Loading…

Arterial inflammation on 18FFDG PET/CT in melanoma patients treated with and without immune checkpoint inhibitors: CHECK-FLAME I

Immune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state an...

Full description

Saved in:
Bibliographic Details
Published in:Atherosclerosis 2024-11, Vol.398, p.118595
Main Authors: Polomski, Elissa A S, Kapiteijn, Ellen W, Heemelaar, Julius C, van der Kolk, Anne V, Kalisvaart, Timo M, van de Burgt, Alina, Dibbets-Schneider, Petra, van Velden, Floris H P, Seijkens, Tom T P, Stöger, J Lauran, Jukema, J Wouter, de Geus-Oei, Lioe-Fee, Antoni, M Louisa
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by
cites
container_end_page
container_issue
container_start_page 118595
container_title Atherosclerosis
container_volume 398
creator Polomski, Elissa A S
Kapiteijn, Ellen W
Heemelaar, Julius C
van der Kolk, Anne V
Kalisvaart, Timo M
van de Burgt, Alina
Dibbets-Schneider, Petra
van Velden, Floris H P
Seijkens, Tom T P
Stöger, J Lauran
Jukema, J Wouter
de Geus-Oei, Lioe-Fee
Antoni, M Louisa
description Immune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.BACKGROUND AND AIMSImmune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.Patients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.METHODSPatients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.We included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p < 0.001)
doi_str_mv 10.1016/j.atherosclerosis.2024.118595
format article
fullrecord <record><control><sourceid>proquest</sourceid><recordid>TN_cdi_proquest_miscellaneous_3108388326</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3108388326</sourcerecordid><originalsourceid>FETCH-proquest_miscellaneous_31083883263</originalsourceid><addsrcrecordid>eNqVTU1Lw0AUXETB-vEf3kXwknRfkrZbbyUmVlTwkHtZ4yvZuh9xd4NXf7orevAqDDPDzMAwdoU8R47L-SGXcSDvQq-_WYW84EWVI4rFenHEZihW6wwrUR3_8afsLIQD57xaoZixz42P5JXUoOxeS2NkVM5CAoq2vb2D56ab111qwZCW1hkJY9qQjQGiJxnpFT5UHEDaH-OmCMqYyRL0A_Vvo1M2JXZQLyo6H26g3jb1Q9Y-bp4auL9gJ3upA13-6jm7bpuu3majd-8ThbgzKvSk0ze5KexK5KIUoiyW5T-mXwCCXto</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3108388326</pqid></control><display><type>article</type><title>Arterial inflammation on 18FFDG PET/CT in melanoma patients treated with and without immune checkpoint inhibitors: CHECK-FLAME I</title><source>BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS</source><source>Elsevier</source><creator>Polomski, Elissa A S ; Kapiteijn, Ellen W ; Heemelaar, Julius C ; van der Kolk, Anne V ; Kalisvaart, Timo M ; van de Burgt, Alina ; Dibbets-Schneider, Petra ; van Velden, Floris H P ; Seijkens, Tom T P ; Stöger, J Lauran ; Jukema, J Wouter ; de Geus-Oei, Lioe-Fee ; Antoni, M Louisa</creator><creatorcontrib>Polomski, Elissa A S ; Kapiteijn, Ellen W ; Heemelaar, Julius C ; van der Kolk, Anne V ; Kalisvaart, Timo M ; van de Burgt, Alina ; Dibbets-Schneider, Petra ; van Velden, Floris H P ; Seijkens, Tom T P ; Stöger, J Lauran ; Jukema, J Wouter ; de Geus-Oei, Lioe-Fee ; Antoni, M Louisa</creatorcontrib><description>Immune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.BACKGROUND AND AIMSImmune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.Patients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.METHODSPatients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.We included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p &lt; 0.001) and in patients without calcifications (p = 0.013).RESULTSWe included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p &lt; 0.001) and in patients without calcifications (p = 0.013).A significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.CONCLUSIONSA significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.</description><identifier>ISSN: 1879-1484</identifier><identifier>EISSN: 1879-1484</identifier><identifier>DOI: 10.1016/j.atherosclerosis.2024.118595</identifier><language>eng</language><ispartof>Atherosclerosis, 2024-11, Vol.398, p.118595</ispartof><rights>Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Polomski, Elissa A S</creatorcontrib><creatorcontrib>Kapiteijn, Ellen W</creatorcontrib><creatorcontrib>Heemelaar, Julius C</creatorcontrib><creatorcontrib>van der Kolk, Anne V</creatorcontrib><creatorcontrib>Kalisvaart, Timo M</creatorcontrib><creatorcontrib>van de Burgt, Alina</creatorcontrib><creatorcontrib>Dibbets-Schneider, Petra</creatorcontrib><creatorcontrib>van Velden, Floris H P</creatorcontrib><creatorcontrib>Seijkens, Tom T P</creatorcontrib><creatorcontrib>Stöger, J Lauran</creatorcontrib><creatorcontrib>Jukema, J Wouter</creatorcontrib><creatorcontrib>de Geus-Oei, Lioe-Fee</creatorcontrib><creatorcontrib>Antoni, M Louisa</creatorcontrib><title>Arterial inflammation on 18FFDG PET/CT in melanoma patients treated with and without immune checkpoint inhibitors: CHECK-FLAME I</title><title>Atherosclerosis</title><description>Immune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.BACKGROUND AND AIMSImmune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.Patients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.METHODSPatients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.We included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p &lt; 0.001) and in patients without calcifications (p = 0.013).RESULTSWe included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p &lt; 0.001) and in patients without calcifications (p = 0.013).A significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.CONCLUSIONSA significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.</description><issn>1879-1484</issn><issn>1879-1484</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqVTU1Lw0AUXETB-vEf3kXwknRfkrZbbyUmVlTwkHtZ4yvZuh9xd4NXf7orevAqDDPDzMAwdoU8R47L-SGXcSDvQq-_WYW84EWVI4rFenHEZihW6wwrUR3_8afsLIQD57xaoZixz42P5JXUoOxeS2NkVM5CAoq2vb2D56ab111qwZCW1hkJY9qQjQGiJxnpFT5UHEDaH-OmCMqYyRL0A_Vvo1M2JXZQLyo6H26g3jb1Q9Y-bp4auL9gJ3upA13-6jm7bpuu3majd-8ThbgzKvSk0ze5KexK5KIUoiyW5T-mXwCCXto</recordid><startdate>20241101</startdate><enddate>20241101</enddate><creator>Polomski, Elissa A S</creator><creator>Kapiteijn, Ellen W</creator><creator>Heemelaar, Julius C</creator><creator>van der Kolk, Anne V</creator><creator>Kalisvaart, Timo M</creator><creator>van de Burgt, Alina</creator><creator>Dibbets-Schneider, Petra</creator><creator>van Velden, Floris H P</creator><creator>Seijkens, Tom T P</creator><creator>Stöger, J Lauran</creator><creator>Jukema, J Wouter</creator><creator>de Geus-Oei, Lioe-Fee</creator><creator>Antoni, M Louisa</creator><scope>7X8</scope></search><sort><creationdate>20241101</creationdate><title>Arterial inflammation on 18FFDG PET/CT in melanoma patients treated with and without immune checkpoint inhibitors: CHECK-FLAME I</title><author>Polomski, Elissa A S ; Kapiteijn, Ellen W ; Heemelaar, Julius C ; van der Kolk, Anne V ; Kalisvaart, Timo M ; van de Burgt, Alina ; Dibbets-Schneider, Petra ; van Velden, Floris H P ; Seijkens, Tom T P ; Stöger, J Lauran ; Jukema, J Wouter ; de Geus-Oei, Lioe-Fee ; Antoni, M Louisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_miscellaneous_31083883263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Polomski, Elissa A S</creatorcontrib><creatorcontrib>Kapiteijn, Ellen W</creatorcontrib><creatorcontrib>Heemelaar, Julius C</creatorcontrib><creatorcontrib>van der Kolk, Anne V</creatorcontrib><creatorcontrib>Kalisvaart, Timo M</creatorcontrib><creatorcontrib>van de Burgt, Alina</creatorcontrib><creatorcontrib>Dibbets-Schneider, Petra</creatorcontrib><creatorcontrib>van Velden, Floris H P</creatorcontrib><creatorcontrib>Seijkens, Tom T P</creatorcontrib><creatorcontrib>Stöger, J Lauran</creatorcontrib><creatorcontrib>Jukema, J Wouter</creatorcontrib><creatorcontrib>de Geus-Oei, Lioe-Fee</creatorcontrib><creatorcontrib>Antoni, M Louisa</creatorcontrib><collection>MEDLINE - Academic</collection><jtitle>Atherosclerosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Polomski, Elissa A S</au><au>Kapiteijn, Ellen W</au><au>Heemelaar, Julius C</au><au>van der Kolk, Anne V</au><au>Kalisvaart, Timo M</au><au>van de Burgt, Alina</au><au>Dibbets-Schneider, Petra</au><au>van Velden, Floris H P</au><au>Seijkens, Tom T P</au><au>Stöger, J Lauran</au><au>Jukema, J Wouter</au><au>de Geus-Oei, Lioe-Fee</au><au>Antoni, M Louisa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Arterial inflammation on 18FFDG PET/CT in melanoma patients treated with and without immune checkpoint inhibitors: CHECK-FLAME I</atitle><jtitle>Atherosclerosis</jtitle><date>2024-11-01</date><risdate>2024</risdate><volume>398</volume><spage>118595</spage><pages>118595-</pages><issn>1879-1484</issn><eissn>1879-1484</eissn><abstract>Immune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.BACKGROUND AND AIMSImmune checkpoint inhibitors (ICIs) revolutionized cancer treatment. However, ICIs may increase the immune response to non-tumor cells, possibly resulting in increased arterial inflammation, raising the risk of atherosclerotic events. Nevertheless, malignancies may induce a pro-inflammatory state and the association between ICIs and arterial inflammation remains to be clarified. This study aims to assess differences in increase in arterial inflammation between patients with advanced melanoma treated with ICIs compared to a control group without ICIs.Patients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.METHODSPatients with advanced melanoma who underwent [18F]FDG PET/CT scans at baseline, 6 months (T1) and 18 months (T2) were included in this retrospective observational study. Arterial inflammation was evaluated in eight segments by calculating the target-to-background ratio (TBR). The primary study outcome was the difference in increase in mean TBRmax between patients treated with and without ICIs.We included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p &lt; 0.001) and in patients without calcifications (p = 0.013).RESULTSWe included 132 patients of whom 72.7 % were treated with ICIs. After exclusion for the use of anti-inflammatory medication, patients treated with ICIs showed a significant increase in mean TBRmax between baseline and T1 from 1.29 ± 0.12 to 1.33 ± 0.13 (p = 0.017), while in the control group, no change in mean TBRmax (1.30 ± 0.12 to 1.28 ± 0.10, p = 0.22) was observed (p = 0.027). During longer follow-up, mean TBRmax remained stable in both groups. Arterial inflammation increased significantly after ICI therapy in patients without active inflammation (p &lt; 0.001) and in patients without calcifications (p = 0.013).A significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.CONCLUSIONSA significant increase in arterial inflammation as measured on [18F]FDG PET/CT was observed in patients with advanced melanoma treated with ICIs only in the first six months after initiation of therapy, whereas no changes were observed in the control group. Moreover, arterial inflammation was mainly increased in patients without pre-existing inflammatory activity and with non-calcified lesions.</abstract><doi>10.1016/j.atherosclerosis.2024.118595</doi></addata></record>
fulltext fulltext
identifier ISSN: 1879-1484
ispartof Atherosclerosis, 2024-11, Vol.398, p.118595
issn 1879-1484
1879-1484
language eng
recordid cdi_proquest_miscellaneous_3108388326
source BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS; Elsevier
title Arterial inflammation on 18FFDG PET/CT in melanoma patients treated with and without immune checkpoint inhibitors: CHECK-FLAME I
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T00%3A58%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Arterial%20inflammation%20on%2018FFDG%20PET/CT%20in%20melanoma%20patients%20treated%20with%20and%20without%20immune%20checkpoint%20inhibitors:%20CHECK-FLAME%20I&rft.jtitle=Atherosclerosis&rft.au=Polomski,%20Elissa%20A%20S&rft.date=2024-11-01&rft.volume=398&rft.spage=118595&rft.pages=118595-&rft.issn=1879-1484&rft.eissn=1879-1484&rft_id=info:doi/10.1016/j.atherosclerosis.2024.118595&rft_dat=%3Cproquest%3E3108388326%3C/proquest%3E%3Cgrp_id%3Ecdi_FETCH-proquest_miscellaneous_31083883263%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=3108388326&rft_id=info:pmid/&rfr_iscdi=true