A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer

Purpose To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials Twenty women with locally advanced ce...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:International journal of radiation oncology, biology, physics biology, physics, 2009-10, Vol.75 (2), p.611-617
Hauptverfasser: Semple, Scott I.K., Ph.D, Harry, Vanessa N., MRCOG, Parkin, David E., FRCOG, Gilbert, Fiona J., FRCR
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 617
container_issue 2
container_start_page 611
container_title International journal of radiation oncology, biology, physics
container_volume 75
creator Semple, Scott I.K., Ph.D
Harry, Vanessa N., MRCOG
Parkin, David E., FRCOG
Gilbert, Fiona J., FRCR
description Purpose To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results Pretherapy radiologic parameters and pharmacokinetic Ktrans correlated with response ( p < 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.
doi_str_mv 10.1016/j.ijrobp.2009.04.069
format Article
fullrecord <record><control><sourceid>proquest_osti_</sourceid><recordid>TN_cdi_osti_scitechconnect_21282068</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0360301609006671</els_id><sourcerecordid>21094179</sourcerecordid><originalsourceid>FETCH-LOGICAL-c540t-933f92582f5844ca10462a9b99e0f6b9cfb443061339c1d67e5158f27f0cf8193</originalsourceid><addsrcrecordid>eNqFUl2LFDEQHETx1tN_IBIQfJuxM995EZbx1IMVj1PBt5DJ9OxmbybZS7IL-7_8gSbMguCLT6E7VdVNVSfJawoZBVq_32dqb01_yHIAlkGZQc2eJCvaNiwtqurX02QFRQ1pEcBXyQvn9gBAaVM-T64oa4qqbZtV8ntNOjP3SuNA7nbCzkKah1B5JYnQA7kXgzKT2YZy7Rw6N6P2xIzk41mLOXQ7o70Vzqc3eie0DDJfxXbh36MzOvbI7Sy2Sm_JncVBSe_i18Foh8Qb0u1wNjbMEV4ZTZQmGyPFNJ3Jejgtkh3akwo90sXavkyejWJy-OryXic_P9386L6km2-fb7v1JpVVCT5lRTGyvGrzsWrLUgoKZZ0L1jOGMNY9k2NflgXUtCiYpEPdYEWrdsybEeTYUlZcJ28XXeO84k4qj3InjdYoPc9p3uZQtwH1bkEdrHk8ovN8Vk7iNAmN5ugCEFhJmyhXLkBpjXMWR36wahb2zCnwmCnf8yVTHjPlUPKQaaC9uegf-xmHv6RLiAHwYQFg8OKk0MZVMRqnbNx0MOp_E_4VkJPS0fAHPKPbm6PVwWdOucs58O_xruJZAQOo64YWfwAeasuH</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>21094179</pqid></control><display><type>article</type><title>A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Semple, Scott I.K., Ph.D ; Harry, Vanessa N., MRCOG ; Parkin, David E., FRCOG ; Gilbert, Fiona J., FRCR</creator><creatorcontrib>Semple, Scott I.K., Ph.D ; Harry, Vanessa N., MRCOG ; Parkin, David E., FRCOG ; Gilbert, Fiona J., FRCR</creatorcontrib><description>Purpose To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results Pretherapy radiologic parameters and pharmacokinetic Ktrans correlated with response ( p &lt; 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.</description><identifier>ISSN: 0360-3016</identifier><identifier>EISSN: 1879-355X</identifier><identifier>DOI: 10.1016/j.ijrobp.2009.04.069</identifier><identifier>PMID: 19735887</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenocarcinoma - drug therapy ; Adenocarcinoma - metabolism ; Adenocarcinoma - pathology ; Adenocarcinoma - radiotherapy ; Adult ; Aged ; Aged, 80 and over ; Carcinoma, Squamous Cell - drug therapy ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Carcinoma, Squamous Cell - radiotherapy ; Cervical cancer ; CHEMOTHERAPY ; Combined Modality Therapy - methods ; Contrast Media - pharmacokinetics ; Dynamic MRI ; Efficacy ; Female ; Hematology, Oncology and Palliative Medicine ; Humans ; Image Enhancement - methods ; Linear Models ; Magnetic Resonance Imaging - methods ; Middle Aged ; NEOPLASMS ; NMR IMAGING ; PATIENTS ; Prospective Studies ; Radiology ; RADIOLOGY AND NUCLEAR MEDICINE ; RADIOTHERAPY ; SIMULATION ; Treatment Outcome ; Uterine Cervical Neoplasms - drug therapy ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - pathology ; Uterine Cervical Neoplasms - radiotherapy ; WOMEN</subject><ispartof>International journal of radiation oncology, biology, physics, 2009-10, Vol.75 (2), p.611-617</ispartof><rights>Elsevier Inc.</rights><rights>2009 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-933f92582f5844ca10462a9b99e0f6b9cfb443061339c1d67e5158f27f0cf8193</citedby><cites>FETCH-LOGICAL-c540t-933f92582f5844ca10462a9b99e0f6b9cfb443061339c1d67e5158f27f0cf8193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0360301609006671$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19735887$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/21282068$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Semple, Scott I.K., Ph.D</creatorcontrib><creatorcontrib>Harry, Vanessa N., MRCOG</creatorcontrib><creatorcontrib>Parkin, David E., FRCOG</creatorcontrib><creatorcontrib>Gilbert, Fiona J., FRCR</creatorcontrib><title>A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer</title><title>International journal of radiation oncology, biology, physics</title><addtitle>Int J Radiat Oncol Biol Phys</addtitle><description>Purpose To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results Pretherapy radiologic parameters and pharmacokinetic Ktrans correlated with response ( p &lt; 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.</description><subject>Adenocarcinoma - drug therapy</subject><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - pathology</subject><subject>Adenocarcinoma - radiotherapy</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Carcinoma, Squamous Cell - radiotherapy</subject><subject>Cervical cancer</subject><subject>CHEMOTHERAPY</subject><subject>Combined Modality Therapy - methods</subject><subject>Contrast Media - pharmacokinetics</subject><subject>Dynamic MRI</subject><subject>Efficacy</subject><subject>Female</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Image Enhancement - methods</subject><subject>Linear Models</subject><subject>Magnetic Resonance Imaging - methods</subject><subject>Middle Aged</subject><subject>NEOPLASMS</subject><subject>NMR IMAGING</subject><subject>PATIENTS</subject><subject>Prospective Studies</subject><subject>Radiology</subject><subject>RADIOLOGY AND NUCLEAR MEDICINE</subject><subject>RADIOTHERAPY</subject><subject>SIMULATION</subject><subject>Treatment Outcome</subject><subject>Uterine Cervical Neoplasms - drug therapy</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Uterine Cervical Neoplasms - pathology</subject><subject>Uterine Cervical Neoplasms - radiotherapy</subject><subject>WOMEN</subject><issn>0360-3016</issn><issn>1879-355X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUl2LFDEQHETx1tN_IBIQfJuxM995EZbx1IMVj1PBt5DJ9OxmbybZS7IL-7_8gSbMguCLT6E7VdVNVSfJawoZBVq_32dqb01_yHIAlkGZQc2eJCvaNiwtqurX02QFRQ1pEcBXyQvn9gBAaVM-T64oa4qqbZtV8ntNOjP3SuNA7nbCzkKah1B5JYnQA7kXgzKT2YZy7Rw6N6P2xIzk41mLOXQ7o70Vzqc3eie0DDJfxXbh36MzOvbI7Sy2Sm_JncVBSe_i18Foh8Qb0u1wNjbMEV4ZTZQmGyPFNJ3Jejgtkh3akwo90sXavkyejWJy-OryXic_P9386L6km2-fb7v1JpVVCT5lRTGyvGrzsWrLUgoKZZ0L1jOGMNY9k2NflgXUtCiYpEPdYEWrdsybEeTYUlZcJ28XXeO84k4qj3InjdYoPc9p3uZQtwH1bkEdrHk8ovN8Vk7iNAmN5ugCEFhJmyhXLkBpjXMWR36wahb2zCnwmCnf8yVTHjPlUPKQaaC9uegf-xmHv6RLiAHwYQFg8OKk0MZVMRqnbNx0MOp_E_4VkJPS0fAHPKPbm6PVwWdOucs58O_xruJZAQOo64YWfwAeasuH</recordid><startdate>20091001</startdate><enddate>20091001</enddate><creator>Semple, Scott I.K., Ph.D</creator><creator>Harry, Vanessa N., MRCOG</creator><creator>Parkin, David E., FRCOG</creator><creator>Gilbert, Fiona J., FRCR</creator><general>Elsevier Inc</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>7U7</scope><scope>C1K</scope><scope>OTOTI</scope></search><sort><creationdate>20091001</creationdate><title>A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer</title><author>Semple, Scott I.K., Ph.D ; Harry, Vanessa N., MRCOG ; Parkin, David E., FRCOG ; Gilbert, Fiona J., FRCR</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-933f92582f5844ca10462a9b99e0f6b9cfb443061339c1d67e5158f27f0cf8193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adenocarcinoma - drug therapy</topic><topic>Adenocarcinoma - metabolism</topic><topic>Adenocarcinoma - pathology</topic><topic>Adenocarcinoma - radiotherapy</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - metabolism</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Carcinoma, Squamous Cell - radiotherapy</topic><topic>Cervical cancer</topic><topic>CHEMOTHERAPY</topic><topic>Combined Modality Therapy - methods</topic><topic>Contrast Media - pharmacokinetics</topic><topic>Dynamic MRI</topic><topic>Efficacy</topic><topic>Female</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Image Enhancement - methods</topic><topic>Linear Models</topic><topic>Magnetic Resonance Imaging - methods</topic><topic>Middle Aged</topic><topic>NEOPLASMS</topic><topic>NMR IMAGING</topic><topic>PATIENTS</topic><topic>Prospective Studies</topic><topic>Radiology</topic><topic>RADIOLOGY AND NUCLEAR MEDICINE</topic><topic>RADIOTHERAPY</topic><topic>SIMULATION</topic><topic>Treatment Outcome</topic><topic>Uterine Cervical Neoplasms - drug therapy</topic><topic>Uterine Cervical Neoplasms - metabolism</topic><topic>Uterine Cervical Neoplasms - pathology</topic><topic>Uterine Cervical Neoplasms - radiotherapy</topic><topic>WOMEN</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Semple, Scott I.K., Ph.D</creatorcontrib><creatorcontrib>Harry, Vanessa N., MRCOG</creatorcontrib><creatorcontrib>Parkin, David E., FRCOG</creatorcontrib><creatorcontrib>Gilbert, Fiona J., FRCR</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>OSTI.GOV</collection><jtitle>International journal of radiation oncology, biology, physics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Semple, Scott I.K., Ph.D</au><au>Harry, Vanessa N., MRCOG</au><au>Parkin, David E., FRCOG</au><au>Gilbert, Fiona J., FRCR</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer</atitle><jtitle>International journal of radiation oncology, biology, physics</jtitle><addtitle>Int J Radiat Oncol Biol Phys</addtitle><date>2009-10-01</date><risdate>2009</risdate><volume>75</volume><issue>2</issue><spage>611</spage><epage>617</epage><pages>611-617</pages><issn>0360-3016</issn><eissn>1879-355X</eissn><abstract>Purpose To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results Pretherapy radiologic parameters and pharmacokinetic Ktrans correlated with response ( p &lt; 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19735887</pmid><doi>10.1016/j.ijrobp.2009.04.069</doi><tpages>7</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0360-3016
ispartof International journal of radiation oncology, biology, physics, 2009-10, Vol.75 (2), p.611-617
issn 0360-3016
1879-355X
language eng
recordid cdi_osti_scitechconnect_21282068
source MEDLINE; Elsevier ScienceDirect Journals Complete
subjects Adenocarcinoma - drug therapy
Adenocarcinoma - metabolism
Adenocarcinoma - pathology
Adenocarcinoma - radiotherapy
Adult
Aged
Aged, 80 and over
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - metabolism
Carcinoma, Squamous Cell - pathology
Carcinoma, Squamous Cell - radiotherapy
Cervical cancer
CHEMOTHERAPY
Combined Modality Therapy - methods
Contrast Media - pharmacokinetics
Dynamic MRI
Efficacy
Female
Hematology, Oncology and Palliative Medicine
Humans
Image Enhancement - methods
Linear Models
Magnetic Resonance Imaging - methods
Middle Aged
NEOPLASMS
NMR IMAGING
PATIENTS
Prospective Studies
Radiology
RADIOLOGY AND NUCLEAR MEDICINE
RADIOTHERAPY
SIMULATION
Treatment Outcome
Uterine Cervical Neoplasms - drug therapy
Uterine Cervical Neoplasms - metabolism
Uterine Cervical Neoplasms - pathology
Uterine Cervical Neoplasms - radiotherapy
WOMEN
title A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T06%3A39%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_osti_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Combined%20Pharmacokinetic%20and%20Radiologic%20Assessment%20of%20Dynamic%20Contrast-Enhanced%20Magnetic%20Resonance%20Imaging%20Predicts%20Response%20to%20Chemoradiation%20in%20Locally%20Advanced%20Cervical%20Cancer&rft.jtitle=International%20journal%20of%20radiation%20oncology,%20biology,%20physics&rft.au=Semple,%20Scott%20I.K.,%20Ph.D&rft.date=2009-10-01&rft.volume=75&rft.issue=2&rft.spage=611&rft.epage=617&rft.pages=611-617&rft.issn=0360-3016&rft.eissn=1879-355X&rft_id=info:doi/10.1016/j.ijrobp.2009.04.069&rft_dat=%3Cproquest_osti_%3E21094179%3C/proquest_osti_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=21094179&rft_id=info:pmid/19735887&rft_els_id=S0360301609006671&rfr_iscdi=true