Invasive mediastinal nodal staging is recommended before curative-intent resection in patients with non–small cell lung cancer deemed at risk for mediastinal lymph node involvement. We evaluated the ...use and survival effect of preoperative invasive mediastinal nodal staging in a population-based non–small cell lung cancer cohort.
We analyzed all curative-intent resections for non–small cell lung cancer from 2009 to 2018 in 11 hospitals in 4 contiguous Dartmouth Hospital Referral Regions, comparing patients who did not have invasive mediastinal nodal staging with those who did.
Preoperative invasive nodal staging was used in 22% of 2916 patients, including mediastinoscopy only in 13%, minimally invasive procedures only in 6%, and both approaches in 3%. Sixty-three percent of patients at risk for nodal disease (tumor size ≥3.0 cm/T2-T4; N1-N3 by computed tomography or positron-emission tomography-computerized tomography criterion) did not undergo invasive staging; among those who did not have invasive testing, 47% had at least 1 of the 3 clinical indications. Mediastinoscopy yielded a median of 3 lymph nodes and 2 nodal stations; 17% of mediastinoscopies and 31% of endobronchial ultrasound procedures yielded no lymph node material. Patients not invasively staged were more likely to have no nodes (6% vs 2%; P < .0001) and no mediastinal nodes (20% vs 11%; P < .0001) examined at surgery. Invasive staging was associated with significantly better survival (P = .0157).
More than a decade after the 2001 American College of Surgeons Patient Care Evaluation report, preoperative invasive nodal staging remains underused and of variable quality, but was associated with survival benefit in high-risk patients.
The use and survival effect of invasive mediastinal staging for patients undergoing NSCLC surgery. Display omitted
Large‐scale bioprocessing is key to the successful manufacturing of a biopharmaceutical. However, cell viability and productivity are often lower in the scale‐up from laboratory to production. In ...this study, we analyzed CHO cells, which showed lower percent viabilities and productivity in a 5‐KL production scale bioreactor compared to a 20‐L bench‐top scale under seemingly identical process parameters. An increase in copper concentration in the media from 0.02 µM to 0.4 µM led to a doubling of percent viability in the production scale albeit still at a lower level than the bench‐top scale. Combined metabolomics and proteomics revealed the increased copper reduced the presence of reactive oxygen species (ROS) in the 5‐KL scale process. The reduction in oxidative stress was supported by the increased level of glutathione peroxidase in the lower copper level condition. The excess ROS was shown to be due to hypoxia (intermittent), as evidenced by the reduction in fibronectin with increased copper. The 20‐L scale showed much less hypoxia and thus less excess ROS generation, resulting in little to no impact to productivity with the increased copper in the media. The study illustrates the power of 'Omics in aiding in the understanding of biological processes in biopharmaceutical production.
For biopharmaceutical industrial scale production, productivity is often reduced compared to laboratory scale using seemingly identical parameters. The authors found that in a 5‐kL reactor, an increase in copper concentration increased titer, but still below a 20‐L scale, the latter with only minor change from copper increase. Combined metabolomics and proteomics revealed that the 5‐kL was under increased oxidative stress compared to the 20‐L scale and that this stress was due to intermittent hypoxia in the industrial scale resulting in lower titer.
The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously ...uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.
The American College of Surgeons Oncology Group Z0030 found no survival difference between patients with early stage NSCLC who had mediastinal nodal dissection or systematic sampling. However, a ...meta-analysis of 1980 patients in five randomized controlled trials from 1989 to 2007 associated better survival with nodal dissection. We tested the survival impact of the extent of nodal dissection in curative-intent resections for early stage NSCLC in a population-based observational cohort.
Resections for clinical T1 or T2, N0 or nonhilar N1, M0 NSCLC in four contiguous United States Hospital Referral Regions from 2009 to 2019 were categorized into mediastinal nodal dissection, systematic sampling, and “neither” on the basis of of the evaluation of lymph node stations. We compared demographic and clinical characteristics, perioperative complication rates, and survival after assessing statistical interactions and confounding.
Of the 1942 eligible patients, 18% had nodal dissection, 6% had systematic sampling, and 75% had an intraoperative nodal evaluation that met neither standard. In teaching hospitals, nodal dissection was associated with a lower hazard of death than “neither” resections (0.57 95% confidence interval: 0.41–0.79) but not systematic sampling (0.74 0.40–1.37) after adjusting for multiple comparisons. There was no significant difference in hazard ratios at nonteaching institutions (p > 0.3 for all comparisons). Perioperative complication rates were not significantly worse after mediastinal nodal dissection or systematic sampling, compared with “neither,” (p > 0.1 for all comparisons).
In teaching institutions, mediastinal nodal dissection was associated with superior survival over less-comprehensive pathologic nodal staging. There was no survival difference between teaching and nonteaching institutions, a finding that warrants further investigation.
To eliminate them, non-small cell lung cancer (NSCLC) care and outcome disparities need to be better understood.
How does rurality interact with NSCLC care and outcome disparities?
We examined ...guideline-concordant use of active treatment for NSCLC across five institutions in one community-based health care system spanning 44% of the Delta Regional Authority catchment area from 2011 to 2017. Institution- and patient-level rurality were based on Rural-Urban Commuting Area codes. Chi-squared, F-tests, and logistic regressions were used to analyze differences across institutions and rurality; survival was examined using log-rank tests and Cox regression.
Of 6,259 patients, 47% resided in rural areas; two of five institutions were rurally located and provided care for 20% of patients. Compared with rural residents at rural institutions, urban and rural residents attending urban institutions were more likely to receive stage-preferred treatment: OR 1.68 (95%CI, 1.44-1.96), and 1.33 (1.11-1.61), respectively, after adjusting for insurance, age, and clinical stage. Urban and rural residents attending urban institutions had a lower hazard of death compared with rural residents attending rural institutions: hazard ratio (HR) 0.69 (0.64-0.75) and 0.61 (0.55-0.67), respectively. Among recipients of stage-preferred treatment, care at urban institutions remained less hazardous: HR 0.7 (0.63-0.79). When further stratified by stage, care for late-stage patients at urban institutions remained less hazardous: HR 0.8 (0.71-0.91).
Rurality-associated treatment and survival disparities were present at the patient and institution levels, but the institution-level disparity was greater. Rural residents receiving care at urban institutions had similar outcomes to urban residents receiving care at urban hospitals. To overcome rurality-associated NSCLC survival disparity, interventions should preferentially target the institution level, including expanding access to higher-quality guideline-concordant care.
Background The National Comprehensive Cancer Network (NCCN) surgical resection guidelines for non-small cell lung cancer recommend anatomic resection, negative margins, examination of ...hilar/intrapulmonary lymph nodes, and examination of three or more mediastinal nodal stations. We examined the survival impact of these criteria. Methods A population-based observational study was done using patient-level data from all curative-intent, non-small cell lung cancer resections from 2004 to 2013 at 11 institutions in four contiguous Dartmouth Hospital referral regions in three US states. We used an adjusted Cox proportional hazards model to assess the overall survival impact of attaining NCCN guidelines. Results Of 2,429 eligible resections, 91% were anatomic, 94% had negative margins, 51% sampled hilar nodes, and 26% examined three or more mediastinal nodal stations. Only 17% of resections met all four criteria; however, there was a significant increasing trend from 2% in 2004 to 39% in 2013 ( p < 0.001). Compared with patients whose surgery missed one or more criteria, the hazard ratio for patients whose surgery met all four criteria was 0.71 (95% confidence interval: 0.59 to 0.86, p < 0.001). Margin status and the nodal staging criteria were most strongly linked with survival. Conclusions Attainment of NCCN surgical quality guidelines was low, but improving, over the past decade in this cohort from a high lung cancer mortality region of the United States. The NCCN quality criteria, especially the nodal examination criteria, were strongly associated with survival. The quality of nodal examination should be a focus of quality improvement in non-small cell lung cancer care.
Lung cancer surgery with a lymph node kit improves patient-level outcomes, but institution-level impact is unproven.
Using an institutional stepped-wedge implementation study design, we compared lung ...cancer resection quality between institutions in preimplementation and postimplementation phases of kit deployment and, within implementing institutions, resections without versus with the kit. Benchmarks included rates of nonexamination of lymph nodes, nonexamination of mediastinal lymph nodes, and attainment of American College of Surgeons Operative Standard 5.8. We report institution-level adjusted ORs (aORs) for attaining quality benchmarks.
From 2009 to 2020, three preimplementing hospitals had 953 resections; 11 implementing hospitals had 4013 resections, 58% without and 42% with the kit. Quality was better in implementing institutions and with kit cases. Compared with preimplementing institutions, the aOR for nonexamination of lymph nodes was 0.62 (0.49–0.8, p = 0.002), nonexamination of mediastinal lymph nodes was 0.56 (0.47–0.68, p < 0.0001), and attainment of Operative Standard 5.8 was 7.3 (5.6–9.4, p < 0.0001); aORs for kit cases were 0.01 (0.001–0.06), 0.08 (0.06–0.11), and 11.6 (9.9–13.7), respectively (p < 0.0001 for all). Surgical quality was persistently poor in preimplementing institutions but sequentially improved in implementing institutions in parallel with kit adoption. In implementing institutions, resections with the kit had a uniformly high level of quality, whereas nonkit cases had a low level of quality, approximating that of preimplementing institutions. Within implementing institutions, 5-year overall survival was 61% versus 51% after surgery with versus without the kit (p < 0.001).
Surgery with a lymph node specimen collection kit improved institution-level quality of curative-intent lung cancer resection.
Lung cancer screening saves lives, but implementation is challenging. We evaluated two approaches to early lung cancer detection-low-dose computed tomography screening (LDCT) and program-based ...management of incidentally detected lung nodules.
A prospective observational study enrolled patients in the early detection programs. For context, we compared them with patients managed in a Multidisciplinary Care Program. We compared clinical stage distribution, surgical resection rates, 3- and 5-year survival rates, and eligibility for LDCT screening of patients diagnosed with lung cancer.
From 2015 to May 2021, 22,886 patients were enrolled: 5,659 in LDCT, 15,461 in Lung Nodule, and 1,766 in Multidisciplinary Care. Of 150, 698, and 1,010 patients diagnosed with lung cancer in the respective programs, 61%, 60%, and 44% were diagnosed at clinical stage I or II, whereas 19%, 20%, and 29% were stage IV (
= .0005); 47%, 42%, and 32% had curative-intent surgery (
< .0001); aggregate 3-year overall survival rates were 80% (95% CI, 73 to 88) versus 64% (60 to 68) versus 49% (46 to 53); 5-year overall survival rates were 76% (67 to 87) versus 60% (56 to 65) versus 44% (40 to 48), respectively. Only 46% of 1,858 patients with lung cancer would have been deemed eligible for LDCT by US Preventive Services Task Force (USPSTF) 2013 criteria, and 54% by 2021 criteria. Even if all eligible patients by USPSTF 2021 criteria had been enrolled into LDCT, the Nodule Program would have detected 20% of the stage I-II lung cancer in the entire cohort.
LDCT and Lung Nodule Programs are complementary, expanding access to early lung cancer detection and curative treatment to different-risk populations. Implementing Lung Nodule Programs may alleviate emerging disparities in access to early lung cancer detection.
Low-dose computed tomography (LDCT) screening reduces lung cancer mortality, but current eligibility criteria underestimate risk in women and racial minorities. We evaluated the impact of screening ...criteria modifications on LDCT eligibility and lung cancer detection.
Using data from a Lung Nodule Program, we compared persons eligible for LDCT by the following: U.S. Preventive Services Task Force (USPSTF) 2013 criteria (55–80 y, ≥30 pack-years of smoking, and ≤15 y since cessation); USPSTF2021 criteria (50–80 y, ≥20 pack-years of smoking, and ≤15 y since cessation); quit duration expanded to less than or equal to 25 years (USPSTF2021-QD25); reducing the pack-years of smoking to more than or equal to 10 years (USPSTF2021-PY10); and both (USPSTF2021-QD25-PY10). We compare across groups using the chi-square test or analysis of variance.
The 17,421 individuals analyzed were of 56% female sex, 69% white, 28% black; 13% met USPSTF2013 criteria; 17% USPSTF2021; 18% USPSTF2021-QD25; 19% USPSTF2021-PY10; and 21% USPSTF2021-QD25-PY10. Additional eligible individuals by USPSTF2021 (n = 682) and USPSTF2021-QD25-PY10 (n = 1402) were 27% and 29% black, both significantly higher than USPSTF2013 (17%, p < 0.0001). These additional eligible individuals were 55% (USPSTF2021) and 55% (USPSTF2021-QD25-PY10) of female sex, compared with 48% by USPSTF2013 (p < 0.05). Of 1243 persons (7.1%) with lung cancer, 22% were screening eligible by USPSTF13. USPSTF2021-QD25-PY10 increased the total number of persons with lung cancer by 37%. These additional individuals with lung cancer were of 57% female sex (versus 48% with USPSTF2013, p = 0.0476) and 24% black (versus 20% with USPSTF2013, p = 0.3367).
Expansion of LDCT screening eligibility criteria to allow longer quit duration and fewer pack-years of exposure enriches the screening-eligible population for women and black persons.
Pathologic nodal stage is the most significant prognostic factor in resectable non-small cell lung cancer (NSCLC). The International Association for the Study of Lung Cancer NSCLC staging project ...revealed intercontinental differences in N category-stratified survival. These differences may indicate differences not only in cancer biology but also in the thoroughness of the nodal examination.
To determine whether survival was affected by sequentially more stringent definitions of pN staging quality in a cohort of patients with NSCLC after resection with curative intent.
This observational study used the Mid-South Quality of Surgical Resection cohort, a population-based database of lung cancer resections with curative intent. A total of 2047 consecutive patients who underwent surgical resection at 11 hospitals with at least 5 annual lung cancer resections in 4 contiguous US Dartmouth hospital referral regions in northern Mississippi, eastern Arkansas, and western Tennessee (>90% of the eligible population) were included. Resections were performed from January 1, 2009, through January 25, 2016. Survival was evaluated with the Kaplan-Meier method and Cox proportional hazards models.
Eight sequentially more stringent pN staging quality strata included the following: all patients (group 1); those with complete resections only (group 2); those with examination of at least 1 mediastinal lymph node (group 3); those with examination of at least 10 lymph nodes (group 4); those with examination of at least 3 hilar or intrapulmonary and at least 3 mediastinal lymph nodes (group 5); those with examination of at least 10 lymph nodes, including at least 1 mediastinal lymph node (group 6); those with examination of at least 1 hilar or intrapulmonary and at least 3 mediastinal nodal stations (group 7); and those with examination of at least 1 hilar or intrapulmonary lymph node, at least 10 total lymph nodes, and at least 3 mediastinal nodal stations (group 8).
N category-stratified overall survival.
Of the total 2047 patients (1046 men 51.1% and 1001 women 48.9%; mean SD age, 67.0 9.6 years) included in the analysis, the eligible analysis population ranged from 541 to 2047, depending on stringency. Sequential improvement in the N category-stratified 5-year survival of pN0 and pN1 tumors was found from the least stringent group (0.63 95% CI, 0.59-0.66 for pN0 vs 0.46 95% CI, 0.38-0.54 for pN1) to the most stringent group (0.71 95% CI, 0.60-0.79 for pN0 vs 0.60 95% CI, 0.43-0.73 for pN1). The pN1 cohorts with 3 or more mediastinal nodal stations examined had the most striking survival improvements. More stringently defined mediastinal nodal examination was associated with better separation in survival curves between patients with pN1 and pN2 tumors.
The prognostic value of pN stratification depends on the thoroughness of examination. Differences in thoroughness of nodal staging may explain a large proportion of intercontinental survival differences. More thorough nodal examination practice must be disseminated to improve the prognostic value of the TNM staging system. Future updates of the TNM staging system should incorporate more quality restraints.
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