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BACKGROUND AND OBJECTIVES: There has been limited assessment between anterior cervical diskectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) on patient-reported outcome measures (PROMs) in the treatment of cervical spondylotic myelopathy. We sought to compare PROMs from two-level ACDF with single-level ACCF procedures. We evaluate these results in the context of minimum clinically important difference (MCID) thresholds, which have not been performed previously. METHODS: This retrospective analysis of prospectively collected data from the Quality Outcomes Database Spine Collaborative Research Study Group compared two-level ACDF and single-level ACCF at 3-, 12-, and 24 months postoperatively. PROMs included arm pain Numeric Rating Scale, neck pain Numeric Rating Scale, Neck Disability Index, and North American Spine Society Patient Satisfaction Index. Multivariate logistic regression was used to determine differences in perioperative outcomes, as well as the impact of two-level ACDF vs one-level ACCF on PROMs. MCID thresholds were based off previously established limits. RESULTS: Three hundred and thirty patients were included (236 ACDF, 94 ACCF), and the follow-up rate was 82% at 2 years. There was a significantly higher baseline age, American Society of Anesthesiologists grade, proportion of diabetes, osteoarthritis, ambulation dependence, and myelopathy severity in the ACCF cohort. On multivariable analysis, the ACCF group had greater average length of stay and estimated blood loss. There were no significant differences between reoperation rates or nonroutine discharge. There were similar rates of MCID achievement for PROMs at all time points. CONCLUSION: This study suggests that both ACDF and ACCF procedures for cervical spondylotic myelopathy are able to achieve similar, clinically meaningful improvements in PROMs by 2 years. Patients undergoing single-level ACCF have more estimated blood loss and longer length of stay, as well as worse baseline myelopathy. Both procedures have efficacious, durable outcomes. It is reasonable that other factors, such as radiographic characteristics and patient symptoms, may influence patient selection for ACDF vs ACCF.

Abstract Introduction Resilient smokers, who maintain respiratory health despite smoking, remain poorly characterized. Airway epithelial cell gene expression in resilient smokers can provide insight into mechanisms and pathways that may protect smokers from developing smoking-related lung disease. The objective of this study is to identify genes and potential pathways associated with lung-related resilience. Methods Resilient smokers were defined based on a previously published multi-dimensional definition which includes the absence of: 1) spirometric airflow limitation, 2) symptoms (cough/sputum, dyspnea), 3) radiographic (HRCT) abnormalities, 4) exacerbations, and 5) an accelerated FEV1 decline. “Non-resilient” smokers had preserved spirometry but showed abnormalities in at least one domain of resilience. We analyzed airway epithelial brush samples from 21 resilient and 34 non-resilient smokers from SPIROMICS. Differential gene expression was performed using DESeq2 package in R, which estimates differential expression using generalized linear models. We adjusted for sequencing batch, age (continuous), race, gender, and current smoking status. While controlling for these covariates we evaluated differential gene expression between resilient and non-resilient smokers, the interaction between resilience and smoking status, and in each sub-category of resilient (absence of symptoms, radiographic abnormalities, exacerbations, and accelerated decline in FEV1). Results We identified 98 genes that were differentially expressed (FDR ≤0.1) when comparing resilient to non-resilient smokers, 20 of those genes were up regulated in resilient smokers (Figure 1). Notable genes included cadherin-12 (CDH12), aspartate beta-hydroxylase (ASPH), and protein kinase AMP-activated alpha 2 (PRKAA2). CDH12 is involved in cell adhesion and epithelial integrity. ASPH influences cell adhesion and signaling. PRKAA2 plays role in cellular homeostasis and stress response, which may be altered in non-resilient smokers, affecting cellular metabolism and inflammation. BPI folding containing family A member (BPIFA1) was significantly associated with smoking status in the interaction analysis, suggesting its role in modulating the impact of smoking on resilience. BPIFA1 has anti-microbial properties, regulates immune responses, and contributes mucosal surface protection. Sub-category analysis identified 17 genes associated with resilience to symptoms and 2 genes related to physiologic resilience (FEV1 decline), though no significant genes were associated with radiographic or exacerbation resilience. Conclusion Differential gene expression of airway epithelial cells identified distinct expression patterns between resilient and non-resilient smokers. Specifically, genes associated with epithelial cell adhesion, signaling, and cellular homeostasis were up regulated in resilient smokers. These findings suggest that resilient smokers may have transcriptomic profiles and potential mechanisms that mitigate the effects of cigarette smoke.

Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

Abstract Rationale: MUC5B and MUC5AC are neighboring genes on chromosome 11p15 that encode the two predominant mucins secreted in the respiratory airways. Increased airway mucin concentrations and an imbalance between these two mucins drive COPD symptoms and the development of airflow obstruction or COPD, but the epigenomic regulation of this loci has not been characterized in the airways. Methods: We isolated DNA from bronchial airway brushings of 72 participants with >20 pack-years smoking history from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS). 36 participants had GOLD-based moderate-to-severe COPD (FEV1/FVC<0.70, FEV1<80%) and 36 were without or with mild COPD. We used the Illumina Infinium Methylation EPIC BeadChip Array to assess proportion of DNA methylation (β) spanning 689,937 CpG sites. We evaluated proportional DNA methylation (β) at 96 CpG loci within a 103kB region using matrixQTL for cis-expression quantitative trait methylation (eQTM: 10kB flanks relative to MUC5AC/MUC5B) integrating bulk RNA-seq data and mQTL models integrating gene sequencing data to identify DNA variation associated with proportion eQTM methylation. Models included age, sex, BMI, clinical site, current smoking vs past smoking, total pack-years, three ancestral components of ancestry, chipset, and position. Results: We identified a top eQTM, cg00524486, marginally associated with MUC5B expression (coefficient estimate=8.75, punadjusted=0.0014, pFDR=0.065, Figure 1B). This eQTM was associated with CT scan parametric response mapping-based functional small airways disease (PRM-fSAD, beta coefficient[β]=3.64, p=0.011). We tested for DNA variation associated with methylation of this top eQTM which identified two methylation quantitative trait loci (mQTL: rs885454 [β=0.044, minor allele frequency[MAF]=0.09, pFDR=0.01], rs868902 [β=0.020, MAF=0.43, pFDR=0.08, Figure 1A) associated with cg00524486 methylation, of which the more frequent mQTL, rs868902, was marginally associated with PRM-fSAD (p=0.07) in the larger SPIROMICS cohort with MUC5B DNA sequencing data. Conclusions: This preliminary multi-omic study of the lower airway epithelium demonstrates that the expression of MUC5B is epigenetically regulated by neighboring CpG probe methylation (eQTM) represented by DNA variation (mQTL). These studies require further confirmation in a larger dataset of airway samples and support a role for epigenetic variation as a biologic contributor and biomarker of early COPD pathogenesis.

Abstract Rationale Chronic obstructive pulmonary disease (COPD) manifests later in life and is a leading cause of death worldwide. While smoking-related lung pathology is a long-recognized COPD etiotype, emerging evidence suggests that early-life growth conditions also play an important role. A recently-developed index of early-life growth conditions – the difference between attained height and genotype-predicted height (height-GaP) – has been validated against prospectevely ascertained adverse early-life growth conditions. This study used height-GaP to evaluate the association of early-life growth conditions with COPD phenotype and prognosis later in life. Methods Among current and former smokers with spirometry-defined COPD in the SubPopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS), we computed height-GaP as the difference between attained height and genotype-predicted height. Regression models were fit for respiratory mortality (defined by primary diagnostic code), dyspnea prevalence (Medical Research Council dyspnea rating >1), chronic bronchitis prevalence, airflow obstruction severity as quantified by FEV1Q, and functional capacity (six-minute walk distance), adjusting for age, age2, sex, race-ethnicity, genotype-predicted height, cigarette smoking status and pack-years. Sensitivity analyses accounted for competing risks of death (Fine-Gray subdistribution hazard model) and accounted for later-life height loss (restricting sample to participants under 50 years). Results Among 1,258 participants with COPD (mean±SD age: 65.4±8.0 years, 42.4% female, mean±SD pack-years: 53.6±28.2, mean±SD FEV1%: 63.3±23.9%), there were 202 respiratory deaths over a median 7.5 years of follow-up (Figure). Larger height-GaP deficit was associated with higher respiratory mortality (adjusted hazard ratio [aHR]: 1.30 [95%CI: 1.12 to 1.50] per 1-SD increment in height-GaP deficit). This association remained significant after accounting for competing events (p=0.001) and when restricted to participants under 50 years (p=0.032). Larger height-GaP deficit was associated with higher dyspnea prevalence (adjusted prevalence ratio: 1.13 [95%CI: 1.02 to 1.25] per 1-SD increment in height-GaP deficit), lower FEV1Q (adjusted mean difference: -0.37 [95%CI: -0.45 to -0.29] per 1-SD height-GaP deficit), and shorter 6-minute walk (adjusted mean difference: -16.6 m [95%CI: -23.1 m to -10.0 m] per 1-SD increment in height-GaP deficit), but not chronic bronchitis or CAT score ≥10 (p>0.05 for each). Conclusions Among current and former smokers with COPD, a quantitative index of early-life conditions was associated with higher respiratory mortality, in addition to dyspnea, airflow obstruction severity and reduced functional capacity. These results suggest that early-life growth conditions may influence COPD phenotype and prognosis later in life.

Abstract RATIONALE: Hypereosinophilic syndrome (HES) is a group of rare diseases characterized by persistent hypereosinophilia causing organ damage/dysfunction. Idiopathic and lymphocytic HES (I-HES/L-HES) subgroups exclude clonal and reactive HES. We evaluated real-world clinical outcomes of patients with I-HES/L-HES. METHODS: This retrospective observational cohort study of patients with I-HES/L-HES collected data from the TriNetX Linked Network of de-identified Electronic Health Records plus Claims in the US. Patients had a HES diagnosis (ICD-10-CM: D72.11) between 10/01/2020–09/12/2023, with ≥12 months continuous enrollment before their first HES diagnosis record (index date [ID]). Patients with myeloproliferative/reactive HES, or a diagnosis of eosinophilic granulomatosis with polyangiitis after HES diagnosis, were excluded. Baseline was defined as 12 months prior to ID. Year 1 was defined as 12 months after ID. Patients were followed up until either 09/12/2023, disenrollment from insurance, death, or 24 months after ID, whichever came first. Clinical response was defined as ≥3 months without HES symptoms and a blood eosinophil (bEOS) count ≤750 cells/µL. Complete hematological remission was defined as a bEOS count ≤500 cells/µL. Partial remission was defined as a bEOS count <50% of baseline value, but >500 cells/µL. Kaplan-Meier curves estimated time to first HES flare and hematological remission. Analyses were descriptive. RESULTS: At ID, patients with I-HES/L-HES (N=110) had a mean (standard deviation [SD]) age of 43.8 (21.3) years; 66 (60.0%) were male, 58 (52.7%) were White and 30 (27.3%) were Black or African American. Mean (SD) follow-up was 15.1 (7.7) months. Median (95% confidence interval [CI]) time from ID to first flare (n=47) was 18.0 (11.0, not estimated) months (Table 1). Median (95% CI) time to first complete or partial hematological remission (n=52) was 15.3 (10.8, 21.6) months. The proportion of patients with a definite or probable HES flare was lower at Year 1 (10/69 [14.5%]) versus baseline (40/110 [36.4%]). Few patients achieved clinical response at baseline (10/110 [9.1%]) and Year 1 (5/69 [7.2%]). Among patients with bEOS data, mean (SD) bEOS count was 2235.3 (4351.7) cells/µL at baseline (n=51) and 833.6 (1396.0) cells/µL at Year 1 (n=11). The proportion of patients with a bEOS count <500 cells/µL was 20/51 (39.2%) at baseline and 7/11 (63.6%) at Year 1. CONCLUSION: Despite a reduced proportion of patients experiencing flares within a year after diagnosis, many did not experience hematological remission or clinical response by Year 1; suggesting high disease burden with existing treatment and the need for novel therapies to better manage I-HES/L-HES.

Abstract Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have different clinical trajectories, some with minimal symptom burden, others experiencing recurrent exacerbations, the most severe of which require hospitalization. Existing diagnostics, including spirometry and symptom assessments, lack the precision to identify high-risk patients who may benefit from timely preventive therapies. Nuclear cell-free DNA (ncfDNA) is a well-established marker of systemic tissue injury, implicated in amplifying inflammation by triggering type 1 interferon release by activating DNA-sensing pathways. Because COPD is accompanied by inflammation and tissue injury systemically, we hypothesized that ncfDNA is associated with increased risk of severe exacerbations requiring hospitalization. Methods: Design: We utilized baseline plasma samples randomly selected from 672 individuals with COPD from the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) cohort, which prospectively collected exacerbation numbers and type. The primary endpoint was exacerbation requiring hospitalization. Secondary endpoints included total number of exacerbations (defined as use of oral steroids, antibiotics, or healthcare utilization) and severe exacerbations (defined as requiring emergency room care or hospitalization). Measure: We measured plasma ncfDNA using digital droplet PCR. Analysis: We assessed the association of ncfDNA with exacerbation outcomes using negative binomial regression or Cox regression, adjusting for age, percent post-bronchodilator forced expiratory volume in one second (FEV1), supplemental oxygen use, and smoking status. Results: In total, 57% (n=383) of COPD participants experienced exacerbations, 29% (n=197) at least one severe, and 22% (n=145) requiring hospitalization, the latter at a median of 622 days from enrollment (IQR=287-997). Higher ncfDNA levels at enrollment correlated with measures of COPD severity, including baseline FEV1 (beta = -0.12, 95% CI -0.18 to -0.049, p <0.001). Higher ncfDNA associated with increased risk of COPD exacerbation requiring hospitalization (incidence rate ratio (IRR) 1.40, 95% CI 1.12-1.75, p =0.003) and severe exacerbations (IRR 1.36, 95% CI 1.11-1.67, p=0.002) and a trend towards total exacerbations (IRR 1.11, 95% CI 0.98-1.26, p= 0.09). The primary outcome, risk of time-to-first hospitalization, correlated significantly with higher ncfDNA with hazard ratio (HR) 1.23, 95% CI 1.01-1.49, p=0.037. Conclusion: These results suggest that ncfDNA may serve as a predictor for severe and hospitalization-associated COPD exacerbations. To better understand the relationship between ncfDNA and COPD pathophysiology, follow-up studies should explore longitudinal trends and cfDNA tissue sources, and their link to COPD exacerbations.

Abstract Rationale: We have previously shown reduced total IgG, IgG subclasses, and levels/function of pneumococcal-specific antibodies are associated with increased risk for exacerbations of COPD (ECOPD). The binding of IgG to its receptor, the Fc receptor for IgG (FcγR) on immune cells, has a critical role in determining antibody levels and function. In addition to our research demonstrating that IgG heavy chain gene (IGHG) variants are associated with ECOPD, single nucleotide variants (SNVs) in genes encoding FcγR (FCGR1-3, which encode receptor subtypes FcγRI, FcγRIIa/b/c, and FcγRIIIa/b) may also result in antibody deficiency and increased exacerbation risk. Due to technical challenges in accurately identifying SNVs in FCGR, this region has not been well-characterized. The limited data that exist are from people of European descent, and prior studies have not included African American participants. We therefore sought to investigate the hypothesis that distinct SNVs in genes encoding FcγR are associated with disease severity and history of exacerbations in African American people with COPD. Methods: We developed a novel pipeline to identify SNVs in the coding (CDS) regions of chromosome 1 using short-read whole genome sequence data. The pipeline was benchmarked using paired long-read samples from Genome in a Bottle. SNVs were called within CDS regions and analyzed in a meta-analysis of self-reported African American participants in SPIROMICS and COPDGene (n=3063). Genetic variants were tested for association with COPD severity (GOLD spirometry stage 1-2 vs 3-4) as well as COPD exacerbations, adjusting for age, sex and principal components controlling for population structure. Results: Eight SNVs were significantly associated with frequent ECOPD (≥2 in one year) in the meta-analysis of African American COPDGene and SPIROMICS participants (Table). Seven of these 8 SNVs were found in FCGR3; 4 in the activating FCGR3A subtype, and 3 in FCGR3B. Seven of 11 SNVs associated with COPD severity were in FCGR3 (4 in FCGR3A; 3 in FCGR3B). One SNV (rs371849) was associated with both frequent exacerbations (P=0.002) and COPD severity (P=0.044). Conclusions: We used a cutting-edge variant calling pipeline to identify multiple SNVs in FCGR, primarily involving FcγRIII receptor subtypes, associated with COPD severity and exacerbations in African American participants in SPIROMICS and COPDGene. FcγRIII variants are known to cause impaired antibody levels and function in people of European descent. The structural and functional importance of newly recognized variants in African American cohorts require further study, as they may represent immunogenetic risk factors for antibody deficiency and exacerbations.

ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by clinicians and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and 2 (online only) for more. PURPOSE To develop a clinical practice guideline and recommendations for symptom management of patients with well-differentiated grade 1 to grade 3 metastatic gastroenteropancreatic neuroendocrine tumors. METHODS ASCO convened an Expert Panel to develop a clinical practice guideline by reviewing the literature for relevant guidelines, systematic reviews, randomized controlled trials (RCTs), and observational studies to develop recommendations for clinical practice. RESULTS The literature review identified eight guidelines, 19 systematic reviews, and three RCTs that informed the development of guideline recommendations. RECOMMENDATIONS Recommendations are included for carcinoid syndrome, carcinoid heart disease and carcinoid crisis, and functional pancreatic neuroendocrine tumor syndromes. Recommendations are provided for surgical management, liver-directed therapy, and systemic therapy options, as well as palliative care. Limited guidance is provided for sequencing of interventions. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Abstract The Phase 2 IMPRIME 1 study evaluated the combination of the pathogen-associated molecular pattern (PAMP) Imprime with the immune checkpoint inhibitor (ICI) pembrolizumab as second or later line of treatment (2 L+) for patients with metastatic triple-negative breast cancer (mTNBC). Eligible patients with mTNBC received weekly Imprime (4 mg/kg) intravenously in combination with pembrolizumab (200 mg every 3 weeks). Primary endpoints were overall response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression free survival (PFS), and overall survival (OS). Exploratory endpoints included correlations between immune cell activation markers in tumor tissues and blood and response to therapy. Of the 42 evaluable patients, six had a response (one complete, five partial), with an ORR of 14.3% by RECIST v1.1. Median PFS was 2.7 months, median OS was 16.4 months, and DCR was 54.8%, with responders achieving a median DoR of 15.2 months. Therapy was generally well tolerated and resulted in an increase of immune activation markers, with higher levels of activation in peripheral blood associated with response and improved survival. The combination of Imprime and pembrolizumab was safe and demonstrated immune activation in tumor tissues and peripheral blood in patients with TNBC. Improved response rates were observed compared to historical studies of ICI monotherapy in similar patient populations. Study number (ClinicalTrials.gov trial registration): NCT02981303.