The Relationship Between Cyclooxygenase-2 Expression and Colorectal Cancer
CONTEXT Epidemiological studies have implicated the inducible form of cyclooxygenase (COX-2) in the pathogenesis of colorectal cancer; however, its role is not fully understood. OBJECTIVE To examine the relationship between the expression of COX-2 in human colorectal cancer and patient survival. DES...
Gespeichert in:
| Veröffentlicht in: | JAMA : the journal of the American Medical Association 1999-10, Vol.282 (13), p.1254-1257 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1257 |
|---|---|
| container_issue | 13 |
| container_start_page | 1254 |
| container_title | JAMA : the journal of the American Medical Association |
| container_volume | 282 |
| creator | Sheehan, Katherine M Sheahan, Kieran O'Donoghue, Diarmuid P MacSweeney, Fergus Conroy, Ronan M Fitzgerald, Desmond J Murray, Frank E |
| description | CONTEXT Epidemiological studies have implicated the inducible form of cyclooxygenase
(COX-2) in the pathogenesis of colorectal cancer; however, its role is not
fully understood. OBJECTIVE To examine the relationship between the expression of COX-2 in human
colorectal cancer and patient survival. DESIGN Patients diagnosed as having colorectal cancer were evaluated and followed
up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were
stained for COX-2 using a rabbit polyclonal antibody raised against human
COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome.
Preabsorption of the anti–COX-2 antibody with a COX-2 peptide abolished
the staining, demonstrating the specificity of the assay. SETTING Gastrointestinal unit of a large general teaching hospital in Dublin,
Ireland. PARTICIPANTS Seventy-six patients (median age, 66.5 years) with colorectal cancer
(Dukes tumor stage A, n=9; Dukes B, n=30; Dukes C, n=25; Dukes D, n=12) whose
diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were
stained for COX-2 as controls. MAIN OUTCOME MEASURES Survival in years following diagnosis compared by extent of COX-2 epithelial
staining (grade 1, |
| doi_str_mv | 10.1001/jama.282.13.1254 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_proquest_miscellaneous_70823609</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><ama_id>191965</ama_id><sourcerecordid>70823609</sourcerecordid><originalsourceid>FETCH-LOGICAL-a436t-a3e2f3f08505d28c3210d955af64f795efcc9913cacee92c89d49d8563bd2ca83</originalsourceid><addsrcrecordid>eNpd0UtLw0AQAOBFFFurd71IEPGWuI9sdveoob4oCFLPYbqZ2JQ8ajbB9t-70IriXOYwH8M8CDlnNGKUstsV1BBxzSMmIsZlfEDGTAodCmn0IRlTanSoYh2PyIlzK-qDCXVMRoxKpmKux-RlvsTgDSvoy7Zxy3Id3GP_hdgE6dZWbbvZfmADDkMeTDfrDp3zLoAmD9K2aju0PVRBCo3F7pQcFVA5PNvnCXl_mM7Tp3D2-vic3s1CiEXShyCQF6KgWlKZc20FZzQ3UkKRxIUyEgtrjWHCgkU03GqTxybXMhGLnFvQYkJudn3XXfs5oOuzunQWqwoabAeXKaq5SKjx8OofXLVD1_jZMs6YYIpS6dHlHg2LGvNs3ZU1dNvs50QeXO8BOAtV0fllS_frjEqMUp5d7Jh_yZ8iM4kU3-UTfQk</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>211317005</pqid></control><display><type>article</type><title>The Relationship Between Cyclooxygenase-2 Expression and Colorectal Cancer</title><source>MEDLINE</source><source>American Medical Association Journals</source><creator>Sheehan, Katherine M ; Sheahan, Kieran ; O'Donoghue, Diarmuid P ; MacSweeney, Fergus ; Conroy, Ronan M ; Fitzgerald, Desmond J ; Murray, Frank E</creator><creatorcontrib>Sheehan, Katherine M ; Sheahan, Kieran ; O'Donoghue, Diarmuid P ; MacSweeney, Fergus ; Conroy, Ronan M ; Fitzgerald, Desmond J ; Murray, Frank E</creatorcontrib><description>CONTEXT Epidemiological studies have implicated the inducible form of cyclooxygenase
(COX-2) in the pathogenesis of colorectal cancer; however, its role is not
fully understood. OBJECTIVE To examine the relationship between the expression of COX-2 in human
colorectal cancer and patient survival. DESIGN Patients diagnosed as having colorectal cancer were evaluated and followed
up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were
stained for COX-2 using a rabbit polyclonal antibody raised against human
COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome.
Preabsorption of the anti–COX-2 antibody with a COX-2 peptide abolished
the staining, demonstrating the specificity of the assay. SETTING Gastrointestinal unit of a large general teaching hospital in Dublin,
Ireland. PARTICIPANTS Seventy-six patients (median age, 66.5 years) with colorectal cancer
(Dukes tumor stage A, n=9; Dukes B, n=30; Dukes C, n=25; Dukes D, n=12) whose
diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were
stained for COX-2 as controls. MAIN OUTCOME MEASURES Survival in years following diagnosis compared by extent of COX-2 epithelial
staining (grade 1, <1%; grade 2, 1%-19%; grade 3, 20%-49%; grade 4, ≥
50%), Dukes stage, tumor size, and lymph mode metastasis. RESULTS COX-2 was found in tumor epithelial cells, inflammatory cells, vascular
endothelium, and/or fibroblasts. The extent of epithelial staining was heterogeneous,
varying markedly among different tumors. Normal tissue adjacent to the tumors
also stained weakly for COX-2. No COX-2 was detected in control tissue samples.
The Kaplan-Meier survival estimate was 68% in patients who had grade 1 tumor
epithelial staining compared with 35% in those with higher grades combined
(log-rank χ2=5.7; P=.02). Greater
expression of COX-2 correlated with more advanced Dukes stage (Kendall τ-b,
0.22; P=.03) and larger tumor size (Kendall τ-b,
0.21; P=.02) and was particularly evident in tumors
with lymph node involvement (Kendall τ-b, 0.26; P=.02). CONCLUSIONS Our data indicate that COX-2 expression in colorectal cancer may be
related to survival. These data add to the growing epidemiological and experimental
evidence that COX-2 may play a role in colorectal tumorigenesis.</description><identifier>ISSN: 0098-7484</identifier><identifier>EISSN: 1538-3598</identifier><identifier>DOI: 10.1001/jama.282.13.1254</identifier><identifier>PMID: 10517428</identifier><identifier>CODEN: JAMAAP</identifier><language>eng</language><publisher>Chicago, IL: American Medical Association</publisher><subject>Aged ; Biological and medical sciences ; Colorectal cancer ; Colorectal Neoplasms - chemistry ; Colorectal Neoplasms - mortality ; Colorectal Neoplasms - pathology ; Cyclooxygenase 2 ; Epidemiology ; Female ; Follow-Up Studies ; Gastroenterology. Liver. Pancreas. Abdomen ; Humans ; Isoenzymes - analysis ; Lymphatic Metastasis ; Male ; Medical research ; Medical sciences ; Membrane Proteins ; Neoplasm Staging ; Prognosis ; Prostaglandin-Endoperoxide Synthases - analysis ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Survival Analysis ; Tumors</subject><ispartof>JAMA : the journal of the American Medical Association, 1999-10, Vol.282 (13), p.1254-1257</ispartof><rights>1999 INIST-CNRS</rights><rights>Copyright American Medical Association Oct 6, 1999</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a436t-a3e2f3f08505d28c3210d955af64f795efcc9913cacee92c89d49d8563bd2ca83</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jamanetwork.com/journals/jama/articlepdf/10.1001/jama.282.13.1254$$EPDF$$P50$$Gama$$H</linktopdf><linktohtml>$$Uhttps://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.282.13.1254$$EHTML$$P50$$Gama$$H</linktohtml><link.rule.ids>64,314,776,780,3327,27901,27902,76232,76235</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1976977$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10517428$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sheehan, Katherine M</creatorcontrib><creatorcontrib>Sheahan, Kieran</creatorcontrib><creatorcontrib>O'Donoghue, Diarmuid P</creatorcontrib><creatorcontrib>MacSweeney, Fergus</creatorcontrib><creatorcontrib>Conroy, Ronan M</creatorcontrib><creatorcontrib>Fitzgerald, Desmond J</creatorcontrib><creatorcontrib>Murray, Frank E</creatorcontrib><title>The Relationship Between Cyclooxygenase-2 Expression and Colorectal Cancer</title><title>JAMA : the journal of the American Medical Association</title><addtitle>JAMA</addtitle><description>CONTEXT Epidemiological studies have implicated the inducible form of cyclooxygenase
(COX-2) in the pathogenesis of colorectal cancer; however, its role is not
fully understood. OBJECTIVE To examine the relationship between the expression of COX-2 in human
colorectal cancer and patient survival. DESIGN Patients diagnosed as having colorectal cancer were evaluated and followed
up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were
stained for COX-2 using a rabbit polyclonal antibody raised against human
COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome.
Preabsorption of the anti–COX-2 antibody with a COX-2 peptide abolished
the staining, demonstrating the specificity of the assay. SETTING Gastrointestinal unit of a large general teaching hospital in Dublin,
Ireland. PARTICIPANTS Seventy-six patients (median age, 66.5 years) with colorectal cancer
(Dukes tumor stage A, n=9; Dukes B, n=30; Dukes C, n=25; Dukes D, n=12) whose
diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were
stained for COX-2 as controls. MAIN OUTCOME MEASURES Survival in years following diagnosis compared by extent of COX-2 epithelial
staining (grade 1, <1%; grade 2, 1%-19%; grade 3, 20%-49%; grade 4, ≥
50%), Dukes stage, tumor size, and lymph mode metastasis. RESULTS COX-2 was found in tumor epithelial cells, inflammatory cells, vascular
endothelium, and/or fibroblasts. The extent of epithelial staining was heterogeneous,
varying markedly among different tumors. Normal tissue adjacent to the tumors
also stained weakly for COX-2. No COX-2 was detected in control tissue samples.
The Kaplan-Meier survival estimate was 68% in patients who had grade 1 tumor
epithelial staining compared with 35% in those with higher grades combined
(log-rank χ2=5.7; P=.02). Greater
expression of COX-2 correlated with more advanced Dukes stage (Kendall τ-b,
0.22; P=.03) and larger tumor size (Kendall τ-b,
0.21; P=.02) and was particularly evident in tumors
with lymph node involvement (Kendall τ-b, 0.26; P=.02). CONCLUSIONS Our data indicate that COX-2 expression in colorectal cancer may be
related to survival. These data add to the growing epidemiological and experimental
evidence that COX-2 may play a role in colorectal tumorigenesis.</description><subject>Aged</subject><subject>Biological and medical sciences</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - chemistry</subject><subject>Colorectal Neoplasms - mortality</subject><subject>Colorectal Neoplasms - pathology</subject><subject>Cyclooxygenase 2</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Humans</subject><subject>Isoenzymes - analysis</subject><subject>Lymphatic Metastasis</subject><subject>Male</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Membrane Proteins</subject><subject>Neoplasm Staging</subject><subject>Prognosis</subject><subject>Prostaglandin-Endoperoxide Synthases - analysis</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Survival Analysis</subject><subject>Tumors</subject><issn>0098-7484</issn><issn>1538-3598</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0UtLw0AQAOBFFFurd71IEPGWuI9sdveoob4oCFLPYbqZ2JQ8ajbB9t-70IriXOYwH8M8CDlnNGKUstsV1BBxzSMmIsZlfEDGTAodCmn0IRlTanSoYh2PyIlzK-qDCXVMRoxKpmKux-RlvsTgDSvoy7Zxy3Id3GP_hdgE6dZWbbvZfmADDkMeTDfrDp3zLoAmD9K2aju0PVRBCo3F7pQcFVA5PNvnCXl_mM7Tp3D2-vic3s1CiEXShyCQF6KgWlKZc20FZzQ3UkKRxIUyEgtrjWHCgkU03GqTxybXMhGLnFvQYkJudn3XXfs5oOuzunQWqwoabAeXKaq5SKjx8OofXLVD1_jZMs6YYIpS6dHlHg2LGvNs3ZU1dNvs50QeXO8BOAtV0fllS_frjEqMUp5d7Jh_yZ8iM4kU3-UTfQk</recordid><startdate>19991006</startdate><enddate>19991006</enddate><creator>Sheehan, Katherine M</creator><creator>Sheahan, Kieran</creator><creator>O'Donoghue, Diarmuid P</creator><creator>MacSweeney, Fergus</creator><creator>Conroy, Ronan M</creator><creator>Fitzgerald, Desmond J</creator><creator>Murray, Frank E</creator><general>American Medical Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QL</scope><scope>7QP</scope><scope>7TK</scope><scope>7TS</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19991006</creationdate><title>The Relationship Between Cyclooxygenase-2 Expression and Colorectal Cancer</title><author>Sheehan, Katherine M ; Sheahan, Kieran ; O'Donoghue, Diarmuid P ; MacSweeney, Fergus ; Conroy, Ronan M ; Fitzgerald, Desmond J ; Murray, Frank E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a436t-a3e2f3f08505d28c3210d955af64f795efcc9913cacee92c89d49d8563bd2ca83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Aged</topic><topic>Biological and medical sciences</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - chemistry</topic><topic>Colorectal Neoplasms - mortality</topic><topic>Colorectal Neoplasms - pathology</topic><topic>Cyclooxygenase 2</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Humans</topic><topic>Isoenzymes - analysis</topic><topic>Lymphatic Metastasis</topic><topic>Male</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>Membrane Proteins</topic><topic>Neoplasm Staging</topic><topic>Prognosis</topic><topic>Prostaglandin-Endoperoxide Synthases - analysis</topic><topic>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</topic><topic>Survival Analysis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sheehan, Katherine M</creatorcontrib><creatorcontrib>Sheahan, Kieran</creatorcontrib><creatorcontrib>O'Donoghue, Diarmuid P</creatorcontrib><creatorcontrib>MacSweeney, Fergus</creatorcontrib><creatorcontrib>Conroy, Ronan M</creatorcontrib><creatorcontrib>Fitzgerald, Desmond J</creatorcontrib><creatorcontrib>Murray, Frank E</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Physical Education Index</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>JAMA : the journal of the American Medical Association</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sheehan, Katherine M</au><au>Sheahan, Kieran</au><au>O'Donoghue, Diarmuid P</au><au>MacSweeney, Fergus</au><au>Conroy, Ronan M</au><au>Fitzgerald, Desmond J</au><au>Murray, Frank E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Relationship Between Cyclooxygenase-2 Expression and Colorectal Cancer</atitle><jtitle>JAMA : the journal of the American Medical Association</jtitle><addtitle>JAMA</addtitle><date>1999-10-06</date><risdate>1999</risdate><volume>282</volume><issue>13</issue><spage>1254</spage><epage>1257</epage><pages>1254-1257</pages><issn>0098-7484</issn><eissn>1538-3598</eissn><coden>JAMAAP</coden><abstract>CONTEXT Epidemiological studies have implicated the inducible form of cyclooxygenase
(COX-2) in the pathogenesis of colorectal cancer; however, its role is not
fully understood. OBJECTIVE To examine the relationship between the expression of COX-2 in human
colorectal cancer and patient survival. DESIGN Patients diagnosed as having colorectal cancer were evaluated and followed
up for up to 9.4 years (median follow-up, 2.7 years). Tumor sections were
stained for COX-2 using a rabbit polyclonal antibody raised against human
COX-2. The extent of COX-2 staining was graded by 2 observers blinded to outcome.
Preabsorption of the anti–COX-2 antibody with a COX-2 peptide abolished
the staining, demonstrating the specificity of the assay. SETTING Gastrointestinal unit of a large general teaching hospital in Dublin,
Ireland. PARTICIPANTS Seventy-six patients (median age, 66.5 years) with colorectal cancer
(Dukes tumor stage A, n=9; Dukes B, n=30; Dukes C, n=25; Dukes D, n=12) whose
diagnosis was made between 1988 and 1991. Fourteen normal colon biopsies were
stained for COX-2 as controls. MAIN OUTCOME MEASURES Survival in years following diagnosis compared by extent of COX-2 epithelial
staining (grade 1, <1%; grade 2, 1%-19%; grade 3, 20%-49%; grade 4, ≥
50%), Dukes stage, tumor size, and lymph mode metastasis. RESULTS COX-2 was found in tumor epithelial cells, inflammatory cells, vascular
endothelium, and/or fibroblasts. The extent of epithelial staining was heterogeneous,
varying markedly among different tumors. Normal tissue adjacent to the tumors
also stained weakly for COX-2. No COX-2 was detected in control tissue samples.
The Kaplan-Meier survival estimate was 68% in patients who had grade 1 tumor
epithelial staining compared with 35% in those with higher grades combined
(log-rank χ2=5.7; P=.02). Greater
expression of COX-2 correlated with more advanced Dukes stage (Kendall τ-b,
0.22; P=.03) and larger tumor size (Kendall τ-b,
0.21; P=.02) and was particularly evident in tumors
with lymph node involvement (Kendall τ-b, 0.26; P=.02). CONCLUSIONS Our data indicate that COX-2 expression in colorectal cancer may be
related to survival. These data add to the growing epidemiological and experimental
evidence that COX-2 may play a role in colorectal tumorigenesis.</abstract><cop>Chicago, IL</cop><pub>American Medical Association</pub><pmid>10517428</pmid><doi>10.1001/jama.282.13.1254</doi><tpages>4</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0098-7484 |
| ispartof | JAMA : the journal of the American Medical Association, 1999-10, Vol.282 (13), p.1254-1257 |
| issn | 0098-7484 1538-3598 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70823609 |
| source | MEDLINE; American Medical Association Journals |
| subjects | Aged Biological and medical sciences Colorectal cancer Colorectal Neoplasms - chemistry Colorectal Neoplasms - mortality Colorectal Neoplasms - pathology Cyclooxygenase 2 Epidemiology Female Follow-Up Studies Gastroenterology. Liver. Pancreas. Abdomen Humans Isoenzymes - analysis Lymphatic Metastasis Male Medical research Medical sciences Membrane Proteins Neoplasm Staging Prognosis Prostaglandin-Endoperoxide Synthases - analysis Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Survival Analysis Tumors |
| title | The Relationship Between Cyclooxygenase-2 Expression and Colorectal Cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T03%3A14%3A22IST&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=The%20Relationship%20Between%20Cyclooxygenase-2%20Expression%20and%20Colorectal%20Cancer&rft.jtitle=JAMA%20:%20the%20journal%20of%20the%20American%20Medical%20Association&rft.au=Sheehan,%20Katherine%20M&rft.date=1999-10-06&rft.volume=282&rft.issue=13&rft.spage=1254&rft.epage=1257&rft.pages=1254-1257&rft.issn=0098-7484&rft.eissn=1538-3598&rft.coden=JAMAAP&rft_id=info:doi/10.1001/jama.282.13.1254&rft_dat=%3Cproquest_pubme%3E70823609%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=211317005&rft_id=info:pmid/10517428&rft_ama_id=191965&rfr_iscdi=true |