-free survival (DFS) and overall survival (OS) differ by segmentectomy location after intentional segmentectomy for clinical T1 N0 M0 NSCLC.

Methods: Patients who received intentional segmentectomy for cT1 N0 M0 NSCLC from 2000 to 2018 were reviewed. Patients with prior lung cancer, forced expiratory volume in 1 second of less than 50%, or R1/R2 resection were excluded. Segmentectomy groups were left (L) basilar, L segment 6, L lingula, L trisegment; right (R): basilar (R_Bas), segment 6 (R_S6), and R upper. The 5- and 10-year DFS and OS were estimated using Kaplan-Meier and compared between groups using the log-rank test. Factors associated with DFS and OS were determined using Cox proportional hazards models.

Results: In total, 416 patients met the inclusion criteria. Segmentectomy groups differed with regard to surgical approach, mediastinal lymphadenectomy, lymphovascular invasion, tumor histology, margin distance, and adjuvant therapy. Long-term outcomes were worst after R_S6 resection (5-year DFS, 57.6% [95% confidence interval {CI}, 45.7%-72.7%]; OS, 66.3% [95% CI, 54.7%-80.3%]) and best after R_Bas resection (5-year DFS, 77.1% [95% CI, 59.2%-100%]; OS, 79.5% [95% CI, 60.9%-100%]). On multivariable analysis, R_S6 resection was independently associated with DFS vs R_Bas (hazard ratio, 2.89; 95% CI, 1.18-7.08; P = .02) and OS vs R_Bas (hazard ratio, 4.35; 95% CI, 1.61-11.76; P = .004).

Conclusions: Resection of R_S6 is independently associated with worse DFS and OS in patients receiving intentional segmentectomy for cT1 N0 M0 NSCLC and may warrant more extensive resection, complete lymph node dissection, and closer postoperative surveillance.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.166DOI Listing
March 2021

Propensity-matched Analysis Demonstrates Long-term Risk of Respiratory and Cardiac Mortality After Pneumonectomy Compared With Lobectomy for Lung Cancer.

Ann Surg 2020 Jun 11. Epub 2020 Jun 11.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Objective: We sought to quantify and characterize long-term consequences of pneumonectomy, with particular attention to nononcologic mortality.

Summary Of Background Data: Pneumonectomy is associated with profound changes in cardiopulmonary physiology. Studies of long-term outcomes after pneumonectomy typically report generalized measures, such as disease-free and overall survival.

Methods: Patients undergoing lobectomy or pneumonectomy for lung cancer at our institution from 2000 to 2018 were reviewed. Propensity-score matching was performed for 12 clinicopathologic factors. Ninety-day complications and deaths were compared. Five-year cumulative incidence of oncologic and nononcologic mortality were compared using competing risks approaches.

Results: From 3339 lobectomy and 355 pneumonectomy patients identified, we derived 318 matched pairs. At 90 days, rates of overall complications were similar (46% for pneumonectomy vs 43% for lobectomy; P = 0.40), but rates of major complications (21% vs 13%; P = 0.005) and deaths (6.9% vs 1.9%; P = 0.002) were higher the pneumonectomy cohort. The cumulative incidence of oncologic mortality was not significantly different between cohorts (P = 0.9584). However, the cumulative incidence of nononcologic mortality was substantially higher in the pneumonectomy cohort for both date of surgery and 1-year landmark analyses (P < 0.0001 and P = 0.0002, respectively). Forty-five pneumonectomy patients (18%) died of nononcologic causes 1-5 years after surgery; pneumonia (n = 21) and myocardial infarction (n = 10) were the most common causes. In pneumonectomy patients, preexisting cardiac comorbidity and low diffusion capacity of the lungs for carbon monoxide were predictive of nononcologic mortality.

Conclusions: Compared to lobectomy, excess mortality after pneumonectomy extends beyond 1 year and is driven primarily by nononcologic causes. Pneumonectomy patients require lifelong monitoring and may benefit from expeditious assessment and intervention at the initial signs of illness.
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http://dx.doi.org/10.1097/SLA.0000000000004065DOI Listing
June 2020

Commentary: Minimally invasive sleeve lobectomy: Time to roll up our "sleeves" and learn something new?

J Thorac Cardiovasc Surg 2021 02 19;161(2):415-416. Epub 2020 Mar 19.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.02.121DOI Listing
February 2021

Time-varying analysis of readmission and mortality during the first year after pneumonectomy.

J Thorac Cardiovasc Surg 2020 Jul 7;160(1):247-255.e5. Epub 2020 Mar 7.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objectives: Mortality rates of 5% to 10% after pneumonectomy have remained constant during the last decade. To understand the patterns of outcomes after pneumonectomy, we investigated the time-varying risks of readmission and death during the first postoperative year and examined the contributions of specific causes to these patterns over time.

Methods: We retrospectively reviewed all pneumonectomies for lung cancer at our institution from 2000 to 2018. The time-varying instantaneous risk of all-cause readmission and mortality up to 1 year after pneumonectomy was estimated using parametric analyses and was repeated for each primary cause of readmission (oncologic, infectious, pulmonary, cardiac, or other) and death (oncologic or nononcologic).

Results: In our cohort of 355 patients who underwent pneumonectomy, risk of readmission was highest immediately after discharge and was halved by 14 days. This risk reached a nadir and remained constant from 4 to 8 months, after which it gradually increased. Pulmonary causes accounted for most readmissions within 90 days, after which oncologic causes predominated. Likewise, the overall risk of death was highest immediately after surgery, was halved by 7 days, reached a nadir at 90 days, and then increased throughout the remainder of the first year. All deaths during the first 90 days after surgery were due to nononcologic causes.

Conclusions: Nononcologic causes of readmission and death predominate in the first 90 days after pneumonectomy, after which oncologic causes prevail. We also identify specific causes that pose the highest risk of readmission immediately after discharge. Efforts are warranted to define the effects of specific causes of readmission on overall mortality after pneumonectomy.
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http://dx.doi.org/10.1016/j.jtcvs.2020.02.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348691PMC
July 2020

Commentary: Opioid dependence in the lobectomy patient: A hard pill to swallow.

Authors:
Matthew J Bott

J Thorac Cardiovasc Surg 2020 02 24;159(2):703-704. Epub 2019 Oct 24.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2019.10.061DOI Listing
February 2020

Neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer.

J Thorac Cardiovasc Surg 2019 11 29;158(5):1471-1474. Epub 2019 Aug 29.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

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http://dx.doi.org/10.1016/j.jtcvs.2019.06.114DOI Listing
November 2019

Commentary: Cell proliferation and immune evasion: A dangerous combination.

Authors:
Matthew J Bott

J Thorac Cardiovasc Surg 2019 09 15;158(3):920-921. Epub 2019 Jun 15.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2019.05.079DOI Listing
September 2019

Perioperative blood transfusion has a dose-dependent relationship with disease recurrence and survival in patients with non-small cell lung cancer.

J Thorac Cardiovasc Surg 2019 06 12;157(6):2469-2477.e10. Epub 2019 Feb 12.

Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: Perioperative blood transfusions have been implicated in decreased overall survival (OS) and disease-free survival (DFS) after resection for non-small cell lung cancer (NSCLC). We investigated the effects of single- and multiple-unit blood transfusions on OS, DFS, and recurrence after anatomic pulmonary resection.

Methods: From January 1, 2000, to June 30, 2016, 5709 consecutive patients underwent pulmonary resection for NSCLC at our institution. Exclusion criteria were stage IIIB-IV disease, incomplete resections, ill-defined histologic subtypes, and nonanatomic wedge resections. For the 0 versus single-unit analysis, propensity scores were calculated from a logistic regression model that predicted the probability of patients receiving a single-unit transfusion. The resulting matching weights were incorporated into Cox models for OS, DFS, and cumulative incidence of recurrence, to compare no versus single-unit blood transfusion. We determined whether increasing numbers of blood transfusions influenced survival or recurrence using multivariable Cox models.

Results: Approximately 10% of patients received perioperative blood transfusion (median follow-up, 7.46 years [25th-75th percentile, 3.98-11.8]). There was no difference in OS, DFS, or cumulative incidence of recurrence between patients receiving no transfusion and those receiving single-unit transfusion (P > .05). However, a dose-response relationship was observed, demonstrating worse OS (overall P < .001), DFS (overall P < .001), and recurrence (overall P = .010) with increasing units of blood transfused.

Conclusions: Although a single-unit blood transfusion did not affect survival in patients undergoing resection for NSCLC, greater unit perioperative blood transfusions were associated with significantly decreased long-term outcomes in a dose-dependent manner, suggesting avoidance or minimization of transfusions could improve long-term survival after lung resection.
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http://dx.doi.org/10.1016/j.jtcvs.2018.12.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626561PMC
June 2019

Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer.

J Thorac Cardiovasc Surg 2019 07 13;158(1):269-276. Epub 2018 Dec 13.

Division of Thoracic Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Md. Electronic address:

Objective: We conducted a phase I trial of neoadjuvant nivolumab, a monoclonal antibody to the programmed cell death protein 1 checkpoint receptor, in patients with resectable non-small cell lung cancer. We analyzed perioperative outcomes to assess the safety of this strategy.

Methods: Patients with untreated stage I-IIIA non-small cell lung cancer underwent neoadjuvant therapy with 2 cycles of nivolumab (3 mg/kg), 4 and 2 weeks before resection. Patients underwent invasive mediastinal staging as indicated and post-treatment computed tomography. Primary study end points were safety and feasibility of neoadjuvant nivolumab followed by pulmonary resection. Data on additional surgical details were collected through chart review.

Results: Of 22 patients enrolled, 20 underwent resection. One was unresectable; another had small cell histologic subtype. There were no delays to surgical resection. Median time from first treatment to surgery was 33 (range, 17-43) days. There were 15 lobectomies, 2 pneumonectomies, 1 bilobectomy, 1 sleeve lobectomy, and 1 wedge resection. Of 13 procedures attempted via a video-assisted thoracoscopic surgery or robotic approach, 7 (54%) required thoracotomy. Median operative time was 228 (range, 132-312) minutes; estimated blood loss was 100 (range, 25-1000) mL; length of hospital stay was 4 (range, 2-17) days. There was no operative mortality. Morbidity occurred in 10 of 20 patients (50%). The most common postoperative complication was atrial arrhythmia (6/20; 30%). Major pathologic response was identified in 9 of 20 patients (45%).

Conclusions: Neoadjuvant therapy with nivolumab was not associated with unexpected perioperative morbidity or mortality. More than half of the video-assisted thoracoscopic surgery/robotic cases were converted to thoracotomy, often because of hilar inflammation and fibrosis.
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http://dx.doi.org/10.1016/j.jtcvs.2018.11.124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653596PMC
July 2019

More isn't always better…but sometimes it is.

Authors:
Matthew J Bott

J Thorac Cardiovasc Surg 2019 Mar 12;157(3):1284-1285. Epub 2018 Dec 12.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2018.11.121DOI Listing
March 2019

NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination.

Science 2018 12;362(6421):1416-1422

Department of Cancer Biology and Genetics, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor-α and intercellular adhesion molecule-1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non-cell autonomous mechanisms involving NK cell surveillance.
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http://dx.doi.org/10.1126/science.aas9090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711172PMC
December 2018

Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non-small cell lung cancer: A propensity-matched analysis.

J Thorac Cardiovasc Surg 2019 02 10;157(2):743-753.e3. Epub 2018 Oct 10.

Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: Comparative survival between neoadjuvant chemotherapy and adjuvant chemotherapy for patients with cT2-4N0-1M0 non-small cell lung cancer has not been extensively studied.

Methods: Patients with cT2-4N0-1M0 non-small cell lung cancer who received platinum-based chemotherapy were retrospectively identified. Exclusion criteria included stage IV disease, induction radiotherapy, and targeted therapy. The primary end point was disease-free survival. Secondary end points were overall survival, chemotherapy tolerance, and ability of Response Evaluation Criteria In Solid Tumors response to predict survival. Survival was estimated using the Kaplan-Meier method, compared using the log-rank test and Cox proportional hazards models, and stratified using matched pairs after propensity score matching.

Results: In total, 330 patients met the inclusion criteria (n = 92/group after propensity-score matching; median follow-up, 42 months). Five-year disease-free survival was 49% (95% confidence interval, 39-61) for neoadjuvant chemotherapy versus 48% (95% confidence interval, 38-61) for adjuvant chemotherapy (P = .70). On multivariable analysis, disease-free survival was not associated with neoadjuvant chemotherapy or adjuvant chemotherapy (hazard ratio, 1.1; 95% confidence interval, 0.64-1.90; P = .737), nor was overall survival (hazard ratio, 1.21; 95% confidence interval, 0.63-2.30; P = .572). The neoadjuvant chemotherapy group was more likely to receive full doses and cycles of chemotherapy (P = .014/0.005) and had fewer grade 3 or greater toxicities (P = .001). Response Evaluation Criteria In Solid Tumors response to neoadjuvant chemotherapy was associated with disease-free survival (P = .035); 15% of patients receiving neoadjuvant chemotherapy (14/92) had a major pathologic response.

Conclusions: Timing of chemotherapy, before or after surgery, is not associated with an improvement in overall or disease-free survival among patients with cT2-4N0-1M0 non-small cell lung cancer who undergo complete surgical resection.
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http://dx.doi.org/10.1016/j.jtcvs.2018.09.098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344258PMC
February 2019

Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score-Matched Analysis.

J Thorac Oncol 2019 01 19;14(1):87-98. Epub 2018 Sep 19.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Introduction: Spread through air spaces (STAS) is a form of invasion wherein tumor cells extend beyond the tumor edge within the lung parenchyma. In lung adenocarcinoma (ADC), we investigated the (1) association between STAS and procedure-specific outcomes (sublobar resection and lobectomy), (2) effect of surgical margin-to-tumor diameter ratio in STAS-positive patients, and (3) potential utility of frozen sections (FSs) for detecting STAS intraoperatively.

Methods: We investigated 1497 patients who underwent lobectomy (n = 970) or sublobar resection (n = 527) for T1N0M0 lung ADC after propensity score matching. Outcomes were analyzed by using a competing risks approach. The effect of margin-to-tumor ratio on recurrence pattern (locoregional and distant) was investigated in patients who underwent sublobar resection. Five pathologists evaluated the feasibility of intraoperatively identifying STAS by using FSs (sensitivity, specificity, and interrater reliability).

Results: On multivariable analysis after propensity score matching (349 pairs/procedure), sublobar resection was significantly associated with recurrence (subhazard ratio = 2.84 [p < 0.001]) and lung cancer-specific death (subhazard ratio = 2.63 [p = 0.021]) in patients with STAS but not in those without STAS. Patients with STAS who underwent sublobar resection had a higher risk of locoregional recurrence regardless of margin-to-tumor ratio (for a margin-to-tumor ratio of ≥1 versus <1, the 5-year cumulative incidence of recurrence rates were 16% and 25%, respectively); among patients without STAS, locoregional recurrences occurred in patients with margin-to-tumor ratio lower than 1 (a 5-year cumulative incidence of recurrence rate of 7%). The sensitivity and specificity for detecting STAS by use of FSs were 71% and 92%, with substantial interrater reliability (Gwet's AC1, 0.67).

Conclusions: In patients with T1 lung ADC with STAS, lobectomy was associated with better outcomes than sublobar resection was. Pathologists can recognize STAS on FSs.
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http://dx.doi.org/10.1016/j.jtho.2018.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309668PMC
January 2019

Multimodality Therapy for N2 Non-Small Cell Lung Cancer: An Evolving Paradigm.

Ann Thorac Surg 2019 01 15;107(1):277-284. Epub 2018 Sep 15.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Induction chemoradiation for resectable N2 non-small cell lung cancer (NSCLC) is used with the intent to optimize locoregional control, whereas induction chemotherapy given in systemic doses is meant to optimally target potential distant disease. However, the optimal preoperative treatment regimen is still unknown and practice patterns continue to vary widely. We compared multiinstitutional oncologic outcomes for N2 NSCLC from 4 experienced lung cancer treatment centers.

Methods: This collaborative retrospective study unites 4 major thoracic oncology centers. Patients with N2 NSCLC undergoing surgical resection after induction chemotherapy (CxT) or concurrent chemoradiation (CxRT) were included. Primary outcomes were overall and disease-free survival (OS and DFS).

Results: 822 patients were identified (CxT = 662 and CxRT = 160). There were no differences in 5-year OS (CxT 39.9% versus CxRT 42.9%, p = 0.250) nor in DFS (CxT 28.7% versus 29.8%, p = 0.207). Recurrence rates (CxT 46.8% versus CxRT 51.6%, p = 0.282) and recurrence patterns were not significantly different (Local: CxT 9.8% versus CxRT 9.7%; and Distant: CxT 30.4% versus CxRT 33.1%, p = 0.764). There was no difference in perioperative mortality. In the analyses of patients who underwent pretreatment invasive mediastinal staging (n = 555), there were still no significant differences in OS (p = 0.341) and DFS (p = 0.455) between the 2 treatment strategies.

Conclusions: Both treatment strategies produce equivalent and better than expected outcomes compared with historical controls for N2 NSCLC, with no differences in recurrence patterns. How these conventional therapeutic strategies will compare with those involving immunotherapy combined with surgical locoregional disease control for N2 disease remains to be determined.
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http://dx.doi.org/10.1016/j.athoracsur.2018.07.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993842PMC
January 2019

Prolonged air leak: Another instance where time is money.

Authors:
Matthew J Bott

J Thorac Cardiovasc Surg 2018 09 31;156(3):1222-1223. Epub 2018 May 31.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2018.05.032DOI Listing
September 2018

Postoperative Radiotherapy for Surgically Resected ypN2 Non-Small Cell Lung Cancer.

Ann Thorac Surg 2018 09 26;106(3):848-855. Epub 2018 May 26.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: The role of postoperative radiotherapy (PORT) in patients with clinical stage III-N2 (cIII-N2) non-small cell lung cancer (NSCLC) treated with induction chemotherapy and surgical resection with persistent ypN2 disease is not well established.

Methods: We retrospectively reviewed a prospectively maintained database for patients with cIII-N2 NSCLC who underwent induction chemotherapy followed by resection (2004-2016). Exclusion criteria included induction radiotherapy, non-biopsy-confirmed cN2 disease, incomplete resection, ypN0/1, and nonanatomic resection. The primary outcome was locoregional recurrence (LR); secondary outcomes were disease-free survival (DFS), lung cancer-specific death (LCSD), and overall survival (OS). Associations between variables and outcomes were assessed using Fine and Gray competing risk regression for LR/LCSD and Cox proportional hazard models for survival.

Results: Of the 501 patients identified with cIII-N2 disease, 99 met the inclusion criteria. Median follow-up was 25 months (range, 3-137 months). Sixty-nine patients (70%) received PORT. Sixty (61%) developed a recurrence: 3 (5%) with an initial isolated LR and 57 (95%) with an initial distant recurrence. On multivariable analysis, PORT was not associated with LR (HR, 0.51 [95% CI, 0.22-1.21], p = 0.13). PORT was also not associated with DFS (p = 0.6) or LCSD (p = 0.1). PORT was associated with improved 3-year OS (55% [95% CI, 42%-71%]) versus the no-PORT group (50% [95% CI, 34%-74%]) (p = 0.04).

Conclusions: PORT is not independently associated with decreased LR or improved DFS/LCSD in this patient population. Given that the predominant failure pattern was distant recurrence, future clinical trials should focus on adjuvant systemic therapies, which may decrease distant recurrences in ypN2 patients.
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http://dx.doi.org/10.1016/j.athoracsur.2018.04.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136648PMC
September 2018

Predicting outcomes in esophageal cancer: No such thing as a crystal ball.

Authors:
Matthew J Bott

J Thorac Cardiovasc Surg 2018 08 5;156(2):845-846. Epub 2018 Apr 5.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2018.03.133DOI Listing
August 2018

Neutrophil to Lymphocyte Ratio as Predictor of Treatment Response in Esophageal Squamous Cell Cancer.

Ann Thorac Surg 2018 09 5;106(3):864-871. Epub 2018 May 5.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: The aim of this study was to assess the difference (Δ) in neutrophil to lymphocyte ratio (NLR), before and after chemoradiotherapy, as a predictor of treatment response and a prognostic factor for recurrence and disease-free survival in patients with esophageal squamous cell cancer treated with chemoradiotherapy with or without surgery.

Methods: Patients with locally advanced esophageal squamous cell cancer treated with chemoradiation with and without surgery who had a complete blood count before and after chemoradiotherapy were included. Pretreatment and posttreatment NLR were calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The ΔNLR was defined as posttreatment minus pretreatment NLR. Characteristics were evaluated for association with ΔNLR using the Wilcoxon signed rank test or the Kruskal-Wallis test. Risk of recurrence and disease-free survival were evaluated using Gray's and the log rank tests, respectively.

Results: We included 217 patients. Of them, 133 patients (61.3%) received only chemoradiotherapy and 84 (38.7%) underwent surgery after chemoradiotherapy. Among the surgical patients, 43% with pathologic complete response showed significantly lower median ΔNLR than patients with residual disease (-0.03 versus 1.04, p = 0.004). High ΔNLR was a negative predictor of treatment response (odds ratio 0.77, 95% confidence interval: 0.62 to 0.9, p = 0.004). A significant association between high ΔNLR and increased risk of recurrence was also identified.

Conclusions: The ΔNLR was inversely related to pathologic complete response and associated with risk of recurrence. This simple test, in concert with other clinical tools, can help identify patients with pathologic complete response.
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http://dx.doi.org/10.1016/j.athoracsur.2018.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117834PMC
September 2018

Safety and Feasibility of Lung Resection After Immunotherapy for Metastatic or Unresectable Tumors.

Ann Thorac Surg 2018 07 14;106(1):178-183. Epub 2018 Mar 14.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Surgeons are increasingly asked to operate on patients with residual disease after immunotherapy. The safety and utility of lung resection in this setting are unknown.

Methods: We retrospectively reviewed patients who underwent lung resection within 6 months of treatment with checkpoint blockade agents for metastatic or unresectable cancer. Survival was estimated from the first resection using the Kaplan-Meier approach.

Results: Database query identified 19 patients who underwent 22 resections for suspected residual disease with therapeutic intent after immunotherapy between 2012 and 2016. Lung cancer was the most common diagnosis (47%), followed by metastatic melanoma (37%). The most frequently used agents were nivolumab (32%), pembrolizumab (32%), and ipilimumab (16%). Patients received a mean of 21 doses (range, 1 to 70 doses). The final dose was administered at an average of 75 days (range, 7 to 183 days) before the operation. Anatomic resection (lobectomy or greater) was performed in 11 patients (50%). Four lobectomies were attempted minimally invasively, and one required conversion to thoracotomy. Of the resected patients, 68% had viable tumor remaining. R0 resection was achieved in 95%. Mean operative time for lobectomy was 227 minutes (range, 150 to 394 minutes). Complications occurred in 32% of patients; all but 1 were minor (grade 1/2). The 2-year overall and disease-free survival were 77% and 42%, respectively.

Conclusions: In patients with previously metastatic or unresectable cancer, lung resection for suspected residual disease after immunotherapy is feasible, with high rates of R0 resection. Operations can be technically challenging, but significant morbidity appears to be rare. Outcomes are encouraging, with reasonable survivals during short-interval follow-up.
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http://dx.doi.org/10.1016/j.athoracsur.2018.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357770PMC
July 2018

Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery for stage II to III esophageal squamous cell carcinoma.

J Thorac Cardiovasc Surg 2018 06 15;155(6):2710-2721.e3. Epub 2018 Feb 15.

Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: Definitive chemoradiotherapy (CRT) remains the most commonly used treatment for locally advanced esophageal squamous cell carcinoma (SCC), because of perceptions that esophagectomy offers an unclear survival advantage. We compare recurrence, overall survival (OS), and disease-free survival (DFS) in patients treated with definitive CRT or neoadjuvant CRT followed by surgery (trimodality).

Methods: This was a retrospective cohort study of patients with stage II and III SCC of the middle and distal esophagus in patients who completed CRT. Treatment groups were matched (1:1) on covariates using a propensity score-matching approach. The effect of trimodality treatment, compared with definitive CRT, on OS, DFS, and site-specific recurrence was evaluated as a time-dependent variable and analyzed using Cox regression with a gamma frailty term for matched units.

Results: We included 232 patients treated between 2000 and 2016: 124 (53%) with definitive CRT and 108 (47%) with trimodality. Trimodality was used less frequently over time (61% before 2009 and 29% after 2009; P < .0001). After matching, each group contained 56 patients. Median OS and DFS were 3.1 and 1.8 years for trimodality versus 2.3 and 1.0 years for CRT. Surgery was independently associated with improved OS (hazard ratio, 0.57; 95% confidence interval, 0.34-0.97; P = .039) and DFS (hazard ratio, 0.51; 95% confidence interval, 0.32-0.83; P = .007).

Conclusions: CRT followed by surgery might decrease local recurrence and increase DFS and OS in patients with esophageal SCC. Until better tools to select patients with pathological complete response are available, surgery should remain an integral component of the treatment of locally advanced esophageal SCC.
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http://dx.doi.org/10.1016/j.jtcvs.2018.01.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960990PMC
June 2018

Factors associated with distant recurrence following R0 lobectomy for pN0 lung adenocarcinoma.

J Thorac Cardiovasc Surg 2018 03 13;155(3):1212-1224.e3. Epub 2017 Nov 13.

Thoracic Surgery Service, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address:

Objective: We investigated factors associated with distant recurrence, disease-free survival (DFS), and overall survival (OS) following R0 lobectomy for pathologic node-negative (pN0) lung adenocarcinoma.

Methods: We performed a retrospective analysis of a prospectively maintained database of patients with pT1-3N0M0 non-small cell lung cancer. Exclusion criteria included metachronous lung cancer, sublobar/incomplete resection, nonadenocarcinoma histology, and induction/adjuvant therapy. The primary outcome was distant recurrence; secondary outcomes were DFS and OS. Associations between variables and outcomes were assessed by Fine-Gray competing-risk regression for distant recurrence and Cox proportional hazard models for DFS and OS.

Results: Of 2392 patients identified with pT1-3N0M0 lung adenocarcinoma, 893 met the inclusion criteria. Median follow-up was 35.0 months (range, 0.1-202 months). Thirteen percent of patients developed recurrence (n = 115), of which 86% (n = 99) were distant. The 5-year cumulative incidence of distant recurrence was 14% (95% confidence interval [CI], 11%-17%). On multivariable analysis, pT2a (hazard ratio [HR], 2.84; 95% CI, 1.56-5.16; P = .001) and pT2b/3 (HR, 6.53; 95% CI, 3.17-13.5; P < .001) tumors were associated with distant recurrence. Recent surgery was associated with decreased distant recurrence (HR, 0.43; 95% CI, 0.20-0.91; P = .028), and lymphovascular invasion was strongly associated with distant recurrence (HR, 1.62; 95% CI, 1.00-2.63; P = .05). DFS was independently associated with pT stage (P < .001) and lymphovascular invasion (P = .004).

Conclusions: In patients undergoing R0 lobectomy with pN0 lung adenocarcinoma, pT stage and lymphovascular invasion were associated with distant recurrence and decreased DFS. These observations support the inclusion of these patients in future clinical trials investigating adjuvant targeted and immunotherapies.
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http://dx.doi.org/10.1016/j.jtcvs.2017.09.151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816702PMC
March 2018

Patterns of care in hilar node-positive (N1) non-small cell lung cancer: A missed treatment opportunity?

J Thorac Cardiovasc Surg 2016 Jun 12;151(6):1549-1558.e2. Epub 2016 Mar 12.

Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, Mo. Electronic address:

Background: For patients with non-small cell lung cancer (NSCLC) metastatic to hilar lymph nodes (N1), guidelines recommend surgery and adjuvant chemotherapy in operable patients and chemoradiation (CRT) for those deemed inoperable. It is unclear how these recommendations are applied nationally, however.

Methods: The National Cancer Database was queried to identify patients with a tumor <7 cm (T1/T2) with clinically positive N1 nodes. Patients undergoing CRT (comprising chemotherapy and radiation >45 Gy) or surgical resection were considered adequately treated. Remaining patients were classified as receiving inadequate or no treatment.

Results: Of the 20,366 patients who met the study criteria, 63% underwent adequate treatment (48% surgical resection, 15% CRT). The remainder received inadequate treatment (23%) or no treatment (14%). In univariate analysis, the patients receiving inadequate or no treatment were older, tended to be non-Caucasian, had a lower income, and had a higher comorbidity score. Patients undergoing adequate treatment had improved overall survival (OS) compared with those receiving inadequate or no treatment (median OS, 34.0 months vs 11.7 months; P < .001). Of those receiving adequate treatment, logistic regression identified several variables associated with surgical resection, including treatment at an academic facility, Caucasian race, and annual income >$35,000. Increasing age and T2 stage were associated with nonoperative management. Following propensity score matching of 2308 patient pairs undergoing surgery or CRT, resection was associated with longer median OS (34.1 months vs 22.0 months; P < .001).

Conclusions: Despite the established guidelines, many patients with T1-2N1 NSCLC do not receive adequate treatment. Surgery is associated with prolonged survival in selected patients. Surgical input in the multidisciplinary evaluation of these patients should be mandatory.
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http://dx.doi.org/10.1016/j.jtcvs.2016.01.058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876013PMC
June 2016