Research Spotlight

Bliss, D. P., Jr., N. A. Vaughan, R. M. Walk, J. A. Naiditch, A. A. Kane and R. R. Hallac (2019). “Non-Radiographic Severity Measurement of Pectus Excavatum.” J Surg Res 233: 376-380.

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BACKGROUND: To avoid the radiation exposure of CT imaging and the expense of CT or MRI studies, we sought to develop a non-radiographic severity measurement of pectus excavatum based on 3D photogrammetric imaging. METHODS: Over 28 mo, ten consecutive patient volunteers with pectus excavatum underwent 3D stereophotogrammetric imaging. The surface width to surface depth ratio (Surface Lengths Pectus Index), the chest deformity’s surface area to total chest surface area (Pectus Surface Area Ratio), and the chest deformity’s volume to total chest volume (Pectus Volume Ratio) were calculated. Simple linear regression analysis compared the Surface Lengths Pectus Index, Pectus Surface Area Ratio, and Pectus Volume Ratio calculations each to the corresponding known CT pectus index. RESULTS: The correlation between CT pectus index versus Surface Lengths Pectus Index yielded an R-squared value of 0.7637 and a P value of 0.0013. A CT pectus index of 3.4 or greater (eight patients) corresponded to a Surface Lengths Pectus Index of 1.86 or greater (six patients). The CT pectus index versus Pectus Surface Area Ratio (R-squared = 0.4627, P = 0.0305) and the CT pectus index versus the Pectus Volume Ratio (R-squared = 0.3048, P = 0.0990) demonstrated less correlation. CONCLUSION: Surface Lengths Pectus Index corresponds to the CT pectus index and may be adequate to determine severity of pectus excavatum in some patients.

Zhang, Q., A. T. Agoston, T. H. Pham, W. Zhang, X. Zhang, X. Huo, S. Peng, M. Bajpai, K. Das, R. D. Odze, S. J. Spechler and R. F. Souza (2019). “Acidic Bile Salts Induce Epithelial to Mesenchymal Transition via VEGF Signaling in Non-Neoplastic Barrett’s Cells.” Gastroenterology 156(1): 130-144.e110.

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BACKGROUND & AIMS: Metaplastic glands buried under squamous epithelium are frequently detected in patients with Barrett esophagus (BE). This subsquamous intestinal metaplasia might be responsible for cancers that develop despite endoscopic surveillance and for metaplasia recurrences after endoscopic ablation. To determine whether reflux induces BE cells to undergo an epithelial-to-mesenchymal transition (EMT) that produces subsquamous intestinal metaplasia, we assessed EMT in BE cells exposed to acidic bile salts and in rat and human esophageal tissues. METHODS: We compared markers of EMT and cell motility in trans-well and 3-dimensional organotypic culture systems among dysplastic BE epithelial cell lines, nondysplastic telomerase-immortalized BE cell lines (BAR-T), and BAR-T cells exposed acutely or for 20 weeks to acidic bile salts. Vascular endothelial growth factor (VEGF) A was inhibited with a neutralizing antibody or CRISPR-Cas9n and VEGF receptor 2 was inhibited with SU1498 or shRNA, and cells were analyzed by immunohistochemistry, quantitative polymerase chain reaction, or immunoblotting for markers of VEGF signaling and EMT; cell motility was assessed by trans-well assay. We used immunohistochemistry and quantitative polymerase chain reaction to assess EMT markers in the columnar-lined esophagus of rats with surgically induced reflux esophagitis and in esophagectomy specimens from patients with BE. RESULTS: We detected features of EMT (decreased cadherin 1 [CDH1]; increased fibronectin 1, vimentin, and matrix metalloproteinase 2; and increased motility) in dysplastic BE epithelial cell lines and in BAR-T cells exposed for 20 weeks, but not in unexposed BAR-T cells. Acute acidic bile salt exposure induced expression of zinc finger E-box binding homeobox 1 and 2 (ZEB1/2) in BAR-T cells, which decreased their expression of CDH1 and increased motility; inhibitors of VEGF signaling blocked these effects. Columnar-lined esophagus of rats with reflux esophagitis had increased expression of ZEB1/2 and decreased expression of CDH1 compared with controls. Dysplastic BE tissues also had significantly increased levels of ZEB1 and significantly decreased levels of CDH1 compared with nondysplastic BE tissues. CONCLUSIONS: In BE cell lines, acidic bile salts induce EMT by VEGF signaling, which increases expression of ZEB1/2, repressors of CDH1. These observations suggest that reflux induces EMT in metaplastic BE tissues, which promotes development of subsquamous intestinal metaplasia.

Wilson, T. R., A. R. Udyavar, C. W. Chang, J. M. Spoerke, J. Aimi, H. M. Savage, A. Daemen, J. A. O’Shaughnessy, R. Bourgon and M. R. Lackner (2019). “Genomic Alterations Associated with Recurrence and TNBC Subtype in High-Risk Early Breast Cancers.” Mol Cancer Res 17(1): 97-108.

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The identification of early breast cancer patients who may benefit from adjuvant chemotherapy has evolved to include assessment of clinicopathologic features such as tumor size and nodal status, as well as several gene-expression profiles for ER-positive, HER2-negative cancers. However, these tools do not reliably identify patients at the greatest risk of recurrence. The mutation and copy-number landscape of triple-negative breast cancer (TNBC) subtypes defined by gene expression is also largely unknown, and elucidation of this landscape may shed light on novel therapeutic opportunities. The USO01062 phase III clinical trial of standard chemotherapy (with or without capecitabine) enrolled a cohort of putatively high-risk patients based on clinical features, yet only observed a 5-year disease-free survival event rate of 11.6%. In order to uncover genomic aberrations associated with recurrence, a targeted next-generation sequencing panel was used to compare tumor specimens from patients who had a recurrence event with a matched set who did not. The somatic mutation and copy-number alteration landscapes of high-risk early breast cancer patients were characterized and alterations associated with relapse were identified. Tumor mutational burden was evaluated but was not prognostic in this study, nor did it correlate with PDL1 or CD8 gene expression. However, TNBC subtypes had substantial genomic heterogeneity with a distinct pattern of genomic alterations and putative underlying driver mutations. IMPLICATIONS: The present study uncovers a compendium of genomic alterations with utility to more precisely identify high-risk patients for adjuvant trials of novel therapeutic agents.

Werchan, C. A., A. M. Steele, T. Janssens, M. W. Millard and T. Ritz (2019). “Towards an assessment of perceived COPD exacerbation triggers: Initial development and validation of a questionnaire.” Respirology 24(1): 48-54.

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BACKGROUND AND OBJECTIVE: Prevention of exacerbations in chronic obstructive pulmonary disease (COPD) is important to decrease overall declines in functioning and improve quality of life. The present study sought to develop a psychometrically valid measure of perceived triggers of exacerbations in COPD patients, the COPD Exacerbation Trigger Inventory (CETI). METHODS: Participants (n = 192) were recruited through local clinics and online to complete surveys of the CETI, demographic information, disease-specific information and the COPD Assessment Test (CAT). The CETI included a free response section on patients’ individual top triggers, combined with ratings of their controllability. RESULTS: Exploratory principal component analyses identified a stable 5-factor structure (33 items), from which trigger subscales for weather/climate, air pollution/irritants, exercise, infection/illness and psychological factors were formed (internal consistency Cronbach’s alpha = 0.90-0.94). Trigger factors were associated with COPD functional status, exacerbation frequency and healthcare utilization. Participants found personal triggers related to dust, air pollution, smoking and physical activity to be the most easily controlled, whereas those related to psychological factors, climate, infection, respiratory symptoms and sleep to be more difficult to control. Greater perceived controllability of triggers was associated with lower CAT scores, indicating better health status and less impact of the disease on functioning. CONCLUSION: The CETI is a psychometrically valid measure of perceived exacerbation triggers in patients with COPD. Perceived triggers are associated with clinical outcomes. Assessment of trigger classes and their controllability may prove useful in both research and clinical settings with COPD patients and to further our knowledge in prevention and disease management.

Villarreal, R., B. B. Wrobel, L. F. Macias-Valle, G. E. Davis, T. J. Prihoda, A. U. Luong, K. C. McMains, E. K. Weitzel, W. C. Yao, J. Brunworth, D. W. Clark, S. Nair, C. J. Valdes, A. Halderman, D. W. Jang, R. Sivasubramaniam, Z. Zhang and P. G. Chen (2019). “International assessment of inter- and intrarater reliability of the International Frontal Sinus Anatomy Classification system.” Int Forum Allergy Rhinol 9(1): 39-45.

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BACKGROUND: Inconsistencies in the nomenclature of structures of the frontal sinus have impeded the development of a validated “reference standard” classification system that surgeons can reliably agree upon. The International Frontal Sinus Anatomy Classification (IFAC) system was developed as a consensus document, based on expert opinion, attempting to address this issue. The purposes of this study are to: establish the reliability of the IFAC as a tool for classifying cells in the frontal recess among an international group of rhinologists; and improve communication and teaching of frontal endoscopic sinus surgery (ESS). METHODS: Forty-two computed tomography (CT) scans, each with a marked frontal cell, were reviewed by 15 international fellowship-trained rhinologists. Each marked cell was classified into 1 of 7 categories described in the IFAC, on 2 occasions separated by 2 weeks. Inter- and intrarater reliability were evaluated using Light’s kappa (kappa), the interclass correlation coefficient (ICC), and simple proportion of agreement. RESULTS: Interrater reliability showed pairwise kappa values ranging from 0.7248 to 1.0, with a mean of 0.9162 (SD, 0.0537). The ICC was 0.98. Intrarater reliability showed kappa values ranging from 0.8613 to 1.0, with a mean of 0.9407 (SD, 0.0376). The within-rater ICC was 0.98. CONCLUSION: Among a diverse sample of rhinologists (raters), there was substantial to almost perfect agreement between raters, and among individual raters at different timepoints. The IFAC is a reliable tool for classification of cells in the frontal sinus. Further outcome studies are still needed to determine the validity of the IFAC.