Multi-Institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas

Mohammad A. Al Efishat, Marc F. Attiyeh, Anne A. Eaton, Mithat Gönen, Denise Prosser, Anna E. Lokshin, Carlos Fernández del Castillo, Keith D. Lillemoe, Cristina R. Ferrone, Ilaria Pergolini, Mari Mino-Kenudson, Neda Rezaee, Marco Dal Molin, Matthew J Weiss, John L Cameron, Ralph H Hruban, Michael I. D’Angelica, Peter P. Kingham, Ronald P. DeMatteo, William R. Jarnagin & 2 others Christopher Wolfgang, Peter J. Allen

Research output: Contribution to journalArticle

Abstract

OBJECTIVE:: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA:: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS:: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS:: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All 4 CF markers (MMP9, CA72–4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS:: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.

Original languageEnglish (US)
JournalAnnals of Surgery
DOIs
StateAccepted/In press - Jul 11 2017

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Pancreatic Cyst
Cyst Fluid
Validation Studies
Pancreatic Neoplasms
Nomograms
Proteins
Logistic Models
Interleukin-4
Carcinoma

ASJC Scopus subject areas

  • Surgery

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Multi-Institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas. / Al Efishat, Mohammad A.; Attiyeh, Marc F.; Eaton, Anne A.; Gönen, Mithat; Prosser, Denise; Lokshin, Anna E.; Castillo, Carlos Fernández del; Lillemoe, Keith D.; Ferrone, Cristina R.; Pergolini, Ilaria; Mino-Kenudson, Mari; Rezaee, Neda; Dal Molin, Marco; Weiss, Matthew J; Cameron, John L; Hruban, Ralph H; D’Angelica, Michael I.; Kingham, Peter P.; DeMatteo, Ronald P.; Jarnagin, William R.; Wolfgang, Christopher; Allen, Peter J.

In: Annals of Surgery, 11.07.2017.

Research output: Contribution to journalArticle

Al Efishat, MA, Attiyeh, MF, Eaton, AA, Gönen, M, Prosser, D, Lokshin, AE, Castillo, CFD, Lillemoe, KD, Ferrone, CR, Pergolini, I, Mino-Kenudson, M, Rezaee, N, Dal Molin, M, Weiss, MJ, Cameron, JL, Hruban, RH, D’Angelica, MI, Kingham, PP, DeMatteo, RP, Jarnagin, WR, Wolfgang, C & Allen, PJ 2017, 'Multi-Institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas', Annals of Surgery. https://doi.org/10.1097/SLA.0000000000002421
Al Efishat, Mohammad A. ; Attiyeh, Marc F. ; Eaton, Anne A. ; Gönen, Mithat ; Prosser, Denise ; Lokshin, Anna E. ; Castillo, Carlos Fernández del ; Lillemoe, Keith D. ; Ferrone, Cristina R. ; Pergolini, Ilaria ; Mino-Kenudson, Mari ; Rezaee, Neda ; Dal Molin, Marco ; Weiss, Matthew J ; Cameron, John L ; Hruban, Ralph H ; D’Angelica, Michael I. ; Kingham, Peter P. ; DeMatteo, Ronald P. ; Jarnagin, William R. ; Wolfgang, Christopher ; Allen, Peter J. / Multi-Institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas. In: Annals of Surgery. 2017.
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title = "Multi-Institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas",
abstract = "OBJECTIVE:: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA:: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS:: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS:: Within the group of 149 resected patients, 89 (60{\%}) had low-risk disease, and 60 (40{\%}) had high-risk disease. All 4 CF markers (MMP9, CA72–4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS:: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.",
author = "{Al Efishat}, {Mohammad A.} and Attiyeh, {Marc F.} and Eaton, {Anne A.} and Mithat G{\"o}nen and Denise Prosser and Lokshin, {Anna E.} and Castillo, {Carlos Fern{\'a}ndez del} and Lillemoe, {Keith D.} and Ferrone, {Cristina R.} and Ilaria Pergolini and Mari Mino-Kenudson and Neda Rezaee and {Dal Molin}, Marco and Weiss, {Matthew J} and Cameron, {John L} and Hruban, {Ralph H} and D’Angelica, {Michael I.} and Kingham, {Peter P.} and DeMatteo, {Ronald P.} and Jarnagin, {William R.} and Christopher Wolfgang and Allen, {Peter J.}",
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T1 - Multi-Institutional Validation Study of Pancreatic Cyst Fluid Protein Analysis for Prediction of High-Risk Intraductal Papillary Mucinous Neoplasms of the Pancreas

AU - Al Efishat, Mohammad A.

AU - Attiyeh, Marc F.

AU - Eaton, Anne A.

AU - Gönen, Mithat

AU - Prosser, Denise

AU - Lokshin, Anna E.

AU - Castillo, Carlos Fernández del

AU - Lillemoe, Keith D.

AU - Ferrone, Cristina R.

AU - Pergolini, Ilaria

AU - Mino-Kenudson, Mari

AU - Rezaee, Neda

AU - Dal Molin, Marco

AU - Weiss, Matthew J

AU - Cameron, John L

AU - Hruban, Ralph H

AU - D’Angelica, Michael I.

AU - Kingham, Peter P.

AU - DeMatteo, Ronald P.

AU - Jarnagin, William R.

AU - Wolfgang, Christopher

AU - Allen, Peter J.

PY - 2017/7/11

Y1 - 2017/7/11

N2 - OBJECTIVE:: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA:: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS:: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS:: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All 4 CF markers (MMP9, CA72–4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS:: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.

AB - OBJECTIVE:: Preliminary work by our group suggested that proteins within the pancreatic cyst fluid (CF) may discriminate degree of IPMN dysplasia. We sought to externally validate these markers and determine whether their inclusion in a preoperative clinical nomogram could increase diagnostic accuracy. SUMMARY BACKGROUND DATA:: IPMN is the most common radiographically identifiable precursor to pancreatic cancer; however, the timing and frequency of its malignant progression are unknown, and there are currently no reliable preoperative tests that can determine the grade of dysplasia in IPMN. METHODS:: Clinical and radiographic data, as well as CF samples, were obtained from 149 patients who underwent resection for IPMN at 1 of 3 institutions. High-risk disease was defined as the presence of high-grade dysplasia or invasive carcinoma. Multianalyte bead array analysis (Luminex) of CF was performed for 4 protein markers that were previously associated with high-risk disease. Logistic regression models were fit on training data, with and without adjustment for a previously developed clinical nomogram and validated with an external testing set. The models incorporating clinical risk score were presented graphically as nomograms. RESULTS:: Within the group of 149 resected patients, 89 (60%) had low-risk disease, and 60 (40%) had high-risk disease. All 4 CF markers (MMP9, CA72–4, sFASL, and IL-4) were overexpressed in patients with high-risk IPMN (P < 0.05). Two predictive models based on preselected combinations of CF markers had concordance indices of 0.76 (Model-1) and 0.80 (Model-2). Integration of each CF marker model into a previously described clinical nomogram leads to increased discrimination compared with either the CF models or nomogram alone (c-indices of 0.84 and 0.83, respectively). CONCLUSIONS:: This multi-institutional study validated 2 CF protein marker models for preoperative identification of high-risk IPMN. When combined with a clinical nomogram, the ability to predict high-grade dysplasia was even stronger.

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