Evaluation of markers of immunity in different metastatic immune microenvironments suggests more suppression within breast to liver metastases in breast cancer.

PURPOSE: Programmed death receptor ligand-1 (PD-L1) expression and tumor mutational burden (TMB) are approved screening biomarkers for immune checkpoint inhibition (ICI) in advanced triple negative breast cancer. We examined these biomarkers along with characterization of the tumor microenvironment (TME) between breast tumors (BrTs), axillary metastases (AxMs), liver metastases (LvMs), non-axillary lymph node metastases, and non-liver metastases to determine differences related to site of metastatic disease. METHODS: 3076 unpaired biopsies from breast cancer patients were analyzed using whole transcriptome sequencing and NextGen DNA depicting TMB within tumor sites. The PD-L1 positivity was determined with VENTANA PD-L1 (SP142) assay. The immune cell fraction within the TME was calculated by QuantiSeq and MCP-counter. RESULTS: Compared to BrT, more LvM samples had a high TMB (≥ 10 mutations/Mb) and fewer LvM samples had PD-L1+ expression. Evaluation of the TME revealed that LvM sites harbored lower infiltration of adaptive immune cells, such as CD4+, CD8+, and regulatory T-cells compared with the BrT foci. We saw differences in innate immune cell infiltration in LvM compared to BrT, including neutrophils and NK cells. CONCLUSIONS: LvMs are less likely to express PD-L1+ tumor cells but more likely to harbor high TMB as compared to BrTs. Unlike AxMs, LvMs represent a more immunosuppressed TME and demonstrate lower gene expression associated with adaptive immunity compared to BrTs. These findings suggest biopsy site be considered when interpreting results that influence ICI use for treatment and further investigation of immune composition and biomarkers expression by metastatic site.

Race and Ethnicity in Pulmonary Function Test Interpretation: An Official American Thoracic Society Statement.

Current American Thoracic Society (ATS) standards promote the use of race and ethnicity-specific reference equations for pulmonary function test (PFT) interpretation. There is rising concern that the use of race and ethnicity in PFT interpretation contributes to a false view of fixed differences between races and may mask the effects of differential exposures. This use of race and ethnicity may contribute to health disparities by norming differences in pulmonary function. In the United States and globally, race serves as a social construct that is based on appearance and reflects social values, structures, and practices. Classification of people into racial and ethnic groups differs geographically and temporally. These considerations challenge the notion that racial and ethnic categories have biological meaning and question the use of race in PFT interpretation. The ATS convened a diverse group of clinicians and investigators for a workshop in 2021 to evaluate the use of race and ethnicity in PFT interpretation. Review of evidence published since then that challenges current practice and continued discussion concluded with a recommendation to replace race and ethnicity-specific equations with race-neutral average reference equations, which must be accompanied with a broader re-evaluation of how PFTs are used to make clinical, employment, and insurance decisions. There was also a call to engage key stakeholders not represented in this workshop and a statement of caution regarding the uncertain effects and potential harms of this change. Other recommendations include continued research and education to understand the impact of the change, to improve the evidence for the use of PFTs in general, and to identify modifiable risk factors for reduced pulmonary function.

Race/Ethnicity, Spirometry Reference Equations, and Prediction of Incident Clinical Events: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study.

Rationale: Normal values for FEV1 and FVC are currently calculated using cross-sectional reference equations that include terms for race/ethnicity, an approach that may reinforce disparities and is of unclear clinical benefit. Objectives: To determine whether race/ethnicity-based spirometry reference equations improve the prediction of incident chronic lower respiratory disease (CLRD) events and mortality compared with race/ethnicity-neutral equations. Methods: The MESA Lung Study, a population-based, prospective cohort study of White, Black, Hispanic, and Asian adults, performed standardized spirometry from 2004 to 2006. Predicted values for spirometry were calculated using race/ethnicity-based equations following guidelines and, alternatively, race/ethnicity-neutral equations without terms for race/ethnicity. Participants were followed for events through 2019. Measurements and Main Results: The mean age of 3,344 participants was 65 years, and self-reported race/ethnicity was 36% White, 25% Black, 23% Hispanic, and 17% Asian. There were 181 incident CLRD-related events and 547 deaths over a median of 11.6 years. There was no evidence that percentage predicted FEV1 or FVC calculated using race/ethnicity-based equations improved the prediction of CLRD-related events compared with those calculated using race/ethnicity-neutral equations (difference in C statistics for FEV1, -0.005; 95% confidence interval [CI], -0.013 to 0.003; difference in C statistic for FVC, -0.008; 95% CI, -0.016 to -0.0006). Findings were similar for mortality (difference in C statistics for FEV1, -0.002; 95% CI, -0.008 to 0.003; difference in C statistics for FVC, -0.004; 95% CI, -0.009 to 0.001). Conclusions: There was no evidence that race/ethnicity-based spirometry reference equations improved the prediction of clinical events compared with race/ethnicity-neutral equations. The inclusion of race/ethnicity in spirometry reference equations should be reconsidered.

Reconsidering the Utility of Race-Specific Lung Function Prediction Equations.

Rationale: African American individuals have worse outcomes in chronic obstructive pulmonary disease (COPD). Objectives: To assess whether race-specific approaches for estimating lung function contribute to racial inequities by failing to recognize pathological decrements and considering them normal. Methods: In a cohort with and at risk for COPD, we assessed whether lung function prediction equations applied in a race-specific versus universal manner better modeled the relationship between FEV1, FVC, and other COPD outcomes, including the COPD Assessment Test, St. George's Respiratory Questionnaire, computed tomography percent emphysema, airway wall thickness, and 6-minute-walk test. We related these outcomes to differences in FEV1 using multiple linear regression and compared predictive performance between fitted models using root mean squared error and Alpaydin's paired F test. Measurements and Main Results: Using race-specific equations, African American individuals were calculated to have better lung function than non-Hispanic White individuals (FEV1, 76.8% vs. 71.8% predicted; P = 0.02). Using universally applied equations, African American individuals were calculated to have worse lung function. Using Hankinson's Non-Hispanic White equation, FEV1 was 64.7% versus 71.8% (P < 0.001). Using the Global Lung Initiative's Other race equation, FEV1 was 70.0% versus 77.9% (P < 0.001). Prediction errors from linear regression were less for universally applied equations compared with race-specific equations when examining FEV1% predicted with the COPD Assessment Test (P < 0.01), St. George's Respiratory Questionnaire (P < 0.01), and airway wall thickness (P < 0.01). Although African American participants had greater adversity (P < 0.001), less adversity was only associated with better FEV1 in non-Hispanic White participants (P for interaction = 0.041). Conclusions: Race-specific equations may underestimate COPD severity in African American individuals.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Contribution of Individual and Neighborhood Factors to Racial Disparities in Respiratory Outcomes.

Rationale: Black adults have worse health outcomes compared with white adults in certain chronic diseases, including chronic obstructive pulmonary disease (COPD).Objectives: To determine to what degree disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes.Methods: Individual and neighborhood-scale sociodemographic characteristics were determined in 2,649 current or former adult smokers with and without COPD at recruitment into SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). We assessed whether racial differences in symptom, functional, and imaging outcomes (St. George's Respiratory Questionnaire, COPD Assessment Test score, modified Medical Research Council dyspnea scale, 6-minute-walk test distance, and computed tomography [CT] scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed model regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES both separately and sequentially.Measurements and Main Results: After adjusting for COPD risk factors, Black participants had significantly worse respiratory symptoms and quality of life (modified Medical Research Council scale, COPD Assessment Test, and St. George's Respiratory Questionnaire), higher risk of severe exacerbations and higher percentage of emphysema, thicker airways (internal perimeter of 10 mm), and more air trapping on CT metrics compared with white participants. In addition, the association between Black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12-35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26-54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, Black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping, and airway wall thickness).Conclusions: Disadvantages by individual- and neighborhood-level SES each partly explain disparities in respiratory outcomes between Black individuals and white individuals. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.

How Financial Aid Policy Shortchanges American Healthcare.

Issue: Medical school debt is increasing. This trend may reduce access to medical school at a time of historic recognition of the need for greater openness and diversity in medical education by disadvantaging candidates who are underrepresented in medicine. The effects of high education-related debt for medical school needs greater consideration. Evidence: The implementation staircase model is employed as lens for understanding the impact of debt on trainees who are underrepresented in medicine and the healthcare system overall. Higher debt burdens are associated with worse mental health outcomes and increased odds of attrition in medical school. Trainees cite debt as a concern in considering primary care careers. Those with greater debt are less likely to pursue or remain in academic careers. Implications: The current financial aid system's reliance on high debt burden undermines goals to improve the representation of underrepresented candidates in primary care and academic medicine. Alternative models requiring less debt could facilitate the creation of a more diverse workforce in healthcare.

Association of Preoperative Lung Function with Complications after Lobectomy Using Race-Neutral and Race-Specific Normative Equations.

Rationale: Pulmonary function testing (PFT) is performed to aid patient selection before surgical resection for non-small cell lung cancer (NSCLC). The interpretation of PFT data relies on normative equations, which vary by race, but the relative strength of association of lung function using race-specific or race-neutral normative equations with postoperative pulmonary complications is unknown. Objectives: To compare the strength of association of lung function, using race-neutral or race-specific equations, with surgical complications after lobectomy for NSCLC. Methods: We studied 3,311 patients who underwent lobectomy for NSCLC and underwent preoperative PFT from 2001 to 2021. We used Global Lung Function Initiative equations to generate race-specific and race-neutral normative equations to calculate percentage predicted forced expiratory volume in 1 second (FEV1%). The primary outcome of interest was the occurrence of postoperative pulmonary complications within 30 days of surgery. We used unadjusted and race-adjusted logistic regression models and least absolute shrinkage and selection operator analyses adjusted for relevant comorbidities to measure the association of race-specific and race-neutral FEV1% with pulmonary complications. Results: Thirty-one percent of patients who underwent surgery experienced pulmonary complications. Higher FEV1, whether measured with race-neutral (odds ratio [OR], 0.98 per 1% change in FEV1% [95% confidence interval (CI), 0.98-0.99]; P < 0.001) or race-specific (OR, 0.98 per 1% change in FEV1% [95% CI, 0.98-0.98]; P < 0.001) normative equations, was associated with fewer postoperative pulmonary complications. The area under the receiver operator curve for pulmonary complications was similar for race-adjusted race-neutral (0.60) and race-specific (0.60) models. Using least absolute shrinkage and selection operator regression, higher FEV1% was similarly associated with a lower rate of pulmonary complications in race-neutral (OR, 0.99 per 1% [95% CI, 0.98-0.99]) and race-specific (OR, 0.99 per 1%; 95% CI, 0.98-0.99) models. The marginal effect of race on pulmonary complications was attenuated in all race-specific models compared with all race-neutral models. Conclusions: The choice of race-specific or race-neutral normative PFT equations does not meaningfully affect the association of lung function with pulmonary complications after lobectomy for NSCLC, but the use of race-neutral equations unmasks additional effects of self-identified race on pulmonary complications.

The Impact of Changing Race-Specific Equations for Lung Function Tests among Veterans with COPD.

RATIONALE: The American Thoracic Society recommended a single reference equation for spirometry but the impact to patients is not known. OBJECTIVE: To estimate the effect of changing to a single reference equation among Veterans with chronic obstructive pulmonary disease (COPD). METHODS: Cross-sectional study including Veterans aged ≥40 to ≤89 years with COPD and spirometry results from 21 facilities between 2010 - 2019. We collected race/ethnicity data from the electronic health record. We estimated the percentage change in the number of Veterans with lung function meeting clinical thresholds used to determine eligibility for lung resection for cancer, lung volume reduction surgery (LVRS), and lung transplant referral. We estimated the change for each level of VA service connection and financial impact. RESULTS: We identified 44,892 Veterans; Asian (0.5%), Black (11.8%), White (80.8%), and Hispanic (1.8%). When changing to a single reference equation, Asian and Black Veterans had reduced predicted lung function that could result in less surgical lung resection (4.4% and 11.1% respectively), while increasing LVRS (1.7% and 3.8%), and lung transplant evaluation for Black Veterans (1.2%). White Veterans had increased predicted lung function and could experience increased lung resection (8.1%), with less LVRS (3.3%), and lung transplant evaluation (0.9%). Some Asian and Black Veterans could experience an increase in monthly disability payments (+$540.38 and $398.38), while Hispanic White and White Veterans could see a decrease (-$588.79). When aggregated, Hispanic Veterans experienced changes attributable to their racial identity, and because this sample was predominantly Hispanic White, had similar results to White Veterans. CONCLUSIONS: Changing the reference equation could affect access to treatment and disability benefits, depending on race. If adopted, the use of discrete clinical thresholds needs to be reassessed, considering patient-centered outcomes.

Mimicking the breast metastatic microenvironment: characterization of a novel syngeneic model of HER2+ breast cancer.

Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (-LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases.

A new Neu-a syngeneic model of spontaneously metastatic HER2-positive breast cancer.

Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.

Lung Structure and Risk of Sleep Apnea in SPIROMICS.

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions. Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers. Methods: Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk. Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18). Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk.

Race, Racism, and Respiratory Health.

The study and practice of pulmonary medicine have been profoundly influenced by race theory, which was ascendant at the time of key developments within the specialty. We explore how, as a social determinant of health, race remains a powerful driver of present-day health disparities in respiratory diseases. Both legacy and contemporary inequities are identified through Dr DR Williams's model of cultural, structural, and interpersonal racism.

Towards a Race-Neutral System of Pulmonary Function Test Results Interpretation.

It has been observed widely that, on average, Black individuals in the United States have lower FVC than White individuals, which is thought to reflect a combination of genetic, environmental, and socioeconomic factors that are difficult to disentangle. Debate therefore persists even after the American Thoracic Society's 2023 guidelines recommending race-neutral pulmonary function test (PFT) result interpretation strategies. Advocates of race-based PFT results interpretation argue that it allows for more precise measurement and will minimize disease misclassification. In contrast, recent studies have shown that low lung function in Black patients has clinical consequences. Furthermore, the use of race-based algorithms in medicine in general is increasingly being questioned for its risk of perpetuating structural health care disparities. Given these concerns, we believe it is time to adopt a race-neutral approach, but note that more research is urgently needed to understand how race-neutral approaches impact PFT results interpretation, clinical decision-making, and patient outcomes. In this brief case-based discussion, we offer a few examples of how a race-neutral PFT results interpretation strategy will impact individuals from racial and ethnic minority groups at different scenarios and stages of life.

Beta-blocker use in patients with chronic obstructive pulmonary disease: A systematic review: A systematic review of ßB in COPD.

Beta-blockers (ßB) are a frequently used class of medications. Although ßB have many indications, those related to cardiovascular disease are among the most common and important. However, in patients with chronic obstructive pulmonary disease (COPD), ßB are used less often due to concerns about an unfavorable impact on respiratory morbidity and mortality. We performed a systematic review to assess the safety of ßB in patients with COPD. We included a total of 2 randomized controlled trials and 28 observational studies. The majority found statistically significant reductions in mortality. The two higher quality observational studies reported increased mortality with ßB. The risk of COPD exacerbations was reduced in about half of the studies. Nonetheless, there were significant biases that confounded the results. The highest quality RCT found a significant increase in severe and very severe COPD exacerbations with ßB use. In conclusion, data on the safety of ßB in patients with COPD are conflicting. However, given higher quality evidence showed harm with their use, ßB should be prescribed with caution in patients with COPD, including patients with cardiac indication for ßB.

Epidemiology of Sarcoidosis in U.S. Veterans from 2003 to 2019.

Rationale: United States veterans represent an important population to study sarcoidosis. Their unique history of environmental exposures, wide geographic distribution, and long-term enrollment in a single integrated healthcare system provides an unparalleled opportunity to understand the incidence, prevalence, and risk factors for sarcoidosis. Objectives: To determine the epidemiology, patient characteristics, geographic distribution, and associated risk factors of sarcoidosis among U.S. veterans. Methods: We used data from the Veterans Health Administration (VHA) electronic health record system between 2003 and 2019 to evaluate the annual incidence, prevalence, and geographic distribution of sarcoidosis (defined using the International Classification of Diseases codes). We used multivariate logistic regression to examine patient characteristics associated with sarcoidosis incidence. Results: Among more than 13 million veterans who received care through or paid for by the VHA, 23,747 (0.20%) incident diagnoses of sarcoidosis were identified. Compared with selected VHA control subjects using propensity score matching, veterans with sarcoidosis were more likely to be female (13.5% vs. 9.0%), of Black race (52.2% vs. 17.0%), and ever-tobacco users (74.2% vs. 64.5%). There was an increase in the annual incidence of sarcoidosis between 2004 and 2019 (from 38 to 52 cases/100,000 person-years) and the annual prevalence between 2003 and 2019 (from 79 to 141 cases/100,000 persons). In a multivariate logistic regression model, Black race (odds ratio [OR], 4.49; 95% confidence interval [CI], 4.33-4.65), female sex (OR, 1.64; 95% CI, 1.56-1.73), living in the Northeast compared with the western region (OR, 1.57; 95% CI, 1.48-1.67), history of tobacco use (OR, 1.36; 95% CI, 1.31-1.41), and serving in the Army, Air Force, or multiple branches compared with the Navy (OR, 1.08; 95% CI, 1.03-1.13; OR, 1.10; 95% CI, 1.04-1.17; OR, 1.27; 95% CI, 1.16-1.39, respectively) were significantly associated with incident sarcoidosis (P < 0.0001). Conclusions: The incidence and prevalence of sarcoidosis are higher among veterans than in the general population. Alongside traditionally recognized risk factors such as Black race and female sex, we found that a history of tobacco use within the Veterans Affairs population and serving in the Army, Air Force, or multiple service branches were associated with increased sarcoidosis risk.