Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma

Can F. Koyuncu; Cheng Lu; Kaustav Bera; Zelin Zhang; Jun Xu; Paula Toro; German Corredor; Deborah Chute; Pingfu Fu; Wade L. Thorstad; F. Faraji; Justin A. Bishop; Mitra Mehrad; Patricia D. Castro; Andrew G. Sikora; Lester D.R. Thompson; R. D. Chernock; Krystle A. Lang Kuhs; Jingqin Luo; Vlad Sandulache; David J. Adelstein; Shlomo Koyfman; James S. Lewis; Anant Madabhushi

doi:10.1172/JCI145488

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma

Can F. Koyuncu
, Cheng Lu
, Kaustav Bera
, Zelin Zhang
, Jun Xu
, Paula Toro
, German Corredor
, Deborah Chute
, Pingfu Fu
, Wade L. Thorstad
, F. Faraji
, Justin A. Bishop
, Mitra Mehrad
, Patricia D. Castro
, Andrew G. Sikora
, Lester D.R. Thompson
, R. D. Chernock
, Krystle A. Lang Kuhs
, Jingqin Luo
, Vlad Sandulache

David J. Adelstein, Shlomo Koyfman, James S. Lewis, Anant Madabhushi

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

BACKGROUND. Patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability. METHODS. We present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI. RESULTS. The MuNI was prognostic for DFS, overall survival (OS), or distant metastasis-free survival (DMFS) in p16+ OPSCC, with HRs of 1.78 (95% CI: 1.37-2.30), 1.94 (1.44-2.60), and 1.88 (1.43-2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately. CONCLUSION. MuNI holds promise as a low-cost, tissue-nondestructive, H&E stain-based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.

Original language	English
Article number	e145488
Journal	Journal of Clinical Investigation
Volume	131
Issue number	8
DOIs	https://doi.org/10.1172/JCI145488
State	Published - Apr 15 2021

Bibliographical note

Publisher Copyright:
© 2021, American Society for Clinical Investigation.

Funding

This work was supported by the NCI, NIH (1U24CA199374-01, R01CA202752-01A, R01CA208236-01A1, R01CA216579- 01A1, R01CA220581-01A1, 1U01CA239055-01); the National Institute for Biomedical Imaging and Bioengineering, NIH (1R43EB028736-01); the National Center for Research Resources, NIH (1C06RR12463-01); a VA Merit Review Award (IBX004121A) from the US Department of VA Biomedical Laboratory Research and Development Service; a US DOD Breast Cancer Research Program Breakthrough Level 1 Award (W81XWH-19-1-0668); a US DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558); a US DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440); the US DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329); the Ohio Third Frontier Technology Validation Fund; the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; a CTSA award to Case Western Reserve University; NCI Cancer Center Support Grant P30CA125123, NIH; Career Development Award 1 IK2 CX001953 from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant (NCI-CA125123), NIH; and the Computational Genomic Epidemiology of Cancer Program at Case Comprehensive Cancer Center (T32CA094186). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government. FUNDING. National Cancer Institute (NCI), NIH; National Institute for Biomedical Imaging and Bioengineering, NIH; National Center for Research Resources, NIH; VA Merit Review Award from the US Department of VA Biomedical Laboratory Research and Development Service; US Department of Defense (DOD) Breast Cancer Research Program Breakthrough Level 1 Award; DOD Prostate Cancer Idea Development Award; DOD Lung Cancer Investigator-Initiated Translational Research Award; DOD Peer-Reviewed Cancer Research Program; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award (CTSA) program, Case Western Reserve University; NCI Cancer Center Support Grant, NIH; Career Development Award from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant, NIH; and Computational Genomic Epidemiology of Cancer Program, Case Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government. This work was supported by the NCI, NIH (1U24CA199374-01, R01CA202752-01A, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, 1U01CA239055-01); the National Institute for Biomedical Imaging and Bioengineering, NIH (1R43EB028736-01); the National Center for Research Resources, NIH (1C06RR12463-01); a VA Merit Review Award (IBX004121A) from the US Department of VA Biomedical Laboratory Research and Development Service; a US DOD Breast Cancer Research Program Breakthrough Level 1 Award (W81XWH-19-1-0668); a US DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558); a US DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440); the US DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329); the Ohio Third Frontier Technology Validation Fund; the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; a CTSA award to Case Western Reserve University; NCI Cancer Center Support Grant P30CA125123, NIH; Career Development Award 1 IK2 CX001953 from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant (NCI-CA125123), NIH; and the Computational Genomic Epidemiology of Cancer Program at Case Comprehensive Cancer Center (T32CA094186). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government.

Funders	Funder number
Department of Biomedical Engineering
Ohio Third Frontier Technology Validation Fund
US DOD	W81XWH-16-1-0329
US Department of Defence/Department of Army
US Department of Veterans Affairs Biomedical Laboratory Research and Development Service
US Department of VA Clinical Sciences Research and Development Program	NCI-CA125123
National Institutes of Health (NIH)	R01CA202752-01A, R01CA220581-01A1, 1U01CA239055-01, 1U24CA199374-01, R01CA208236-01A1
National Institutes of Health (NIH)
U.S. Department of Defense	W81XWH-15-1-0558, W81XWH-18-1-0440, W81XWH-19-1-0668
U.S. Department of Defense
National Childhood Cancer Registry – National Cancer Institute	R01CA216579, P30CA125123, T32CA094186
National Childhood Cancer Registry – National Cancer Institute
National Institute of Biomedical Imaging and Bioengineering	1R43EB028736-01
National Institute of Biomedical Imaging and Bioengineering
National Center for Research Resources	IBX004121A, 1C06RR12463-01
National Center for Research Resources
Wallace H. Coulter Foundation
Case Western Reserve University	1 IK2 CX001953
Case Western Reserve University
DOD Peer Reviewed Cancer Research Program
Government of South Australia

ASJC Scopus subject areas

General Medicine

Access to Document

10.1172/JCI145488

Cite this

Koyuncu, C. F., Lu, C., Bera, K., Zhang, Z., Xu, J., Toro, P., Corredor, G., Chute, D., Fu, P., Thorstad, W. L., Faraji, F., Bishop, J. A., Mehrad, M., Castro, P. D., Sikora, A. G., Thompson, L. D. R., Chernock, R. D., Lang Kuhs, K. A., Luo, J., ... Madabhushi, A. (2021). Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma. Journal of Clinical Investigation, 131(8), Article e145488. https://doi.org/10.1172/JCI145488

@article{e45764d7bec84f3da05d1021a29f2624,

title = "Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma",

abstract = "BACKGROUND. Patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability. METHODS. We present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H\&E-stained slides. Representative H\&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI. RESULTS. The MuNI was prognostic for DFS, overall survival (OS), or distant metastasis-free survival (DMFS) in p16+ OPSCC, with HRs of 1.78 (95\% CI: 1.37-2.30), 1.94 (1.44-2.60), and 1.88 (1.43-2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately. CONCLUSION. MuNI holds promise as a low-cost, tissue-nondestructive, H\&E stain-based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.",

author = "Koyuncu, \{Can F.\} and Cheng Lu and Kaustav Bera and Zelin Zhang and Jun Xu and Paula Toro and German Corredor and Deborah Chute and Pingfu Fu and Thorstad, \{Wade L.\} and F. Faraji and Bishop, \{Justin A.\} and Mitra Mehrad and Castro, \{Patricia D.\} and Sikora, \{Andrew G.\} and Thompson, \{Lester D.R.\} and Chernock, \{R. D.\} and \{Lang Kuhs\}, \{Krystle A.\} and Jingqin Luo and Vlad Sandulache and Adelstein, \{David J.\} and Shlomo Koyfman and Lewis, \{James S.\} and Anant Madabhushi",

note = "Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = apr,

day = "15",

doi = "10.1172/JCI145488",

language = "English",

volume = "131",

number = "8",

}

Koyuncu, CF, Lu, C, Bera, K, Zhang, Z, Xu, J, Toro, P, Corredor, G, Chute, D, Fu, P, Thorstad, WL, Faraji, F, Bishop, JA, Mehrad, M, Castro, PD, Sikora, AG, Thompson, LDR, Chernock, RD, Lang Kuhs, KA, Luo, J, Sandulache, V, Adelstein, DJ, Koyfman, S, Lewis, JS & Madabhushi, A 2021, 'Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma', Journal of Clinical Investigation, vol. 131, no. 8, e145488. https://doi.org/10.1172/JCI145488

TY - JOUR

T1 - Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma

AU - Koyuncu, Can F.

AU - Lu, Cheng

AU - Bera, Kaustav

AU - Zhang, Zelin

AU - Xu, Jun

AU - Toro, Paula

AU - Corredor, German

AU - Chute, Deborah

AU - Fu, Pingfu

AU - Thorstad, Wade L.

AU - Faraji, F.

AU - Bishop, Justin A.

AU - Mehrad, Mitra

AU - Castro, Patricia D.

AU - Sikora, Andrew G.

AU - Thompson, Lester D.R.

AU - Chernock, R. D.

AU - Lang Kuhs, Krystle A.

AU - Luo, Jingqin

AU - Sandulache, Vlad

AU - Adelstein, David J.

AU - Koyfman, Shlomo

AU - Lewis, James S.

AU - Madabhushi, Anant

PY - 2021/4/15

Y1 - 2021/4/15

N2 - BACKGROUND. Patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability. METHODS. We present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI. RESULTS. The MuNI was prognostic for DFS, overall survival (OS), or distant metastasis-free survival (DMFS) in p16+ OPSCC, with HRs of 1.78 (95% CI: 1.37-2.30), 1.94 (1.44-2.60), and 1.88 (1.43-2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately. CONCLUSION. MuNI holds promise as a low-cost, tissue-nondestructive, H&E stain-based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.

AB - BACKGROUND. Patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability. METHODS. We present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI. RESULTS. The MuNI was prognostic for DFS, overall survival (OS), or distant metastasis-free survival (DMFS) in p16+ OPSCC, with HRs of 1.78 (95% CI: 1.37-2.30), 1.94 (1.44-2.60), and 1.88 (1.43-2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately. CONCLUSION. MuNI holds promise as a low-cost, tissue-nondestructive, H&E stain-based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.

UR - https://www.scopus.com/pages/publications/85104191246

UR - https://www.scopus.com/pages/publications/85104191246#tab=citedBy

U2 - 10.1172/JCI145488

DO - 10.1172/JCI145488

M3 - Article

C2 - 33651718

AN - SCOPUS:85104191246

SN - 0021-9738

VL - 131

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 8

M1 - e145488

ER -

Computerized tumor multinucleation index (MuNI) is prognostic in p16+ oropharyngeal carcinoma

Abstract

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