Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma
Background Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, with surgery as the only curative treatment. Identification of new biomarkers related to survival may help guide discovery of new pathophysiologic pathways and potential therapeutic targets. As long-chain ceramides have bee...
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| Veröffentlicht in: | Annals of surgical oncology 2024-12, Vol.31 (13), p.8725-8733 |
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| creator | Mitchell, Joshua D. Panni, Usman Fergestrom, Nicole Toriola, Adetunji T. Nywening, Timothy M. Goedegebuure, S. Peter Jiang, Xuntian Mudd, Jacqueline L. Cao, Yin Ippolito, Joseph Fields, Ryan C. Hawkins, William G. Peterson, Linda R. |
| description | Background
Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, with surgery as the only curative treatment. Identification of new biomarkers related to survival may help guide discovery of new pathophysiologic pathways and potential therapeutic targets. As long-chain ceramides have been linked to tumor proliferation, we sought to determine if ceramide levels were prognostic in PDAC.
Methods
Patients from two phase I studies of PDAC were followed for all-cause mortality. Ceramide levels (C24:0, C22:0, and C16:0) were quantified before treatment and at study intervals. Multivariable Cox regression models assessed the association of ceramide levels and mortality after adjusting for other univariable predictors, including time-dependent tumor resection. The ability of repeated ceramide measures to discriminate patients at risk for mortality was also assessed using multivariable modeling and the c-statistic.
Results
Higher plasma C16:0 concentration was associated with
higher
all-cause mortality in univariable and multivariable analysis (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] 1.09–1.82;
p
|
| doi_str_mv | 10.1245/s10434-024-16245-1 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3107786033</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3126204449</sourcerecordid><originalsourceid>FETCH-LOGICAL-c256t-de84ccd34a8ee0d9f852b676074338d03669bd5f8328a2e192406fd9aaf1980e3</originalsourceid><addsrcrecordid>eNp9kUtP3TAQha0KVCjtH-gCWWLDJmX8iOOwuwotICFx1cfa8rUnxSgPsJPb8u_rNhQkFqzGc_zNmZEOIR8ZfGJclieJgRSyAC4LprJQsDdkn5VZkkqznfwGpYuaq3KPvEvpFoBVAsq3ZE_UApTibJ_8Xnc29ZY2GG0fPNKGy1M4aZg6BfrVTmGkIdFVSqMLdkJPf4Xphl72d3Hc5u7bHLdhazsaBrrONA5TWpC1HVzELDl6NrspIyuPw-hsdGEYe_ue7La2S_jhsR6QH18-f28uiqvr88tmdVU4Xqqp8Kilc15IqxHB160u-UZVCiophPYglKo3vmy14NpyZDWXoFpfW9uyWgOKA3K8-OaL72dMk-lDcth1dsBxTkYwqCqtQIiMHr1Ab8c5Dvm6THHFQUpZZ4ovlItjShFbcxdDb-ODYWD-5mKWXEzOxfzLxbA8dPhoPW969E8j_4PIgFiAlL-Gnxifd79i-wc1p5av</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3126204449</pqid></control><display><type>article</type><title>Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Mitchell, Joshua D. ; Panni, Usman ; Fergestrom, Nicole ; Toriola, Adetunji T. ; Nywening, Timothy M. ; Goedegebuure, S. Peter ; Jiang, Xuntian ; Mudd, Jacqueline L. ; Cao, Yin ; Ippolito, Joseph ; Fields, Ryan C. ; Hawkins, William G. ; Peterson, Linda R.</creator><creatorcontrib>Mitchell, Joshua D. ; Panni, Usman ; Fergestrom, Nicole ; Toriola, Adetunji T. ; Nywening, Timothy M. ; Goedegebuure, S. Peter ; Jiang, Xuntian ; Mudd, Jacqueline L. ; Cao, Yin ; Ippolito, Joseph ; Fields, Ryan C. ; Hawkins, William G. ; Peterson, Linda R.</creatorcontrib><description>Background
Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, with surgery as the only curative treatment. Identification of new biomarkers related to survival may help guide discovery of new pathophysiologic pathways and potential therapeutic targets. As long-chain ceramides have been linked to tumor proliferation, we sought to determine if ceramide levels were prognostic in PDAC.
Methods
Patients from two phase I studies of PDAC were followed for all-cause mortality. Ceramide levels (C24:0, C22:0, and C16:0) were quantified before treatment and at study intervals. Multivariable Cox regression models assessed the association of ceramide levels and mortality after adjusting for other univariable predictors, including time-dependent tumor resection. The ability of repeated ceramide measures to discriminate patients at risk for mortality was also assessed using multivariable modeling and the c-statistic.
Results
Higher plasma C16:0 concentration was associated with
higher
all-cause mortality in univariable and multivariable analysis (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] 1.09–1.82;
p
< 0.01). In contrast, a higher plasma C24:0/C16:0 ratio was associated with
lower
all-cause mortality in multivariable analysis (aHR 0.69, 95% CI 0.49–0.97;
p
= 0.032). Discrimination of mortality was significantly improved with the addition of either plasma C16:0 or C24:0/C16:0 levels, with optimal discrimination occurring using repeated measures of the C24:0/C16:0 ratio (c-statistic 0.73 vs. c-statistic 0.66;
p
< 0.001).
Conclusions
Higher plasma C16:0 and lower C24:0/C16:0 ratios are independently associated with mortality in PDAC and show an ability to improve discrimination of mortality in this deadly disease. Further studies are needed to confirm this association and evaluate this novel pathway for potential therapeutic targets.</description><identifier>ISSN: 1068-9265</identifier><identifier>ISSN: 1534-4681</identifier><identifier>EISSN: 1534-4681</identifier><identifier>DOI: 10.1245/s10434-024-16245-1</identifier><identifier>PMID: 39306621</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Adenocarcinoma ; Aged ; Biomarkers, Tumor - blood ; Carcinoma, Pancreatic Ductal - blood ; Carcinoma, Pancreatic Ductal - mortality ; Carcinoma, Pancreatic Ductal - pathology ; Carcinoma, Pancreatic Ductal - surgery ; Ceramide ; Ceramides - blood ; Female ; Follow-Up Studies ; Humans ; Male ; Medicine ; Medicine & Public Health ; Middle Aged ; Mortality ; Oncology ; Pancreas ; Pancreatic cancer ; Pancreatic Neoplasms - blood ; Pancreatic Neoplasms - mortality ; Pancreatic Neoplasms - pathology ; Pancreatic Neoplasms - surgery ; Pancreatic Tumors ; Patients ; Plasma ; Prognosis ; Regression analysis ; Surgery ; Surgical Oncology ; Survival ; Survival Rate ; Therapeutic targets ; Tumors</subject><ispartof>Annals of surgical oncology, 2024-12, Vol.31 (13), p.8725-8733</ispartof><rights>Society of Surgical Oncology 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. Society of Surgical Oncology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c256t-de84ccd34a8ee0d9f852b676074338d03669bd5f8328a2e192406fd9aaf1980e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1245/s10434-024-16245-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1245/s10434-024-16245-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39306621$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mitchell, Joshua D.</creatorcontrib><creatorcontrib>Panni, Usman</creatorcontrib><creatorcontrib>Fergestrom, Nicole</creatorcontrib><creatorcontrib>Toriola, Adetunji T.</creatorcontrib><creatorcontrib>Nywening, Timothy M.</creatorcontrib><creatorcontrib>Goedegebuure, S. Peter</creatorcontrib><creatorcontrib>Jiang, Xuntian</creatorcontrib><creatorcontrib>Mudd, Jacqueline L.</creatorcontrib><creatorcontrib>Cao, Yin</creatorcontrib><creatorcontrib>Ippolito, Joseph</creatorcontrib><creatorcontrib>Fields, Ryan C.</creatorcontrib><creatorcontrib>Hawkins, William G.</creatorcontrib><creatorcontrib>Peterson, Linda R.</creatorcontrib><title>Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma</title><title>Annals of surgical oncology</title><addtitle>Ann Surg Oncol</addtitle><addtitle>Ann Surg Oncol</addtitle><description>Background
Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, with surgery as the only curative treatment. Identification of new biomarkers related to survival may help guide discovery of new pathophysiologic pathways and potential therapeutic targets. As long-chain ceramides have been linked to tumor proliferation, we sought to determine if ceramide levels were prognostic in PDAC.
Methods
Patients from two phase I studies of PDAC were followed for all-cause mortality. Ceramide levels (C24:0, C22:0, and C16:0) were quantified before treatment and at study intervals. Multivariable Cox regression models assessed the association of ceramide levels and mortality after adjusting for other univariable predictors, including time-dependent tumor resection. The ability of repeated ceramide measures to discriminate patients at risk for mortality was also assessed using multivariable modeling and the c-statistic.
Results
Higher plasma C16:0 concentration was associated with
higher
all-cause mortality in univariable and multivariable analysis (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] 1.09–1.82;
p
< 0.01). In contrast, a higher plasma C24:0/C16:0 ratio was associated with
lower
all-cause mortality in multivariable analysis (aHR 0.69, 95% CI 0.49–0.97;
p
= 0.032). Discrimination of mortality was significantly improved with the addition of either plasma C16:0 or C24:0/C16:0 levels, with optimal discrimination occurring using repeated measures of the C24:0/C16:0 ratio (c-statistic 0.73 vs. c-statistic 0.66;
p
< 0.001).
Conclusions
Higher plasma C16:0 and lower C24:0/C16:0 ratios are independently associated with mortality in PDAC and show an ability to improve discrimination of mortality in this deadly disease. Further studies are needed to confirm this association and evaluate this novel pathway for potential therapeutic targets.</description><subject>Adenocarcinoma</subject><subject>Aged</subject><subject>Biomarkers, Tumor - blood</subject><subject>Carcinoma, Pancreatic Ductal - blood</subject><subject>Carcinoma, Pancreatic Ductal - mortality</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Carcinoma, Pancreatic Ductal - surgery</subject><subject>Ceramide</subject><subject>Ceramides - blood</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Humans</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Oncology</subject><subject>Pancreas</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - blood</subject><subject>Pancreatic Neoplasms - mortality</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pancreatic Neoplasms - surgery</subject><subject>Pancreatic Tumors</subject><subject>Patients</subject><subject>Plasma</subject><subject>Prognosis</subject><subject>Regression analysis</subject><subject>Surgery</subject><subject>Surgical Oncology</subject><subject>Survival</subject><subject>Survival Rate</subject><subject>Therapeutic targets</subject><subject>Tumors</subject><issn>1068-9265</issn><issn>1534-4681</issn><issn>1534-4681</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtP3TAQha0KVCjtH-gCWWLDJmX8iOOwuwotICFx1cfa8rUnxSgPsJPb8u_rNhQkFqzGc_zNmZEOIR8ZfGJclieJgRSyAC4LprJQsDdkn5VZkkqznfwGpYuaq3KPvEvpFoBVAsq3ZE_UApTibJ_8Xnc29ZY2GG0fPNKGy1M4aZg6BfrVTmGkIdFVSqMLdkJPf4Xphl72d3Hc5u7bHLdhazsaBrrONA5TWpC1HVzELDl6NrspIyuPw-hsdGEYe_ue7La2S_jhsR6QH18-f28uiqvr88tmdVU4Xqqp8Kilc15IqxHB160u-UZVCiophPYglKo3vmy14NpyZDWXoFpfW9uyWgOKA3K8-OaL72dMk-lDcth1dsBxTkYwqCqtQIiMHr1Ab8c5Dvm6THHFQUpZZ4ovlItjShFbcxdDb-ODYWD-5mKWXEzOxfzLxbA8dPhoPW969E8j_4PIgFiAlL-Gnxifd79i-wc1p5av</recordid><startdate>20241201</startdate><enddate>20241201</enddate><creator>Mitchell, Joshua D.</creator><creator>Panni, Usman</creator><creator>Fergestrom, Nicole</creator><creator>Toriola, Adetunji T.</creator><creator>Nywening, Timothy M.</creator><creator>Goedegebuure, S. Peter</creator><creator>Jiang, Xuntian</creator><creator>Mudd, Jacqueline L.</creator><creator>Cao, Yin</creator><creator>Ippolito, Joseph</creator><creator>Fields, Ryan C.</creator><creator>Hawkins, William G.</creator><creator>Peterson, Linda R.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</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>7TO</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>20241201</creationdate><title>Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma</title><author>Mitchell, Joshua D. ; Panni, Usman ; Fergestrom, Nicole ; Toriola, Adetunji T. ; Nywening, Timothy M. ; Goedegebuure, S. Peter ; Jiang, Xuntian ; Mudd, Jacqueline L. ; Cao, Yin ; Ippolito, Joseph ; Fields, Ryan C. ; Hawkins, William G. ; Peterson, Linda R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c256t-de84ccd34a8ee0d9f852b676074338d03669bd5f8328a2e192406fd9aaf1980e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adenocarcinoma</topic><topic>Aged</topic><topic>Biomarkers, Tumor - blood</topic><topic>Carcinoma, Pancreatic Ductal - blood</topic><topic>Carcinoma, Pancreatic Ductal - mortality</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Carcinoma, Pancreatic Ductal - surgery</topic><topic>Ceramide</topic><topic>Ceramides - blood</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Oncology</topic><topic>Pancreas</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - blood</topic><topic>Pancreatic Neoplasms - mortality</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pancreatic Neoplasms - surgery</topic><topic>Pancreatic Tumors</topic><topic>Patients</topic><topic>Plasma</topic><topic>Prognosis</topic><topic>Regression analysis</topic><topic>Surgery</topic><topic>Surgical Oncology</topic><topic>Survival</topic><topic>Survival Rate</topic><topic>Therapeutic targets</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mitchell, Joshua D.</creatorcontrib><creatorcontrib>Panni, Usman</creatorcontrib><creatorcontrib>Fergestrom, Nicole</creatorcontrib><creatorcontrib>Toriola, Adetunji T.</creatorcontrib><creatorcontrib>Nywening, Timothy M.</creatorcontrib><creatorcontrib>Goedegebuure, S. Peter</creatorcontrib><creatorcontrib>Jiang, Xuntian</creatorcontrib><creatorcontrib>Mudd, Jacqueline L.</creatorcontrib><creatorcontrib>Cao, Yin</creatorcontrib><creatorcontrib>Ippolito, Joseph</creatorcontrib><creatorcontrib>Fields, Ryan C.</creatorcontrib><creatorcontrib>Hawkins, William G.</creatorcontrib><creatorcontrib>Peterson, Linda R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of surgical oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mitchell, Joshua D.</au><au>Panni, Usman</au><au>Fergestrom, Nicole</au><au>Toriola, Adetunji T.</au><au>Nywening, Timothy M.</au><au>Goedegebuure, S. Peter</au><au>Jiang, Xuntian</au><au>Mudd, Jacqueline L.</au><au>Cao, Yin</au><au>Ippolito, Joseph</au><au>Fields, Ryan C.</au><au>Hawkins, William G.</au><au>Peterson, Linda R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma</atitle><jtitle>Annals of surgical oncology</jtitle><stitle>Ann Surg Oncol</stitle><addtitle>Ann Surg Oncol</addtitle><date>2024-12-01</date><risdate>2024</risdate><volume>31</volume><issue>13</issue><spage>8725</spage><epage>8733</epage><pages>8725-8733</pages><issn>1068-9265</issn><issn>1534-4681</issn><eissn>1534-4681</eissn><abstract>Background
Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, with surgery as the only curative treatment. Identification of new biomarkers related to survival may help guide discovery of new pathophysiologic pathways and potential therapeutic targets. As long-chain ceramides have been linked to tumor proliferation, we sought to determine if ceramide levels were prognostic in PDAC.
Methods
Patients from two phase I studies of PDAC were followed for all-cause mortality. Ceramide levels (C24:0, C22:0, and C16:0) were quantified before treatment and at study intervals. Multivariable Cox regression models assessed the association of ceramide levels and mortality after adjusting for other univariable predictors, including time-dependent tumor resection. The ability of repeated ceramide measures to discriminate patients at risk for mortality was also assessed using multivariable modeling and the c-statistic.
Results
Higher plasma C16:0 concentration was associated with
higher
all-cause mortality in univariable and multivariable analysis (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] 1.09–1.82;
p
< 0.01). In contrast, a higher plasma C24:0/C16:0 ratio was associated with
lower
all-cause mortality in multivariable analysis (aHR 0.69, 95% CI 0.49–0.97;
p
= 0.032). Discrimination of mortality was significantly improved with the addition of either plasma C16:0 or C24:0/C16:0 levels, with optimal discrimination occurring using repeated measures of the C24:0/C16:0 ratio (c-statistic 0.73 vs. c-statistic 0.66;
p
< 0.001).
Conclusions
Higher plasma C16:0 and lower C24:0/C16:0 ratios are independently associated with mortality in PDAC and show an ability to improve discrimination of mortality in this deadly disease. Further studies are needed to confirm this association and evaluate this novel pathway for potential therapeutic targets.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>39306621</pmid><doi>10.1245/s10434-024-16245-1</doi><tpages>9</tpages></addata></record> |
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| subjects | Adenocarcinoma Aged Biomarkers, Tumor - blood Carcinoma, Pancreatic Ductal - blood Carcinoma, Pancreatic Ductal - mortality Carcinoma, Pancreatic Ductal - pathology Carcinoma, Pancreatic Ductal - surgery Ceramide Ceramides - blood Female Follow-Up Studies Humans Male Medicine Medicine & Public Health Middle Aged Mortality Oncology Pancreas Pancreatic cancer Pancreatic Neoplasms - blood Pancreatic Neoplasms - mortality Pancreatic Neoplasms - pathology Pancreatic Neoplasms - surgery Pancreatic Tumors Patients Plasma Prognosis Regression analysis Surgery Surgical Oncology Survival Survival Rate Therapeutic targets Tumors |
| title | Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma |
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