Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma
To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM). Retrospective cohort study. The study included 240 consecutive patients with UM. Tumors were assessed for GEP sta...
Gespeichert in:
Veröffentlicht in: | American journal of ophthalmology 2018-11, Vol.195, p.154-160 |
---|---|
Hauptverfasser: | , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 160 |
---|---|
container_issue | |
container_start_page | 154 |
container_title | American journal of ophthalmology |
container_volume | 195 |
creator | Cai, Louis Paez-Escamilla, Manuel Walter, Scott D. Tarlan, Bercin Decatur, Christina L. Perez, Barbara M. Harbour, J.William |
description | To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM).
Retrospective cohort study.
The study included 240 consecutive patients with UM. Tumors were assessed for GEP status (Class 1 or Class 2) using a validated 15-gene assay and PRAME expression status using quantitative polymerase chain reaction. TNM staging was according to the American Joint Committee on Cancer 8th edition. Statistical analysis included univariate and multivariate Cox proportional hazard models. Metastasis was the primary endpoint.
GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME status was negative in 157 (65.4%) cases and positive in 83 (34.6%) cases. TNM was stage I in 26 (10.8%) cases, IIA in 67 (27.9%) cases, IIB in 50 (20.8%) cases, IIIA in 59 (24.6%) cases, and IIIB in 38 (15.8%) cases. Metastatic disease was detected in 59 (24.6%) cases after median follow-up of 29 months (mean 42 months; range 1-195 months). Variables associated with metastasis included (in order of decreasing significance): GEP class (P = 1.5 × 10−8), largest basal tumor diameter (P = 2.5 × 10−6), PRAME status (P = 2.6 × 10−6), and TNM stage (P = 3.7 × 10−6). The prognostic accuracy of an optimized 3-category GEP/PRAME model (P = 8.6 × 10−14) was superior to an optimized TNM model (P = 1.3 × 10−5).
In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging. |
doi_str_mv | 10.1016/j.ajo.2018.07.045 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6214741</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0002939418304380</els_id><sourcerecordid>2087589974</sourcerecordid><originalsourceid>FETCH-LOGICAL-c479t-7b3a0bd3bfd3b3b0a52e732e07b5a083d34e466e5f6d679a0865dbb3c2ff717d3</originalsourceid><addsrcrecordid>eNp9kV9r1TAYxoMo7mz6AbyRgjfetOZfkxZBGONsCjs6dPM2pM3bY0qbHJP2sH17U84czotBwsub_J6HvHkQekNwQTARH_pC976gmFQFlgXm5TO0IpWsc1LV5DlaYYxpXrOaH6HjGPvUCsnlS3TEMK4pqfgKzRfgIFvf7gLEaL3LroLv7GDdNtPOZFffTzfr7MekpzlmPyHEVK7n0Yf8qzeQb2DSMS0bF2a7qDofFo-t83GyrZ4WT-uymz3oIdvAoJ0f9Sv0otNDhNf39QTdnK-vzz7nl98uvpydXuYtl_WUy4Zp3BjWdGmzBuuSgmQUsGxKjStmGAcuBJSdMELW6UiUpmlYS7tOEmnYCfp08N3NzQimBTcFPahdsKMOd8prqx7fOPtLbf1eCUq45CQZvL83CP73DHFSo40tDGkM8HNUFFeyrOpa8oS--w_t_RxcGk9RQkVJpRQyUeRAtcHHGKB7eAzBaglV9SqFqpZQFZYqhZo0b_-d4kHxN8UEfDwAkP5ybyGo2FpwLRgboJ2U8fYJ-z-rYbRL</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2126527767</pqid></control><display><type>article</type><title>Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Cai, Louis ; Paez-Escamilla, Manuel ; Walter, Scott D. ; Tarlan, Bercin ; Decatur, Christina L. ; Perez, Barbara M. ; Harbour, J.William</creator><creatorcontrib>Cai, Louis ; Paez-Escamilla, Manuel ; Walter, Scott D. ; Tarlan, Bercin ; Decatur, Christina L. ; Perez, Barbara M. ; Harbour, J.William</creatorcontrib><description>To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM).
Retrospective cohort study.
The study included 240 consecutive patients with UM. Tumors were assessed for GEP status (Class 1 or Class 2) using a validated 15-gene assay and PRAME expression status using quantitative polymerase chain reaction. TNM staging was according to the American Joint Committee on Cancer 8th edition. Statistical analysis included univariate and multivariate Cox proportional hazard models. Metastasis was the primary endpoint.
GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME status was negative in 157 (65.4%) cases and positive in 83 (34.6%) cases. TNM was stage I in 26 (10.8%) cases, IIA in 67 (27.9%) cases, IIB in 50 (20.8%) cases, IIIA in 59 (24.6%) cases, and IIIB in 38 (15.8%) cases. Metastatic disease was detected in 59 (24.6%) cases after median follow-up of 29 months (mean 42 months; range 1-195 months). Variables associated with metastasis included (in order of decreasing significance): GEP class (P = 1.5 × 10−8), largest basal tumor diameter (P = 2.5 × 10−6), PRAME status (P = 2.6 × 10−6), and TNM stage (P = 3.7 × 10−6). The prognostic accuracy of an optimized 3-category GEP/PRAME model (P = 8.6 × 10−14) was superior to an optimized TNM model (P = 1.3 × 10−5).
In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.</description><identifier>ISSN: 0002-9394</identifier><identifier>ISSN: 1879-1891</identifier><identifier>EISSN: 1879-1891</identifier><identifier>DOI: 10.1016/j.ajo.2018.07.045</identifier><identifier>PMID: 30092184</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antigens ; Antigens, Neoplasm - genetics ; Biomarkers ; Biomarkers, Tumor - genetics ; Biopsy, Fine-Needle ; Brachytherapy ; Cancer ; Female ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Iodine Radioisotopes - therapeutic use ; Lymphatic Metastasis - pathology ; Male ; Medical prognosis ; Melanoma ; Melanoma - diagnosis ; Melanoma - genetics ; Melanoma - radiotherapy ; Metastasis ; Middle Aged ; Mortality ; Mutation ; Neoplasm Staging ; Ophthalmology ; Prognosis ; Proportional Hazards Models ; Radiation therapy ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Software ; Tumors ; Ultrasonic imaging ; Uveal Neoplasms - diagnosis ; Uveal Neoplasms - genetics ; Uveal Neoplasms - radiotherapy ; Variables</subject><ispartof>American journal of ophthalmology, 2018-11, Vol.195, p.154-160</ispartof><rights>2018 Elsevier Inc.</rights><rights>Copyright © 2018 Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Nov 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-7b3a0bd3bfd3b3b0a52e732e07b5a083d34e466e5f6d679a0865dbb3c2ff717d3</citedby><cites>FETCH-LOGICAL-c479t-7b3a0bd3bfd3b3b0a52e732e07b5a083d34e466e5f6d679a0865dbb3c2ff717d3</cites><orcidid>0000-0003-3488-9680</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ajo.2018.07.045$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,781,785,886,3551,27926,27927,45997</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30092184$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cai, Louis</creatorcontrib><creatorcontrib>Paez-Escamilla, Manuel</creatorcontrib><creatorcontrib>Walter, Scott D.</creatorcontrib><creatorcontrib>Tarlan, Bercin</creatorcontrib><creatorcontrib>Decatur, Christina L.</creatorcontrib><creatorcontrib>Perez, Barbara M.</creatorcontrib><creatorcontrib>Harbour, J.William</creatorcontrib><title>Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma</title><title>American journal of ophthalmology</title><addtitle>Am J Ophthalmol</addtitle><description>To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM).
Retrospective cohort study.
The study included 240 consecutive patients with UM. Tumors were assessed for GEP status (Class 1 or Class 2) using a validated 15-gene assay and PRAME expression status using quantitative polymerase chain reaction. TNM staging was according to the American Joint Committee on Cancer 8th edition. Statistical analysis included univariate and multivariate Cox proportional hazard models. Metastasis was the primary endpoint.
GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME status was negative in 157 (65.4%) cases and positive in 83 (34.6%) cases. TNM was stage I in 26 (10.8%) cases, IIA in 67 (27.9%) cases, IIB in 50 (20.8%) cases, IIIA in 59 (24.6%) cases, and IIIB in 38 (15.8%) cases. Metastatic disease was detected in 59 (24.6%) cases after median follow-up of 29 months (mean 42 months; range 1-195 months). Variables associated with metastasis included (in order of decreasing significance): GEP class (P = 1.5 × 10−8), largest basal tumor diameter (P = 2.5 × 10−6), PRAME status (P = 2.6 × 10−6), and TNM stage (P = 3.7 × 10−6). The prognostic accuracy of an optimized 3-category GEP/PRAME model (P = 8.6 × 10−14) was superior to an optimized TNM model (P = 1.3 × 10−5).
In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antigens</subject><subject>Antigens, Neoplasm - genetics</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biopsy, Fine-Needle</subject><subject>Brachytherapy</subject><subject>Cancer</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Iodine Radioisotopes - therapeutic use</subject><subject>Lymphatic Metastasis - pathology</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Melanoma</subject><subject>Melanoma - diagnosis</subject><subject>Melanoma - genetics</subject><subject>Melanoma - radiotherapy</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Mutation</subject><subject>Neoplasm Staging</subject><subject>Ophthalmology</subject><subject>Prognosis</subject><subject>Proportional Hazards Models</subject><subject>Radiation therapy</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Retrospective Studies</subject><subject>Software</subject><subject>Tumors</subject><subject>Ultrasonic imaging</subject><subject>Uveal Neoplasms - diagnosis</subject><subject>Uveal Neoplasms - genetics</subject><subject>Uveal Neoplasms - radiotherapy</subject><subject>Variables</subject><issn>0002-9394</issn><issn>1879-1891</issn><issn>1879-1891</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kV9r1TAYxoMo7mz6AbyRgjfetOZfkxZBGONsCjs6dPM2pM3bY0qbHJP2sH17U84czotBwsub_J6HvHkQekNwQTARH_pC976gmFQFlgXm5TO0IpWsc1LV5DlaYYxpXrOaH6HjGPvUCsnlS3TEMK4pqfgKzRfgIFvf7gLEaL3LroLv7GDdNtPOZFffTzfr7MekpzlmPyHEVK7n0Yf8qzeQb2DSMS0bF2a7qDofFo-t83GyrZ4WT-uymz3oIdvAoJ0f9Sv0otNDhNf39QTdnK-vzz7nl98uvpydXuYtl_WUy4Zp3BjWdGmzBuuSgmQUsGxKjStmGAcuBJSdMELW6UiUpmlYS7tOEmnYCfp08N3NzQimBTcFPahdsKMOd8prqx7fOPtLbf1eCUq45CQZvL83CP73DHFSo40tDGkM8HNUFFeyrOpa8oS--w_t_RxcGk9RQkVJpRQyUeRAtcHHGKB7eAzBaglV9SqFqpZQFZYqhZo0b_-d4kHxN8UEfDwAkP5ybyGo2FpwLRgboJ2U8fYJ-z-rYbRL</recordid><startdate>20181101</startdate><enddate>20181101</enddate><creator>Cai, Louis</creator><creator>Paez-Escamilla, Manuel</creator><creator>Walter, Scott D.</creator><creator>Tarlan, Bercin</creator><creator>Decatur, Christina L.</creator><creator>Perez, Barbara M.</creator><creator>Harbour, J.William</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3488-9680</orcidid></search><sort><creationdate>20181101</creationdate><title>Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma</title><author>Cai, Louis ; Paez-Escamilla, Manuel ; Walter, Scott D. ; Tarlan, Bercin ; Decatur, Christina L. ; Perez, Barbara M. ; Harbour, J.William</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-7b3a0bd3bfd3b3b0a52e732e07b5a083d34e466e5f6d679a0865dbb3c2ff717d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antigens</topic><topic>Antigens, Neoplasm - genetics</topic><topic>Biomarkers</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biopsy, Fine-Needle</topic><topic>Brachytherapy</topic><topic>Cancer</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Iodine Radioisotopes - therapeutic use</topic><topic>Lymphatic Metastasis - pathology</topic><topic>Male</topic><topic>Medical prognosis</topic><topic>Melanoma</topic><topic>Melanoma - diagnosis</topic><topic>Melanoma - genetics</topic><topic>Melanoma - radiotherapy</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Mutation</topic><topic>Neoplasm Staging</topic><topic>Ophthalmology</topic><topic>Prognosis</topic><topic>Proportional Hazards Models</topic><topic>Radiation therapy</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Retrospective Studies</topic><topic>Software</topic><topic>Tumors</topic><topic>Ultrasonic imaging</topic><topic>Uveal Neoplasms - diagnosis</topic><topic>Uveal Neoplasms - genetics</topic><topic>Uveal Neoplasms - radiotherapy</topic><topic>Variables</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cai, Louis</creatorcontrib><creatorcontrib>Paez-Escamilla, Manuel</creatorcontrib><creatorcontrib>Walter, Scott D.</creatorcontrib><creatorcontrib>Tarlan, Bercin</creatorcontrib><creatorcontrib>Decatur, Christina L.</creatorcontrib><creatorcontrib>Perez, Barbara M.</creatorcontrib><creatorcontrib>Harbour, J.William</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of ophthalmology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cai, Louis</au><au>Paez-Escamilla, Manuel</au><au>Walter, Scott D.</au><au>Tarlan, Bercin</au><au>Decatur, Christina L.</au><au>Perez, Barbara M.</au><au>Harbour, J.William</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma</atitle><jtitle>American journal of ophthalmology</jtitle><addtitle>Am J Ophthalmol</addtitle><date>2018-11-01</date><risdate>2018</risdate><volume>195</volume><spage>154</spage><epage>160</epage><pages>154-160</pages><issn>0002-9394</issn><issn>1879-1891</issn><eissn>1879-1891</eissn><abstract>To compare the prognostic accuracy of gene expression profiling (GEP) combined with PRAME status vs the clinical Tumor-Node-Metastasis (TNM) staging in patients with uveal melanoma (UM).
Retrospective cohort study.
The study included 240 consecutive patients with UM. Tumors were assessed for GEP status (Class 1 or Class 2) using a validated 15-gene assay and PRAME expression status using quantitative polymerase chain reaction. TNM staging was according to the American Joint Committee on Cancer 8th edition. Statistical analysis included univariate and multivariate Cox proportional hazard models. Metastasis was the primary endpoint.
GEP was Class 1 in 128 (53.3%) cases and Class 2 in 112 (46.7%) cases. PRAME status was negative in 157 (65.4%) cases and positive in 83 (34.6%) cases. TNM was stage I in 26 (10.8%) cases, IIA in 67 (27.9%) cases, IIB in 50 (20.8%) cases, IIIA in 59 (24.6%) cases, and IIIB in 38 (15.8%) cases. Metastatic disease was detected in 59 (24.6%) cases after median follow-up of 29 months (mean 42 months; range 1-195 months). Variables associated with metastasis included (in order of decreasing significance): GEP class (P = 1.5 × 10−8), largest basal tumor diameter (P = 2.5 × 10−6), PRAME status (P = 2.6 × 10−6), and TNM stage (P = 3.7 × 10−6). The prognostic accuracy of an optimized 3-category GEP/PRAME model (P = 8.6 × 10−14) was superior to an optimized TNM model (P = 1.3 × 10−5).
In UM, molecular prognostic testing using GEP and PRAME provides prognostic accuracy that is superior to TNM staging.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30092184</pmid><doi>10.1016/j.ajo.2018.07.045</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-3488-9680</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0002-9394 |
ispartof | American journal of ophthalmology, 2018-11, Vol.195, p.154-160 |
issn | 0002-9394 1879-1891 1879-1891 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6214741 |
source | MEDLINE; Elsevier ScienceDirect Journals Complete |
subjects | Adolescent Adult Aged Aged, 80 and over Antigens Antigens, Neoplasm - genetics Biomarkers Biomarkers, Tumor - genetics Biopsy, Fine-Needle Brachytherapy Cancer Female Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Iodine Radioisotopes - therapeutic use Lymphatic Metastasis - pathology Male Medical prognosis Melanoma Melanoma - diagnosis Melanoma - genetics Melanoma - radiotherapy Metastasis Middle Aged Mortality Mutation Neoplasm Staging Ophthalmology Prognosis Proportional Hazards Models Radiation therapy Real-Time Polymerase Chain Reaction Retrospective Studies Software Tumors Ultrasonic imaging Uveal Neoplasms - diagnosis Uveal Neoplasms - genetics Uveal Neoplasms - radiotherapy Variables |
title | Gene Expression Profiling and PRAME Status Versus Tumor-Node-Metastasis Staging for Prognostication in Uveal Melanoma |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-17T15%3A17%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Gene%20Expression%20Profiling%20and%20PRAME%20Status%20Versus%20Tumor-Node-Metastasis%20Staging%20for%20Prognostication%20in%20Uveal%20Melanoma&rft.jtitle=American%20journal%20of%20ophthalmology&rft.au=Cai,%20Louis&rft.date=2018-11-01&rft.volume=195&rft.spage=154&rft.epage=160&rft.pages=154-160&rft.issn=0002-9394&rft.eissn=1879-1891&rft_id=info:doi/10.1016/j.ajo.2018.07.045&rft_dat=%3Cproquest_pubme%3E2087589974%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2126527767&rft_id=info:pmid/30092184&rft_els_id=S0002939418304380&rfr_iscdi=true |