Ancient developmental genes underlie evolutionary novelties in walking fish.

A critical question in biology is how new traits evolve, but studying this in wild animals remains challenging. Here, we probe the genetic basis of trait gain in sea robin fish, which have evolved specialized leg-like appendages for locomotion and digging along the ocean floor. We use genome sequencing, transcriptional profiling, and interspecific hybrid analysis to explore the molecular and developmental basis of leg formation. We identified the ancient, conserved transcription factor tbx3a as a major determinant of sensory leg development. Genome editing confirms that tbx3a is required for normal leg formation in sea robins, and for formation of enlarged central nervous system lobes, sensory papillae, and adult digging behavior. Our study establishes sea robins as a model organism for studying the evolution of major trait gain and illustrates how ancient developmental control genes can underlie novel organ formation.

Assessing the transportability of radiomic models for lung cancer diagnosis: commercial vs. open-source feature extractors.

Background: Radiomics has shown promise in improving malignancy risk stratification of indeterminate pulmonary nodules (IPNs) with many platforms available, but with no head-to-head comparisons. This study aimed to evaluate transportability of radiomic models across platforms by comparing performances of a commercial radiomic feature extractor (HealthMyne) with an open-source extractor (PyRadiomics) on diagnosis of lung cancer in IPNs. Methods: A commercial radiomic feature extractor was used to segment IPNs from computed tomography (CT) scans, and a previously validated radiomic model based on commercial features was used as baseline (ComRad). Using same segmentation masks, PyRadiomics, an open-source feature extractor was used to build three open-source radiomic models (OpenRad) using different methods: de novo open-source model derived using least absolute shrinkage and selection operator (LASSO) for feature selection, selecting open-source features matched to ComRad features based upon Imaging Biomarker Standardization Initiative (IBSI) nomenclature, and selecting open-source features most highly correlated to ComRad features. Radiomic models were trained on an internal cohort (n=161) and externally validated on 3 cohorts (n=278). We added Mayo clinical risk score to OpenRad and ComRad models, creating integrated clinical radiomic (ClinRad) models. All models were compared using area under the curve (AUC) and evaluated for clinical improvement using bias-corrected clinical net reclassification indices (cNRIs). Results: ComRad AUC was 0.76 [95% confidence interval (CI): 0.71-0.82], and OpenRad AUC was 0.75 (95% CI: 0.69-0.81) for LASSO model, 0.74 (95% CI: 0.68-0.79) for Spearman's correlation, and 0.71 (95% CI: 0.65-0.77) for IBSI. Mayo scores were added to OpenRad LASSO model, which performed best, forming open-source ClinRad model with AUC of 0.80 (95% CI: 0.74-0.86), identical to commercial ClinRad's AUC. Both ClinRad models showed clinical improvement compared to Mayo alone, with commercial ClinRad achieving cNRI of 0.09 (95% CI: 0.02-0.15) for benign and 0.07 (95% CI: 0.00-0.13) for malignant, and open-source ClinRad achieving cNRI of 0.09 (95% CI: 0.02-0.15) for benign and 0.06 (95% CI: 0.00-0.12) for malignant. Conclusions: Transportability of radiomic models across platforms directly does not conserve performance, but radiomic platforms can provide equivalent results when building de novo models allowing for flexibility in feature selection to maximize prediction accuracy.

High-frequency ultrasound accuracy in preoperative cutaneous melanoma assessment: A meta-analysis.

BACKGROUND: High-frequency ultrasound (HFUS) can safely and efficiently visualize cutaneous tumour characteristics including depth. OBJECTIVES: We aimed to evaluate its accuracy in measuring melanoma depth against the gold standard, histopathology, for treatment planning. METHODS: A review of publications was conducted in March 2023 through five electronic databases. Thirty-six included articles studied patients who received HFUS (≥10 MHz) measurements, melanoma biopsy or excision, and reported a tumour depth correlation coefficient between HFUS and histopathology. We analysed correlation coefficients between HFUS and histopathology, measured tumour depths and shed light on reasons for mismeasurements. Additionally, we identified the reporting of critical metrics including, lesion characteristics, melanoma subtype, type of correlation coefficient, 95% confidence intervals for Pearson coefficients and sample size. RESULTS: The most common tumour imaged was superficial spreading melanoma on the trunk and extremities, followed by head/face. Maximum ultrasound frequencies ranged from 13 MHz to 100 MHz with participants ranging from 5 to 264. Histopathology and HFUS correlation coefficients ranged from 0.417 to 0.997 (median: 0.94, mean: 0.89 and SD: 0.13). Lower frequency probes (10-20 MHz) were less accurate in assessing melanoma thickness, with a cumulative mean correlation coefficient of 0.87 compared to 0.94 (20-25 MHz) and 0.98 (≥70 MHz). Studies demonstrated higher sonographic accuracy in melanomas >0.75 mm. Additionally, ultrasound may report increased melanoma depth compared to histopathology for reasons including lymphocytic infiltration, presence of a nevus and shrinkage during specimen processing. Furthermore, we found a gap in the reporting of details such as fundamental characteristics of lesion populations. Specifically, 86% (31 out of 36) of the studies failed to report one or more critical metrics, such as mean, median or range of lesion depths. CONCLUSIONS: HFUS may serve as a supplementary tool for preoperative melanoma assessment, with increased accuracy in thicker tumours. Frequencies <20 MHz are less reliable in assessing depth. Frequencies ≥70 MHz demonstrate stronger correlations to histopathology. Higher ultrasound accuracy was seen for melanomas with Breslow depth >0.75 mm.

Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.

Effects of Anterior Fundoplication on Postoperative Dysphagia and Reflux After Laparoscopic Esophagocardiomyotomy for Pediatric Achalasia.

Introduction: Achalasia among children often fails endoscopic management (e.g., dilation, botulinum toxin). Laparoscopic esophagocardiomyotomy (L-ECM) is a standard intervention to relieve obstruction but can induce gastroesophageal reflux (GER). Concurrent anterior fundoplication (A-fundo) has been evaluated in randomized trials among adults, demonstrating mixed results on controlling postoperative GER without exacerbating dysphagia. Furthermore, evidence for the best approach among children remains sparse. We hypothesized that, among children undergoing L-ECM without mucosal violation, routine A-fundo would not improve postoperative GER control while exacerbating dysphagia. Materials and Methods: Observational data of 47 consecutive achalasia patients ≤18 years who received L-ECM (2002-2023) at a single academic institution were collected. Patient records were culled for demographics, achalasia characteristics, and outcomes. Two L-ECM groups were identified: with or without A-fundo. Patients were screened for postoperative dysphagia (additional procedures) and GER (new antireflux medications). Univariate independence testing was conducted to identify statistically significant variables. Results: Among 47 patients undergoing L-ECM, 28 (59.6%) received concurrent A-fundo. Compared with patients undergoing L-ECM alone, patients with L-ECM/A-fundo had significantly longer hospital stays (P < .01) without statistically different rates of postoperative dysphagia (P = .81) or GER (P = .51). Five children (10.6%) experienced mucosal injury with L-ECM: 4 recognized intraoperatively received A-Fundo without subsequent leak; 1 mucosal injury was missed and did not receive A-Fundo, which subsequently leaked. Conclusion: In this largest observation of pediatric achalasia patients, A-fundo appeared clinically insignificant when determining contributors to control GER or exacerbate postoperative dysphagia. A-fundo should not be routinely adopted in children having L-ECM for achalasia without further multicenter analysis but appears beneficial in cases having inadvertent mucosal violation.

Curating retrospective multimodal and longitudinal data for community cohorts at risk for lung cancer.

BACKGROUND: Large community cohorts are useful for lung cancer research, allowing for the analysis of risk factors and development of predictive models. OBJECTIVE: A robust methodology for (1) identifying lung cancer and pulmonary nodules diagnoses as well as (2) associating multimodal longitudinal data with these events from electronic health record (EHRs) is needed to optimally curate cohorts at scale. METHODS: In this study, we leveraged (1) SNOMED concepts to develop ICD-based decision rules for building a cohort that captured lung cancer and pulmonary nodules and (2) clinical knowledge to define time windows for collecting longitudinal imaging and clinical concepts. We curated three cohorts with clinical data and repeated imaging for subjects with pulmonary nodules from our Vanderbilt University Medical Center. RESULTS: Our approach achieved an estimated sensitivity 0.930 (95% CI: [0.879, 0.969]), specificity of 0.996 (95% CI: [0.989, 1.00]), positive predictive value of 0.979 (95% CI: [0.959, 1.000]), and negative predictive value of 0.987 (95% CI: [0.976, 0.994]) for distinguishing lung cancer from subjects with SPNs. CONCLUSION: This work represents a general strategy for high-throughput curation of multi-modal longitudinal cohorts at risk for lung cancer from routinely collected EHRs.

Coaching Program to Address Burnout, Well-Being, and Professional Development in Pediatric Surgery Trainees: A Randomized Controlled Trial.

OBJECTIVE: To assess impact of participation in a positive psychology coaching program on trainee burnout and well-being. BACKGROUND: Coaching using principles of positive psychology can improve well-being and reduce physician burnout. We hypothesized that participation in a coaching program would improve pediatric surgery trainee well-being. METHODS: With IRB approval, a coaching program was implemented during the COVID-19 pandemic (9/2020-7/2021) in the American Pediatric Surgical Association. Volunteer pediatric surgery trainees (n=43) were randomized to receive either one-on-one quarterly virtual coaching (n=22) from a pediatric surgeon trained in coaching skills or wellness reading materials (n=21). Participants completed pre- and post-study surveys containing validated measures including PERMA (positive emotion, engagement, relationships, meaning, accomplishment), professional fulfillment, burnout, self-valuation, gratitude, coping skills, and workplace experiences. Results were analyzed using Wilcoxon rank sum test, Kruskal-Wallis test, or chi-square test. RESULTS: Forty trainees (93%) completed both the baseline and year-end surveys and were included in the analysis. Twenty-five (64%) were female, mean age 35.7 (SD 2.3), 65% first-year fellows. Coached trainees showed an improved change in PERMA (P=0.034), burnout (P=0.024), and gratitude (P=0.03) scores from pre- to post-coaching compared to non-coached trainees. Coping skills also improved. More coaching sessions was associated with higher self-valuation scores (P=0.042), and more opportunities to reflect was associated with improved burnout and self-valuation. CONCLUSIONS: Despite the stress and challenges of medicine during COVID-19, a virtual positive psychology coaching program provided benefit in well-being and burnout to pediatric surgery trainees. Coaching should be integrated into existing wellness programs to support acquisition of coping skills that help trainees cope with the stressors they will face during their careers.

Robotic versus Electromagnetic bronchoscopy for pulmonary LesIon AssessmeNT: the RELIANT pragmatic randomized trial.

BACKGROUND: Robotic-assisted bronchoscopy has recently emerged as an alternative to electromagnetic navigational bronchoscopy for the evaluation of peripheral pulmonary lesions. While robotic-assisted bronchoscopy is proposed to have several advantages, such as an easier learning curve, it is unclear if it has comparable diagnostic utility as electromagnetic navigational bronchoscopy. METHODS: Robotic versus Electromagnetic bronchoscopy for pulmonary LesIon AssessmeNT (RELIANT) is an investigator-initiated, single-center, open label, noninferiority, cluster randomized controlled trial conducted in two operating rooms at Vanderbilt University Medical Center. Each operating room (OR) is assigned to either robotic-assisted or electromagnetic navigational bronchoscopy each morning, with each OR day considered one cluster. All patients undergoing diagnostic bronchoscopy for evaluation of a peripheral pulmonary lesion in one of the two operating rooms are eligible. Schedulers, patients, and proceduralists are blinded to daily group allocations until randomization is revealed for each operating room each morning. The primary endpoint is the diagnostic yield defined as the proportion of cases yielding lesional tissue. Secondary and safety endpoints include procedure duration and procedural complications. Enrolment began on March 6, 2023, and will continue until 202 clusters have been accrued, with expected enrolment of approximately 400 patients by the time of completion in March of 2024. DISCUSSION: RELIANT is a pragmatic randomized controlled trial that will compare the diagnostic yield of the two most commonly used bronchoscopic approaches for sampling peripheral pulmonary lesions. This will be the first known cluster randomized pragmatic trial in the interventional pulmonology field and the first randomized controlled trial of robotic-assisted bronchoscopy. TRIAL REGISTRATION: ClinicalTrials.gov registration (NCT05705544) on January 30, 2023.

Pediatric Otolaryngology Short-Term Mission Outcomes at a Surgical Mission Hospital in Guatemala.

OBJECTIVE: The frequency of humanitarian surgical mission trips has grown over recent decades. Unfortunately, research on patient outcomes from these trips has not increased proportionately. We aim to analyze the safety and efficacy of surgeries in a low- and middle-income country missions-based surgery center in Guatemala City, Guatemala, and identify factors that influence surgical outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: Guatemalan surgery center is called the Moore Center. METHODS: Pediatric patients underwent otolaryngology surgery between 2017 and 2019. All patients required follow up. We analyzed the effect of patient, surgical, and geographic factors on follow up and complications with univariate and multivariate analyses. RESULTS:  A total of 1094 otolaryngologic surgeries were performed between 2017 to 2019, which comprised 37.4% adenotonsillectomies, 26.8% cleft lip (CL)/cleft palate (CP) repairs, 13.6% otologic, and 20% "other" surgeries. Patients traveled on average 88 km to the center (±164 km). Eighty-nine percent attended their first follow up and 55% attended their second. The 11% who missed their first follow up lived farther from the center (p < .001) and had a higher ASA classification (p < .001) than the 89% who did attend. Sixty-nine (6.3%) patients had 1 or more complications. CL/CP surgery was associated with more complications than other procedures (p < .001). Of 416 tonsillectomies, 4 patients (1%) had a bleeding episode with 2 requiring reoperation. CONCLUSION: This surgical center models effective surgical care in low-resource areas. Complications and follow-up length vary by diagnosis. Areas to improve include retaining complex patients for follow up and reducing complications for CL/CP repair.

Spray Cryotherapy for Benign Large Airway Stenosis: A Multicenter Retrospective Cohort Study of Safety and Practice Patterns.

BACKGROUND: Benign airway stenosis (BAS) represents a significant burden on patients, providers, and healthcare systems. Spray cryotherapy (SCT) has been proposed as an adjunctive treatment to reduce BAS recurrence. We sought to examine safety and practice variations of the latest SCT system when used for BAS. METHODS: We conducted a retrospective multicenter cohort study in seven academic institutions within the Interventional Pulmonary Outcomes Group. All patients who underwent at least one SCT session with a diagnosis of BAS at the time of procedure at these institutions were included. Demographics, procedure characteristics, and adverse events were captured through each center's procedural database and electronic health record. RESULTS: A total of 102 patients underwent 165 procedures involving SCT from 2013 to 2022. The most frequent etiology of BAS was iatrogenic (n = 36, 35%). In most cases, SCT was used prior to other standard BAS interventions (n = 125; 75%). The most frequent SCT actuation time per cycle was five seconds. Pneumothorax complicated four procedures, requiring tube thoracostomy in two. Significant post-SCT hypoxemia was noted in one case, with recovery by case conclusion and no long-term effects. There were no instances of air embolism, hemodynamic compromise, or procedural or in-hospital mortality. CONCLUSION: SCT as an adjunctive treatment for BAS was associated with a low rate of complications in this retrospective multicenter cohort study. SCT-related procedural aspects varied widely in examined cases, including actuation duration, number of actuations, and timing of actuations relative to other interventions.

The genetic basis of novel trait gain in walking fish.

A major goal in biology is to understand how organisms evolve novel traits. Multiple studies have identified genes contributing to regressive evolution, the loss of structures that existed in a recent ancestor. However, fewer examples exist for genes underlying constructive evolution, the gain of novel structures and capabilities in lineages that previously lacked them. Sea robins are fish that have evolved enlarged pectoral fins, six mobile locomotory fin rays (legs) and six novel macroscopic lobes in the central nervous system (CNS) that innervate the corresponding legs. Here, we establish successful husbandry and use a combination of transcriptomics, CRISPR-Cas9 editing, and behavioral assays to identify key transcription factors that are required for leg formation and function in sea robins. We also generate hybrids between two sea robin species with distinct leg morphologies and use allele-specific expression analysis and gene editing to explore the genetic basis of species-specific trait diversity, including a novel sensory gain of function. Collectively, our study establishes sea robins as a new model for studying the genetic basis of novel organ formation, and demonstrates a crucial role for the conserved limb gene tbx3a in the evolution of chemosensory legs in walking fish.

Inter-rater reliability of a novel objective endpoint for benign central airway stenosis interventions: Segmentation-based volume rendering of computed tomography scans.

OBJECTIVES: To evaluate the reliability of a novel segmentation-based volume rendering approach for quantification of benign central airway obstruction (BCAO). DESIGN: A retrospective single-center cohort study. SETTING: Data were ascertained using electronic health records at a tertiary academic medical center in the United States. PARTICIPANTS AND INCLUSION: Patients with airway stenosis located within the trachea on two-dimensional (2D) computed tomography (CT) imaging and documentation of suspected benign etiology were included. Four readers with varying expertise in quantifying tracheal stenosis severity were selected to manually segment each CT using a volume rendering approach with the available free tools in the medical imaging viewing software OsiriX (Bernex, Switzerland). Three expert thoracic radiologists were recruited to quantify the same CTs using traditional subjective methods on a continuous and categorical scale. OUTCOME MEASURES: The interrater reliability for continuous variables was calculated by the intraclass correlation coefficient (ICC) using a two-way mixed model with 95% confidence intervals (CI). RESULTS: Thirty-eight patients met the inclusion criteria, and fifty CT scans were selected for measurement. The most common etiology of BCAO was iatrogenic in 22 patients (58%). There was an even distribution of chest and neck CT imaging within our cohort. The average ICC across all four readers for the volume rendering approach was 0.88 (95% CI, 0.84 to 0.93), suggesting good to excellent agreement. The average ICC for thoracic radiologists for subjective methods on the continuous scale was 0.38 (95% CI, 0.20 to 0.55), suggesting poor to fair agreement. The kappa for the categorical approach was 0.26, suggesting a slight to fair agreement amongst the raters. CONCLUSION: In this retrospective cohort study, agreement was good to excellent for raters with varying expertise in airway cross-sectional imaging using a novel segmentation-based volume rendering approach to quantify BCAO. This proposed measurement outperformed our expert thoracic radiologists using conventional subjective grading methods.

Whole-genome Comparisons Identify Repeated Regulatory Changes Underlying Convergent Appendage Evolution in Diverse Fish Lineages.

Fins are major functional appendages of fish that have been repeatedly modified in different lineages. To search for genomic changes underlying natural fin diversity, we compared the genomes of 36 percomorph fish species that span over 100 million years of evolution and either have complete or reduced pelvic and caudal fins. We identify 1,614 genomic regions that are well-conserved in fin-complete species but missing from multiple fin-reduced lineages. Recurrent deletions of conserved sequences in wild fin-reduced species are enriched for functions related to appendage development, suggesting that convergent fin reduction at the organismal level is associated with repeated genomic deletions near fin-appendage development genes. We used sequencing and functional enhancer assays to confirm that PelA, a Pitx1 enhancer previously linked to recurrent pelvic loss in sticklebacks, has also been independently deleted and may have contributed to the fin morphology in distantly related pelvic-reduced species. We also identify a novel enhancer that is conserved in the majority of percomorphs, drives caudal fin expression in transgenic stickleback, is missing in tetraodontiform, syngnathid, and synbranchid species with caudal fin reduction, and alters caudal fin development when targeted by genome editing. Our study illustrates a broadly applicable strategy for mapping phenotypes to genotypes across a tree of vertebrate species and highlights notable new examples of regulatory genomic hotspots that have been used to evolve recurrent phenotypes across 100 million years of fish evolution.

Tumoral Densities of T-Cells and Mast Cells Are Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

Introduction: Lung cancer is the deadliest cancer in the United States and worldwide, and lung adenocarcinoma (LUAD) is the most prevalent histologic subtype in the United States. LUAD exhibits a wide range of aggressiveness and risk of recurrence, but the biological underpinnings of this behavior are poorly understood. Past studies have focused on the biological characteristics of the tumor itself, but the ability of the immune response to contain tumor growth represents an alternative or complementary hypothesis. Emerging technologies enable us to investigate the spatial distribution of specific cell types within the tumor nest and characterize this immune response. This study aimed to investigate the association between immune cell density within the primary tumor and recurrence-free survival (RFS) in stage I and II LUAD. Methods: This study is a prospective collection with retrospective evaluation. A total of 100 patients with surgically resected LUAD and at least 5-year follow-ups, including 69 stage I and 31 stages II tumors, were enrolled. Multiplexed immunohistochemistry panels for immune markers were used for measurement. Results: Cox regression models adjusted for sex and EGFR mutation status revealed that the risk of recurrence was reduced by 50% for the unit of one interquartile range (IQR) change in the tumoral T-cell (adjusted hazard ratio per IQR increase = 0.50, 95% confidence interval: 0.27-0.93) and decreased by 64% in mast cell density (adjusted hazard ratio per IQR increase = 0.36, confidence interval: 0.15-0.84). The analyses were reported without the type I error correction for the multiple types of immune cell testing. Conclusions: Analysis of the density of immune cells within the tumor and surrounding stroma reveals an association between the density of T-cells and RFS and between mast cells and RFS in early-stage LUAD. This preliminary result is a limited study with a small sample size and a lack of an independent validation set.

Robotic versus Electromagnetic Bronchoscopy for Pulmonary LesIon AssessmeNT: the RELIANT pragmatic randomized trial.

Background: Robotic assisted bronchoscopy has recently emerged as an alternative to electromagnetic navigational bronchoscopy for the evaluation of peripheral pulmonary lesions. While robotic assisted bronchoscopy is proposed to have several advantages, such as an easier learning curve, it is unclear if it has comparable diagnostic utility as electromagnetic navigational bronchoscopy. Methods: Robotic versus Electromagnetic Bronchoscopy for Pulmonary LesIon AssessmeNT (RELIANT) is an investigator-initiated, single-center, open label, noninferiority, cluster randomized controlled trial conducted in two operating rooms at Vanderbilt University Medical Center. Each operating room is assigned to either robotic assisted or electromagnetic navigational bronchoscopy each morning, with each OR day considered one cluster. All patients undergoing diagnostic bronchoscopy for evaluation of a peripheral pulmonary lesion in one of the two operating rooms are eligible. Schedulers, patients and proceduralists are blinded to daily group allocations until randomization is revealed for each operating room each morning. The primary endpoint is the diagnostic yield defined as the proportion of cases yielding lesional tissue. Secondary and safety endpoints include procedure duration and procedural complications. Enrolment began on March 6, 2023, and will continue until 202 clusters have been accrued, with expected enrolment of approximately 400 patients by the time of completion in March of 2024. Discussion: RELIANT is a pragmatic randomized controlled trial that will compare the diagnostic yield of the two most commonly used bronchoscopic approaches for sampling peripheral pulmonary lesions. This will be the first known cluster randomized pragmatic trial in the interventional pulmonology field and the first randomized controlled trial of robotic assisted bronchoscopy. Trial registration: ClinicalTrials.gov registration (NCT05705544) on January 30, 2023.

Validation of a Proteomic Signature of Lung Cancer Risk from Bronchial Specimens of Risk-Stratified Individuals.

A major challenge in lung cancer prevention and cure hinges on identifying the at-risk population that ultimately develops lung cancer. Previously, we reported proteomic alterations in the cytologically normal bronchial epithelial cells collected from the bronchial brushings of individuals at risk for lung cancer. The purpose of this study is to validate, in an independent cohort, a selected list of 55 candidate proteins associated with risk for lung cancer with sensitive targeted proteomics using selected reaction monitoring (SRM). Bronchial brushings collected from individuals at low and high risk for developing lung cancer as well as patients with lung cancer, from both a subset of the original cohort (batch 1: n = 10 per group) and an independent cohort of 149 individuals (batch 2: low risk (n = 32), high risk (n = 34), and lung cancer (n = 83)), were analyzed using multiplexed SRM assays. ALDH3A1 and AKR1B10 were found to be consistently overexpressed in the high-risk group in both batch 1 and batch 2 brushing specimens as well as in the biopsies of batch 1. Validation of highly discriminatory proteins and metabolic enzymes by SRM in a larger independent cohort supported their use to identify patients at high risk for developing lung cancer.

TP53 mutation prevalence in normal airway epithelium as a biomarker for lung cancer risk.

BACKGROUND: There is a need for biomarkers that improve accuracy compared with current demographic risk indices to detect individuals at the highest lung cancer risk. Improved risk determination will enable more effective lung cancer screening and better stratification of lung nodules into high or low-risk category. We previously reported discovery of a biomarker for lung cancer risk characterized by increased prevalence of TP53 somatic mutations in airway epithelial cells (AEC). Here we present results from a validation study in an independent retrospective case-control cohort. METHODS: Targeted next generation sequencing was used to identify mutations within three TP53 exons spanning 193 base pairs in AEC genomic DNA. RESULTS: TP53 mutation prevalence was associated with cancer status (P < 0.001). The lung cancer detection receiver operator characteristic (ROC) area under the curve (AUC) for the TP53 biomarker was 0.845 (95% confidence limits 0.749-0.942). In contrast, TP53 mutation prevalence was not significantly associated with age or smoking pack-years. The combination of TP53 mutation prevalence with PLCOM2012 risk score had an ROC AUC of 0.916 (0.846-0.986) and this was significantly higher than that for either factor alone (P < 0.03). CONCLUSIONS: These results support the validity of the TP53 mutation prevalence biomarker and justify taking additional steps to assess this biomarker in AEC specimens from a prospective cohort and in matched nasal brushing specimens as a potential non-invasive surrogate specimen.

Interrater reproducibility of the Myoton and durometer devices to quantify sclerotic chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a severe complication in long-term survivors of allogeneic hematopoietic stem cell transplantation. This disease is challenging to manage clinically due to a lack of validated tools to quantitatively measure skin sclerosis. The current gold standard for measuring skin sclerosis is the NIH Skin Score which has only moderate agreement among clinicians and experts. To more accurately assess skin sclerosis in cGVHD, the Myoton and durometer devices can be used to directly measure biomechanical parameters of the skin. However, the reproducibility of these devices is not known in patients with cGVHD. To determine this reproducibility, three observers independently measured 10 anatomic sites in each of seven patients with sclerotic cGVHD using the Myoton and durometer. Clinical reproducibility was measured by mean pairwise differences (U-statistic) and intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs). Mean pairwise differences, expressed in true physical units, were used to report typical errors for each anatomic site and device. Mean pairwise differences were less than 11% of the average overall values for all five Myoton parameters and durometer hardness. These were lower for Myoton creep (4.1%), relaxation time (4.7%), and frequency (5.1%) than decrement (9.0%), stiffness (10.4%), and durometer hardness (9.0%). Myoton parameters creep, relaxation time, and frequency showed promise for capturing skin biomechanics more accurately than Myoton stiffness, decrement, or durometer hardness. Mean pairwise differences trended highest in the shin and volar forearm and lowest in the dorsal forearm. The interobserver ICC for overall (averaged across all measured body sites of a patient) creep (0.94; 95% CI 0.87-1.00), relaxation time (0.96; 95% CI 0.90-1.00), and frequency (0.95; 95% CI 0.88-1.00), trended higher than that for decrement (0.43; 95% CI 0.00-0.88), stiffness (0.92; 95% CI 0.81-1.00), and durometer hardness (0.82; 95% CI 0.61-1.00). Similar trends were observed in healthy participants. These findings can help clinicians design better studies to assess therapeutic response to new cGVHD treatments and support the interpretation of future measurements.

Predicting early versus late recovery from sport-related concussion using decision tree analysis.

OBJECTIVE: Accurately predicting early (≤ 14 days) versus typical (15-27 days) or delayed (≥ 28 days) recovery from sport-related concussion (SRC) may allow for improved resource utilization and precision in planning and carrying out rehabilitation. In this study, the authors sought to develop an algorithm that enables accurate differentiation of recovery periods and duration after SRC. The authors hypothesized that data regarding initial symptom burden as quantified by a Post-Concussion Symptom Scale (PCSS) score, time to presentation, and number of prior concussions would be the most useful for analyzing predictive factors for concussion recovery duration. METHODS: A retrospective case-control study was conducted to assess the primary outcome of days to clinical recovery following SRC in pediatric patients. Data from patients 12-18 years old presenting within 28 days of injury to an SRC clinic between November 11, 2017, and October 10, 2020, were analyzed. Patients with positive evidence of injury on head imaging or incomplete records were excluded. The primary outcome was duration of clinical recovery, grouped as early (≤ 14 days), typical (15-27 days), or delayed (≥ 28 days). Recovery was defined as follows: 1) symptom resolution or return to baseline, or 2) initiation of graduated return to play. CHAID (chi-square automatic interaction detection) analysis was used to optimize a decision tree based on 16 input factors, including age, sex, initial PCSS score, time to clinic presentation, number of prior concussions, and presence of defined symptom clusters. The cohort was randomized into training (70%) and test (30%) samples for algorithm validation. RESULTS: A total of 493 patients met the inclusion criteria (mean age 15.7 ± 1.5 years, 68.2% male, 70.0% White). The median time to presentation was 5 days (IQR 2-10 days). Most patients (52.3%) recovered within 14 days of injury, 21.5% recovered within 15-27 days, and 26.2% had a recovery period of 28 days or longer. The variables most predictive of recovery were initial PCSS score (cutoffs ≤ 6, 7-28, or ≥ 29), time to presentation (≤ 7 vs > 7 days), or prior concussions (0 vs ≥ 1). The model accurately discriminated between early versus typical or delayed recovery duration groupings (area under the curve 0.80, Youden index 0.44), and correctly classified > 90% of patients who recovered early. CONCLUSIONS: This novel three-factor predictive tool enabled accurate discrimination of early versus typical or delayed SRC recovery to better allocate resources, counsel patients, and make timely referrals.