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203. Abstract 2536: Mutational landscape of the bronchial epithelium of individuals at high risk for lung cancer

Author

Thomas Stricker, Shih-kai Chu, Pierre P. Massion, Yong Zou, Shilin Zhao, Chen Heidi, Angela B. Hui, Maximilian Diehn, and S. M. Jamshedur Rahman

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Oncology, business.industry, medicine, respiratory system, Lung cancer, medicine.disease, business, Bronchial epithelium
Abstract

Insights into mutational burden of the airway epithelium, the field of cancerization, may play important role in stratifying individuals at different levels of risk for lung cancer. We hypothesized that cytologically normal bronchial epithelium of patients with lung cancer and those at high risk for lung cancer harbor driver mutations. We performed next generation sequence-based targeted CAPP-Seq (CAncer Personalized Profiling by deep Sequencing) and whole exome sequencing (WES) of DNA from the bronchial epithelial cells from the bronchial brushings of individuals at-risk for lung cancer and patients with lung cancer as well as matched lung tumor tissues. We used the Tammemagi risk model to calculate the risk for lung cancer. Both CAPPSeq and WES data analyses showed higher mutation burden in lung tumor tissues compared to bronchial brushings. Using targeted CAPPSeq, a total of 129 nonsynonymous mutations were identified in bronchial brushings. Among individuals without lung cancer, 9 oncogenic driver mutations were identified in 5 out of 13 high risk and 2 out of 7 low risk individuals. Among individuals with cancer, 13 out of 22 brushings harbored 11 driver mutations, of which mutations in TP53 and PTEN were identified in both tumor and brushing matched samples. Mutations detected in the brushings of individuals with and without cancer were TP53, PIK3CA, NOTCH1, KRAS, MET, CUL3, and NF1. Using WES on the DNA from the same brushings (low risk, n=9; high risk, n=8 and lung cancer, n=17), we identified 19478 mutations total, and 90 of that were also identified by CAPPSeq. WES identified 80% of the mutations that were identified by CAPPSeq with >5% variant allelic frequencies (VAF). Mutations identified by CAPPSeq had VAF as low as 0.2% and vast majority of the mutations identified by WES had VAF >5%. Out of 9 mutations in TP53 identified in the brushings by CAPPSeq, 4 were identified by WES. Mutation in KMT2D, a histone methylation enzyme and believed to be a tumor suppressor, was identified by WES in the brushings and the tumor tissues of patients with lung cancer as well as in one high risk brushings. Mutational signature profiling identified tobacco mutational signature in the bronchial epithelium and tobacco, APOBEC and DNA-DSB repair signatures in the tumor tissues. Copy number variation (CNV) data analysis revealed significantly higher CNV levels in tumor samples than brushing samples. Genome-wide CNA profiling identified regions significantly influenced by CNV, such as deletions in chromosome region 19p13.3, which was previously reported to be related to lung cancer. We identified mutations in cancer driver genes in the bronchial brushings of individuals with and without lung cancer. This field of cancerization effect may provide a tool for risk assessment for lung cancer. This research was funded by U01CA196405 to PPM. Citation Format: SM Jamshedur Rahman, Shilin Zhao, Shih-Kai Chu, Yong Zou, Angela B. Hui, Thomas P. Stricker, Chen Heidi, Maximilian Diehn, Pierre P. Massion. Mutational landscape of the bronchial epithelium of individuals at high risk for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2536.

Published
2021

206. Sight Unseen: Diagnostic Yield and Safety Outcomes of a Novel Multimodality Navigation Bronchoscopy Platform with Real-Time Target Acquisition.

Author

Avasarala, Sameer K., Roller, Lance, Katsis, James, Chen, Heidi, Lentz, Robert J., Rickman, Otis B., and Maldonado, Fabien

Subjects
STATISTICS, SCIENTIFIC observation, ACADEMIC medical centers, MULTIVARIATE analysis, LUNG tumors, DESCRIPTIVE statistics, BRONCHOSCOPY, LONGITUDINAL method
Abstract

Background: Several advanced bronchoscopy platforms are currently available, but the clinical data supporting their use vary. Electromagnetic navigation bronchoscopy (ENB) remains the dominant technology; it is limited by its reliance on preoperative computed tomography, which only approximates patient anatomy during the procedure. Recently, ENB was enhanced with the (1) addition of digital tomosynthesis-based navigation correction, (2) improvements in planning algorithms, and (3) continuous real-time guidance (Illumisite™; Medtronic, Minneapolis, MN, USA). There are currently no clinical data on the diagnostic yield and safety profile of this system. Objectives: The primary objective of this study is to describe the diagnostic yield of the first 100 pulmonary parenchymal lesions sampled using the multimodality navigation bronchoscopy (MNB) platform. The secondary objective is to describe safety. Methods: In this single-center prospective observational study, a database was maintained to track patient, procedural, and outcome data for the first 100 consecutive lesions sampled using the MNB platform at an academic quaternary referral center. Descriptive statistics and univariate and multivariate analyses are reported. Results: The overall diagnostic yield of samples acquired was 79% (79/100). In the cohort where digital tomosynthesis was used, the diagnostic yield was 83% (69/83). Sensitivity for malignancy was 71% (52/73). Overall complication rates were low: pneumothorax (n = 3, 3%) and bleeding requiring intervention (n = 2, 2%). There were no procedural-related hospital admissions. Conclusions: The MNB system performed favorably. Platform superiority cannot be established without future prospective and comparative studies. [ABSTRACT FROM AUTHOR]

Published
2022
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211. Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD

Author

Jagasia, Madan, Scheid, Christof, Socie, Gerard, Ayuk, Francis Ayuketang, Tischer, Johanna, Donato, Michele L., Batai, Arpad, Chen, Heidi, Chen, Sheau-Chiann, Chin, Thomas, Boodee, Henri, Mitri, Ghaith, Greinix, Hildegard T., Jagasia, Madan, Scheid, Christof, Socie, Gerard, Ayuk, Francis Ayuketang, Tischer, Johanna, Donato, Michele L., Batai, Arpad, Chen, Heidi, Chen, Sheau-Chiann, Chin, Thomas, Boodee, Henri, Mitri, Ghaith, and Greinix, Hildegard T.

Abstract

The investigation of extracorporeal photopheresis (ECP) plus standard of care (SoC) (SoC+ECP) in chronic graft-versus-host disease (cGVHD) within prospective, randomized clinical studies is limited, despite its frequent clinical use. This phase 1/pilot study was the first randomized, prospective study to investigate ECP use as first-line therapy in cGVHD, based on the 2015 National Institutes of Health (NIH) consensus criteria for diagnosis and response assessment. Adult patients with new-onset (<= 3 years of hematopoietic stem cell transplantation) moderate or severe cGVHD were randomized 1:1 to 26 weeks of SoC+ECP vs SoC (corticosteroids and cyclosporine A/tacrolimus) between 2011 and 2015. The primary endpoint was overall response rate (ORR), defined as complete or partial response, at week 28 in the intention-to-treat population (ITT). Other outcomes included quality of life (QoL) measures and safety. Sixty patients were randomized; ITT included 53 patients (SoC+ECP: 29; SoC: 24). Week 28 ORR was 74.1% (SoC+ECP) and 60.9% (SoC). Investigator-assessed ORR was 56.0% (SoC+ECP) and 66.7% (SoC). Patients treated with SoC experienced a decline in QoL over the 28-week study period; QoL remained unchanged in SoC+ECP patients. Most frequent treatment-emergent adverse events (TEAEs) in SoC+ECP patients were hypertension (31.0%), cough (20.7%), dyspnea (17.2%), and fatigue (17.2%). Seventeen patients (SoC+ECP: 8; SoC: 9) experienced 35 serious adverse events (SAEs). No TEAEs or SAEs were considered related to the ECP instrument or methoxsalen. The encouraging short-term results of this study could inform the design of subsequent studies.

Published
2019

214. 46 - A Multi-Center Collaborative Study of Outcomes of TP53-Mutated MDS/AML Patients Following Allogeneic HCT

Author

Byrne, Michael, Kurian, Tony, Patel, Dilan, Tamari, Roni, Hong, Sanghee, Abdelhakim, Haitham, Klein, Victoria, Rojas, Patricio, Madhavan, Raksha, Kent, Andrew, Logan, Aaron C., Lee, Catherine J., Husnain, Muhammad, Manning, Benjamin, Tschernia, Nicholas, Dias, Ajoy, Margalski, Daniel, Goldenson, Benjamin, Byrne, Nathalie D., Chen, Heidi, Petrova-Drus, Kseniya, Sengsayadeth, Salyka, Goodman, Aaron, Howard, Dianna S., Wood, William A., Gill, Saar, Jimenez, Antonio Jimenez, Gutman, Jonathan A., Gowda, Lohith, Metheny III, Leland, Bhatnagar, Bhavana, Hamilton, Betty K., Mishra, Asmita, and Savona, Michael R.

Published
2022
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216. Cerebrospinal fluid alterations following endoscopic third ventriculostomy with choroid plexus cauterization: a retrospective laboratory analysis of two tertiary care centers

Author

Dewan, Michael C., primary, Dallas, Jonathan, additional, Zhao, Shilin, additional, Smith, Burkely P., additional, Gannon, Stephen, additional, Dawoud, Fakhry, additional, Chen, Heidi, additional, Shannon, Chevis N., additional, Rocque, Brandon G., additional, and Naftel, Robert P., additional

Published
2019
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221. Health Disparities among Pediatric Renal Tumors

Author

Neuzil, Kevin E., primary, Apple, Annie, additional, Phelps, Hannah, additional, Chen, Heidi, additional, Zhao, Shilin, additional, Sybenga, Amelia, additional, Hernan, Correa, additional, Whiteside, Martin, additional, and Lovvorn, Harold, additional

Published
2019
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222. GRAVITY VS SUCTION-DRIVEN THERAPEUTIC THORACENTESIS TO PREVENT PLEURAL-PRESSURE-RELATED COMPLICATIONS: THE GRAVITAS MULTICENTER RANDOMIZED CONTROLLED TRIAL

Author

Lentz, Robert, primary, Shojaee, Samira, additional, Grosu, Horiana, additional, Rickman, Otis, additional, Roller, Lance, additional, Pannu, Jasleen, additional, DePew, Zachary, additional, Debiane, Labib, additional, Cicenia, Joseph, additional, Akulian, Jason, additional, Walston, Charla, additional, Sanchez, Trinidad, additional, Davidson, Kevin, additional, Ahmad, Sahar, additional, Gilbert, Christopher, additional, Huggins, John, additional, Chen, Heidi, additional, Light, Richard, additional, Yarmus, Lonny, additional, Rahman, Najib, additional, and Maldonado, Fabien, additional

Published
2019
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224. Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD

Author

Jagasia, Madan, primary, Scheid, Christof, additional, Socié, Gérard, additional, Ayuk, Francis Ayuketang, additional, Tischer, Johanna, additional, Donato, Michele L., additional, Bátai, Árpád, additional, Chen, Heidi, additional, Chen, Sheau-Chiann, additional, Chin, Thomas, additional, Boodée, Henri, additional, Mitri, Ghaith, additional, and Greinix, Hildegard T., additional

Published
2019
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230. New-Onset Post-Transplant Diabetes Mellitus after Allogeneic Hematopoietic Cell Transplant Is Initiated by Insulin Resistance, Not Immunosuppressive Medications

Author

Engelhardt, Brian G., primary, Savani, Ujjawal, additional, Jung, Dae Kwang, additional, Powers, Alvin C., additional, Jagasia, Madan, additional, Chen, Heidi, additional, Winnick, Jason J., additional, Tamboli, Robyn A., additional, Crowe, James E., additional, and Abumrad, Naji N., additional

Published
2019
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232. Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial

Author

Lentz, Robert J, primary, Lerner, Andrew D, additional, Pannu, Jasleen K, additional, Merrick, Christopher M, additional, Roller, Lance, additional, Walston, Charla, additional, Valenti, Sarah, additional, Goddard, Tracey, additional, Chen, Heidi, additional, Huggins, John T, additional, Rickman, Otis B, additional, Yarmus, Lonny, additional, Psallidas, Ioannis, additional, Rahman, Najib M, additional, Light, Richard W, additional, and Maldonado, Fabien, additional

Published
2019
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237. Delayed Immune Reconstitution and Increased Viral Infections Following Haploidentical BMT with Post-Transplant Cyclophosphamide for Sickle Cell Disease: Results of a Haploidentical Transplant Consortium for Hemoglobinopathies (ICHH)

Author

Patel, Dilan Anil, primary, Dhedin, Nathalie, additional, Chen, Heidi, additional, Karnik, Leena, additional, Gatwood, Katie S., additional, Culos, Kathryn Ann A., additional, Mohan, Sanjay, additional, Connelly, James A, additional, Engelhardt, Brian G., additional, de la Fuente, Josu, additional, and Kassim, Adetola A., additional

Published
2019
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242. 1373

Author

Hanna, Eriny, primary, Betters, Kristina, additional, Chen, Heidi, additional, and Shannon, Chevis, additional

Published
2019
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243. A Prospective Trial of Extracorporeal Photopheresis for Chronic Graft-versus-Host Disease Reveals Significant Disease Response and No Association with Frequency of Regulatory T Cells

Author

Gandelman, Jocelyn S., primary, Song, D. Joanne, additional, Chen, Heidi, additional, Engelhardt, Brian G., additional, Chen, Yi-Bin, additional, Clark, William B., additional, Giver, Cynthia R., additional, Waller, Edmund K., additional, Jung, Dae Kwang, additional, and Jagasia, Madan, additional

Published
2018
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244. Gender Differences in Patient Perceptions of Physicians' Communal Traits and the Impact on Physician Evaluations.

Author

Chen, Heidi, Pierson, Emma, Schmer-Galunder, Sonja, Altamirano, Jonathan, Jurafsky, Dan, Leskovec, Jure, Fassiotto, Magali, and Kothary, Nishita

Subjects
*SEX distribution, *PATIENTS' attitudes
Abstract

Background: Communal traits, such as empathy, warmth, and consensus-building, are not highly valued in the medical hierarchy. Devaluing communal traits is potentially harmful for two reasons. First, data suggest that patients may prefer when physicians show communal traits. Second, if female physicians are more likely to be perceived as communal, devaluing communal traits may increase the gender inequity already prevalent in medicine. We test for both these effects. Materials and Methods: This study analyzed 22,431 Press Ganey outpatient surveys assessing 480 physicians collected from 2016 to 2017 at a large tertiary hospital. The surveys asked patients to provide qualitative comments and quantitative Likert-scale ratings assessing physician effectiveness. We coded whether patients described physicians with "communal" language using a validated word scale derived from previous work. We used multivariate logistic regressions to assess whether (1) patients were more likely to describe female physicians using communal language and (2) patients gave higher quantitative ratings to physicians they described with communal language, when controlling for physician, patient, and comment characteristics. Results: Female physicians had higher odds of being described with communal language than male physicians (odds ratio 1.29, 95% confidence interval 1.18–1.40, p < 0.001). In addition, patients gave higher quantitative ratings to physicians they described with communal language. These results were robust to inclusion of controls. Conclusions: Female physicians are more likely to be perceived as communal. Being perceived as communal is associated with higher quantitative ratings, including likelihood to recommend. Our study indicates a need to reevaluate what types of behaviors academic hospitals reward in their physicians. [ABSTRACT FROM AUTHOR]

Published
2021
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245. Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.

Author

Salisbury-Ruf, Christi, Salisbury-Ruf, Christi, Bertram, Clinton, Vergeade, Aurelia, Lark, Daniel, Shi, Qiong, Heberling, Marlene, Fortune, Niki, Okoye, G, Jerome, W, Wells, Quinn, Fessel, Josh, Moslehi, Javid, Chen, Heidi, Roberts, L, Boutaud, Olivier, Gamazon, Eric, Zinkel, Sandra, Salisbury-Ruf, Christi, Salisbury-Ruf, Christi, Bertram, Clinton, Vergeade, Aurelia, Lark, Daniel, Shi, Qiong, Heberling, Marlene, Fortune, Niki, Okoye, G, Jerome, W, Wells, Quinn, Fessel, Josh, Moslehi, Javid, Chen, Heidi, Roberts, L, Boutaud, Olivier, Gamazon, Eric, and Zinkel, Sandra

Abstract

Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. Bid-/- mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bids membrane binding domain, BidM148T, associates with MI predisposition. Furthermore, Bid but not BidM148T associates with Mcl-1Matrix, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.

Published
2018

246. Extracorporeal Photopheresis (ECP) Therapy with UVADEX (R) (methoxsalen) Improved Quality of Life (QoL) for National Institutes of Health (NIH)-graded Moderate to Severe Chronic Graft-vs-Host Disease (cGvHD)

Author

Jagasia, Madan, Greinix, Hildegard, Scheid, Christoph, Socie, Gerard, Ayuk, Francis, Tischer, Johanna, Donato, Michele, Batai, Arpad, Chen, Heidi, Chen, Sheau-Chiann, Chin, Thomas, Boodee, Henri, Mitri, Ghaith, Jagasia, Madan, Greinix, Hildegard, Scheid, Christoph, Socie, Gerard, Ayuk, Francis, Tischer, Johanna, Donato, Michele, Batai, Arpad, Chen, Heidi, Chen, Sheau-Chiann, Chin, Thomas, Boodee, Henri, and Mitri, Ghaith

Published
2018

247. Quantitative Analysis and Classification of the Nasal Base Using a Parametric Model.

Author

Barnes, Christian H, Barnes, Christian H, Chen, Heidi, Chen, Jason J, Su, Erica, Moy, Wesley J, Wong, Brian JF, Barnes, Christian H, Barnes, Christian H, Chen, Heidi, Chen, Jason J, Su, Erica, Moy, Wesley J, and Wong, Brian JF

Abstract

ImportanceThe nasal base view is often overlooked in rhinoplasty analysis and, unlike lateral and frontal views, lacks detailed quantitative analysis and descriptors. While shape-category analysis of the nasal base is well established, these descriptive methods remain subjective and do not facilitate quantitative analysis.ObjectiveTo establish a simple and quantitative classification scheme using a multiple-parameter numerical model for analyzing and describing the shape of the nasal base.Design, setting, and participantsDeidentified photographs of the nasal base view were analyzed without knowledge of patients' pathology or medical history. Each nose was classified into 1 of 6 categories derived from literature (equilateral, narrow, flat, cloverleaf, boxy, and round). Finite parametric modeling was performed on each nose, and the correlations between the resulting parameters and the 6 categories were analyzed. Photographs for this study were acquired from the practice of a single facial plastic surgeon (B.J.F.W.) at a tertiary care academic medical center. One hundred twenty-one consecutive patients who had nasal base view photographs taken were included in the study.Main outcomes and measuresAll of the 121 images were classified into 1 of the 6 categories by 1 reviewer (C.H.B.). The contour of each nasal base was curve fit to a 5-parameter numerical model. The 5 parameters controlled base size, deviation from the midline, projection-to-width ratio, degree of nasal alar recurvature, and anterior-posterior positioning of nasal base bulk. A numerical value for each nasal base shape type was predicted by the parametric model.ResultsIn 121 patient photographs, the parametric model generated shapes that accurately matched the tracing of the actual nasal base contours with an average correlation coefficient of greater than 0.98. This finding indicates close approximation of the nasal base shape with the curve fit constructed by the PM. Parameters b (projection-to-width r

Published
2018

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