Recurrence and survival after laparoscopy versus laparotomy without lymphadenectomy in early-stage endometrial cancer: Long-term outcomes of a randomised trial
Laparoscopic hysterectomy is accepted worldwide as the standard treatment option for early-stage endometrial cancer. However, there are limited data on long-term survival, particularly when no lymphadenectomy is performed. We compared the survival outcomes of total laparoscopic hysterectomy (TLH) an...
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| Veröffentlicht in: | Gynecologic oncology 2022-02, Vol.164 (2), p.265-270 |
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| creator | Reijntjes, Bianca van Suijlichem, Mieke Woolderink, Jorien M. Bongers, Marlies Y. Reesink-Peters, Nathalie Paulsen, Lasse van der Hurk, Pieter J. Kraayenbrink, Arjan A. Apperloo, Mirjam J.A. Slangen, Brigitte Schukken, Tineke Tummers, Fokkedien H.M.P. van Kesteren, Paul J.M. Huirne, Judith A.F. Boskamp, Dieuwke Lunter, Gerton de Bock, Geertruida H. Mourits, Marian J.E. |
| description | Laparoscopic hysterectomy is accepted worldwide as the standard treatment option for early-stage endometrial cancer. However, there are limited data on long-term survival, particularly when no lymphadenectomy is performed. We compared the survival outcomes of total laparoscopic hysterectomy (TLH) and total abdominal hysterectomy (TAH), both without lymphadenectomy, for early-stage endometrial cancer up to 5 years postoperatively.
Follow-up of a multi-centre, randomised controlled trial comparing TLH and TAH, without routine lymphadenectomy, for women with stage I endometrial cancer. Enrolment was between 2007 and 2009 by 2:1 randomisation to TLH or TAH. Outcomes were disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and primary site of recurrence. Multivariable Cox regression analyses were adjusted for age, stage, grade, and radiotherapy with adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI) reported. To test for significance, non-inferiority margins were defined.
In total, 279 women underwent a surgical procedure, of whom 263 (94%) had follow-up data. For the TLH (n = 175) and TAH (n = 88) groups, DFS (90.3% vs 84.1%; aHR[recurrence], 0.69; 95%CI, 0.31–1.52), OS (89.2% vs 82.8%; aHR[death], 0.60; 95%CI, 0.30–1.19), and DSS (95.0% vs 89.8%; aHR[death], 0.62; 95%CI, 0.23–1.70) were reported at 5 years. At a 10% significance level, and with a non-inferiority margin of 0.20, the null hypothesis of inferiority was rejected for all three outcomes. There were no port-site or wound metastases, and local recurrence rates were comparable.
Disease recurrence and 5-year survival rates were comparable between the TLH and TAH groups and comparable to studies with lymphadenectomy, supporting the widespread use of TLH without lymphadenectomy as the primary treatment for early-stage, low-grade endometrial cancer.
•Long-term outcomes of TLH vs TAH without lymphadenectomy in early EC are reported.•There were no significant differences in DFS, OS and DSS, 5 years postoperatively.•No port-site or wound metastases were found after TLH or TAH.•Our findings support the widespread use of TLH without lymphadenectomy for early EC. |
| doi_str_mv | 10.1016/j.ygyno.2021.12.019 |
| format | Article |
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Follow-up of a multi-centre, randomised controlled trial comparing TLH and TAH, without routine lymphadenectomy, for women with stage I endometrial cancer. Enrolment was between 2007 and 2009 by 2:1 randomisation to TLH or TAH. Outcomes were disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and primary site of recurrence. Multivariable Cox regression analyses were adjusted for age, stage, grade, and radiotherapy with adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI) reported. To test for significance, non-inferiority margins were defined.
In total, 279 women underwent a surgical procedure, of whom 263 (94%) had follow-up data. For the TLH (n = 175) and TAH (n = 88) groups, DFS (90.3% vs 84.1%; aHR[recurrence], 0.69; 95%CI, 0.31–1.52), OS (89.2% vs 82.8%; aHR[death], 0.60; 95%CI, 0.30–1.19), and DSS (95.0% vs 89.8%; aHR[death], 0.62; 95%CI, 0.23–1.70) were reported at 5 years. At a 10% significance level, and with a non-inferiority margin of 0.20, the null hypothesis of inferiority was rejected for all three outcomes. There were no port-site or wound metastases, and local recurrence rates were comparable.
Disease recurrence and 5-year survival rates were comparable between the TLH and TAH groups and comparable to studies with lymphadenectomy, supporting the widespread use of TLH without lymphadenectomy as the primary treatment for early-stage, low-grade endometrial cancer.
•Long-term outcomes of TLH vs TAH without lymphadenectomy in early EC are reported.•There were no significant differences in DFS, OS and DSS, 5 years postoperatively.•No port-site or wound metastases were found after TLH or TAH.•Our findings support the widespread use of TLH without lymphadenectomy for early EC.</description><identifier>ISSN: 0090-8258</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2021.12.019</identifier><identifier>PMID: 34955237</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Carcinoma, Endometrioid - mortality ; Carcinoma, Endometrioid - pathology ; Carcinoma, Endometrioid - surgery ; Disease-Free Survival ; Endometrial cancer ; Endometrial Neoplasms - mortality ; Endometrial Neoplasms - pathology ; Endometrial Neoplasms - surgery ; Female ; Humans ; Hysterectomy ; Hysterectomy - methods ; Laparoscopic surgery ; Laparoscopy - methods ; Laparotomy ; Laparotomy - methods ; Lymph Node Excision ; Lymphadenectomy ; Middle Aged ; Neoplasm Grading ; Neoplasm Recurrence, Local - epidemiology ; Neoplasm Staging ; Radiotherapy, Adjuvant ; Recurrence ; Survival</subject><ispartof>Gynecologic oncology, 2022-02, Vol.164 (2), p.265-270</ispartof><rights>2021 Elsevier Inc.</rights><rights>Copyright © 2021 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c404t-24a090edd5f12f583a5ff02dd85c2b6ff7727d0d80e3d8fc50fe95f41c8c2413</citedby><cites>FETCH-LOGICAL-c404t-24a090edd5f12f583a5ff02dd85c2b6ff7727d0d80e3d8fc50fe95f41c8c2413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ygyno.2021.12.019$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34955237$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Reijntjes, Bianca</creatorcontrib><creatorcontrib>van Suijlichem, Mieke</creatorcontrib><creatorcontrib>Woolderink, Jorien M.</creatorcontrib><creatorcontrib>Bongers, Marlies Y.</creatorcontrib><creatorcontrib>Reesink-Peters, Nathalie</creatorcontrib><creatorcontrib>Paulsen, Lasse</creatorcontrib><creatorcontrib>van der Hurk, Pieter J.</creatorcontrib><creatorcontrib>Kraayenbrink, Arjan A.</creatorcontrib><creatorcontrib>Apperloo, Mirjam J.A.</creatorcontrib><creatorcontrib>Slangen, Brigitte</creatorcontrib><creatorcontrib>Schukken, Tineke</creatorcontrib><creatorcontrib>Tummers, Fokkedien H.M.P.</creatorcontrib><creatorcontrib>van Kesteren, Paul J.M.</creatorcontrib><creatorcontrib>Huirne, Judith A.F.</creatorcontrib><creatorcontrib>Boskamp, Dieuwke</creatorcontrib><creatorcontrib>Lunter, Gerton</creatorcontrib><creatorcontrib>de Bock, Geertruida H.</creatorcontrib><creatorcontrib>Mourits, Marian J.E.</creatorcontrib><title>Recurrence and survival after laparoscopy versus laparotomy without lymphadenectomy in early-stage endometrial cancer: Long-term outcomes of a randomised trial</title><title>Gynecologic oncology</title><addtitle>Gynecol Oncol</addtitle><description>Laparoscopic hysterectomy is accepted worldwide as the standard treatment option for early-stage endometrial cancer. However, there are limited data on long-term survival, particularly when no lymphadenectomy is performed. We compared the survival outcomes of total laparoscopic hysterectomy (TLH) and total abdominal hysterectomy (TAH), both without lymphadenectomy, for early-stage endometrial cancer up to 5 years postoperatively.
Follow-up of a multi-centre, randomised controlled trial comparing TLH and TAH, without routine lymphadenectomy, for women with stage I endometrial cancer. Enrolment was between 2007 and 2009 by 2:1 randomisation to TLH or TAH. Outcomes were disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and primary site of recurrence. Multivariable Cox regression analyses were adjusted for age, stage, grade, and radiotherapy with adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI) reported. To test for significance, non-inferiority margins were defined.
In total, 279 women underwent a surgical procedure, of whom 263 (94%) had follow-up data. For the TLH (n = 175) and TAH (n = 88) groups, DFS (90.3% vs 84.1%; aHR[recurrence], 0.69; 95%CI, 0.31–1.52), OS (89.2% vs 82.8%; aHR[death], 0.60; 95%CI, 0.30–1.19), and DSS (95.0% vs 89.8%; aHR[death], 0.62; 95%CI, 0.23–1.70) were reported at 5 years. At a 10% significance level, and with a non-inferiority margin of 0.20, the null hypothesis of inferiority was rejected for all three outcomes. There were no port-site or wound metastases, and local recurrence rates were comparable.
Disease recurrence and 5-year survival rates were comparable between the TLH and TAH groups and comparable to studies with lymphadenectomy, supporting the widespread use of TLH without lymphadenectomy as the primary treatment for early-stage, low-grade endometrial cancer.
•Long-term outcomes of TLH vs TAH without lymphadenectomy in early EC are reported.•There were no significant differences in DFS, OS and DSS, 5 years postoperatively.•No port-site or wound metastases were found after TLH or TAH.•Our findings support the widespread use of TLH without lymphadenectomy for early EC.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Carcinoma, Endometrioid - mortality</subject><subject>Carcinoma, Endometrioid - pathology</subject><subject>Carcinoma, Endometrioid - surgery</subject><subject>Disease-Free Survival</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - mortality</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Endometrial Neoplasms - surgery</subject><subject>Female</subject><subject>Humans</subject><subject>Hysterectomy</subject><subject>Hysterectomy - methods</subject><subject>Laparoscopic surgery</subject><subject>Laparoscopy - methods</subject><subject>Laparotomy</subject><subject>Laparotomy - methods</subject><subject>Lymph Node Excision</subject><subject>Lymphadenectomy</subject><subject>Middle Aged</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Recurrence, Local - epidemiology</subject><subject>Neoplasm Staging</subject><subject>Radiotherapy, Adjuvant</subject><subject>Recurrence</subject><subject>Survival</subject><issn>0090-8258</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kd1q3DAQhUVoSDZpniBQdNkbuyPZWtuFXpSQP1gIlL0XWmm00WJbrmRv8dP0Vav9aS97JRidM2dmPkLuGeQM2PLLLp-3c-9zDpzljOfAmguyYNCIbFmL5gNZADSQ1VzU1-Qmxh0AFMD4FbkuykYIXlQL8vsH6ikE7DVS1Rsap7B3e9VSZUcMtFWDCj5qP8x0jyFO8VwafTfTX25899NI27kb3pXBHvWx7nqKKrRzFke1RYq98R2OwaW2WqWk8JWufL_NUkJHUwOdviP1lioa1EHsIhp6NHwkl1a1Ee_O7y1ZPz2uH16y1dvz68P3VaZLKMeMlyrtisYIy7gVdaGEtcCNqYXmm6W1VcUrA6YGLExttQCLjbAl07XmJStuyedT2yH4nxPGUaYZNLat6tFPUfIlKytRcVYmaXGS6nSYGNDKIbhOhVkykAcwciePYOQBjGRcJjDJ9ekcMG06NP88f0kkwbeTANOWe4dBRu0OWIwL6azSePffgD8opKWy</recordid><startdate>202202</startdate><enddate>202202</enddate><creator>Reijntjes, Bianca</creator><creator>van Suijlichem, Mieke</creator><creator>Woolderink, Jorien M.</creator><creator>Bongers, Marlies Y.</creator><creator>Reesink-Peters, Nathalie</creator><creator>Paulsen, Lasse</creator><creator>van der Hurk, Pieter J.</creator><creator>Kraayenbrink, Arjan A.</creator><creator>Apperloo, Mirjam J.A.</creator><creator>Slangen, Brigitte</creator><creator>Schukken, Tineke</creator><creator>Tummers, Fokkedien H.M.P.</creator><creator>van Kesteren, Paul J.M.</creator><creator>Huirne, Judith A.F.</creator><creator>Boskamp, Dieuwke</creator><creator>Lunter, Gerton</creator><creator>de Bock, Geertruida H.</creator><creator>Mourits, Marian J.E.</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>7X8</scope></search><sort><creationdate>202202</creationdate><title>Recurrence and survival after laparoscopy versus laparotomy without lymphadenectomy in early-stage endometrial cancer: Long-term outcomes of a randomised trial</title><author>Reijntjes, Bianca ; van Suijlichem, Mieke ; Woolderink, Jorien M. ; Bongers, Marlies Y. ; Reesink-Peters, Nathalie ; Paulsen, Lasse ; van der Hurk, Pieter J. ; Kraayenbrink, Arjan A. ; Apperloo, Mirjam J.A. ; Slangen, Brigitte ; Schukken, Tineke ; Tummers, Fokkedien H.M.P. ; van Kesteren, Paul J.M. ; Huirne, Judith A.F. ; Boskamp, Dieuwke ; Lunter, Gerton ; de Bock, Geertruida H. ; Mourits, Marian J.E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c404t-24a090edd5f12f583a5ff02dd85c2b6ff7727d0d80e3d8fc50fe95f41c8c2413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Carcinoma, Endometrioid - mortality</topic><topic>Carcinoma, Endometrioid - pathology</topic><topic>Carcinoma, Endometrioid - surgery</topic><topic>Disease-Free Survival</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - mortality</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Endometrial Neoplasms - surgery</topic><topic>Female</topic><topic>Humans</topic><topic>Hysterectomy</topic><topic>Hysterectomy - methods</topic><topic>Laparoscopic surgery</topic><topic>Laparoscopy - methods</topic><topic>Laparotomy</topic><topic>Laparotomy - methods</topic><topic>Lymph Node Excision</topic><topic>Lymphadenectomy</topic><topic>Middle Aged</topic><topic>Neoplasm Grading</topic><topic>Neoplasm Recurrence, Local - epidemiology</topic><topic>Neoplasm Staging</topic><topic>Radiotherapy, Adjuvant</topic><topic>Recurrence</topic><topic>Survival</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Reijntjes, Bianca</creatorcontrib><creatorcontrib>van Suijlichem, Mieke</creatorcontrib><creatorcontrib>Woolderink, Jorien M.</creatorcontrib><creatorcontrib>Bongers, Marlies Y.</creatorcontrib><creatorcontrib>Reesink-Peters, Nathalie</creatorcontrib><creatorcontrib>Paulsen, Lasse</creatorcontrib><creatorcontrib>van der Hurk, Pieter J.</creatorcontrib><creatorcontrib>Kraayenbrink, Arjan A.</creatorcontrib><creatorcontrib>Apperloo, Mirjam J.A.</creatorcontrib><creatorcontrib>Slangen, Brigitte</creatorcontrib><creatorcontrib>Schukken, Tineke</creatorcontrib><creatorcontrib>Tummers, Fokkedien H.M.P.</creatorcontrib><creatorcontrib>van Kesteren, Paul J.M.</creatorcontrib><creatorcontrib>Huirne, Judith A.F.</creatorcontrib><creatorcontrib>Boskamp, Dieuwke</creatorcontrib><creatorcontrib>Lunter, Gerton</creatorcontrib><creatorcontrib>de Bock, Geertruida H.</creatorcontrib><creatorcontrib>Mourits, Marian J.E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Reijntjes, Bianca</au><au>van Suijlichem, Mieke</au><au>Woolderink, Jorien M.</au><au>Bongers, Marlies Y.</au><au>Reesink-Peters, Nathalie</au><au>Paulsen, Lasse</au><au>van der Hurk, Pieter J.</au><au>Kraayenbrink, Arjan A.</au><au>Apperloo, Mirjam J.A.</au><au>Slangen, Brigitte</au><au>Schukken, Tineke</au><au>Tummers, Fokkedien H.M.P.</au><au>van Kesteren, Paul J.M.</au><au>Huirne, Judith A.F.</au><au>Boskamp, Dieuwke</au><au>Lunter, Gerton</au><au>de Bock, Geertruida H.</au><au>Mourits, Marian J.E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Recurrence and survival after laparoscopy versus laparotomy without lymphadenectomy in early-stage endometrial cancer: Long-term outcomes of a randomised trial</atitle><jtitle>Gynecologic oncology</jtitle><addtitle>Gynecol Oncol</addtitle><date>2022-02</date><risdate>2022</risdate><volume>164</volume><issue>2</issue><spage>265</spage><epage>270</epage><pages>265-270</pages><issn>0090-8258</issn><eissn>1095-6859</eissn><abstract>Laparoscopic hysterectomy is accepted worldwide as the standard treatment option for early-stage endometrial cancer. However, there are limited data on long-term survival, particularly when no lymphadenectomy is performed. We compared the survival outcomes of total laparoscopic hysterectomy (TLH) and total abdominal hysterectomy (TAH), both without lymphadenectomy, for early-stage endometrial cancer up to 5 years postoperatively.
Follow-up of a multi-centre, randomised controlled trial comparing TLH and TAH, without routine lymphadenectomy, for women with stage I endometrial cancer. Enrolment was between 2007 and 2009 by 2:1 randomisation to TLH or TAH. Outcomes were disease-free survival (DFS), overall survival (OS), disease-specific survival (DSS), and primary site of recurrence. Multivariable Cox regression analyses were adjusted for age, stage, grade, and radiotherapy with adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI) reported. To test for significance, non-inferiority margins were defined.
In total, 279 women underwent a surgical procedure, of whom 263 (94%) had follow-up data. For the TLH (n = 175) and TAH (n = 88) groups, DFS (90.3% vs 84.1%; aHR[recurrence], 0.69; 95%CI, 0.31–1.52), OS (89.2% vs 82.8%; aHR[death], 0.60; 95%CI, 0.30–1.19), and DSS (95.0% vs 89.8%; aHR[death], 0.62; 95%CI, 0.23–1.70) were reported at 5 years. At a 10% significance level, and with a non-inferiority margin of 0.20, the null hypothesis of inferiority was rejected for all three outcomes. There were no port-site or wound metastases, and local recurrence rates were comparable.
Disease recurrence and 5-year survival rates were comparable between the TLH and TAH groups and comparable to studies with lymphadenectomy, supporting the widespread use of TLH without lymphadenectomy as the primary treatment for early-stage, low-grade endometrial cancer.
•Long-term outcomes of TLH vs TAH without lymphadenectomy in early EC are reported.•There were no significant differences in DFS, OS and DSS, 5 years postoperatively.•No port-site or wound metastases were found after TLH or TAH.•Our findings support the widespread use of TLH without lymphadenectomy for early EC.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>34955237</pmid><doi>10.1016/j.ygyno.2021.12.019</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0090-8258 |
| ispartof | Gynecologic oncology, 2022-02, Vol.164 (2), p.265-270 |
| issn | 0090-8258 1095-6859 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2614757214 |
| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Adult Aged Aged, 80 and over Carcinoma, Endometrioid - mortality Carcinoma, Endometrioid - pathology Carcinoma, Endometrioid - surgery Disease-Free Survival Endometrial cancer Endometrial Neoplasms - mortality Endometrial Neoplasms - pathology Endometrial Neoplasms - surgery Female Humans Hysterectomy Hysterectomy - methods Laparoscopic surgery Laparoscopy - methods Laparotomy Laparotomy - methods Lymph Node Excision Lymphadenectomy Middle Aged Neoplasm Grading Neoplasm Recurrence, Local - epidemiology Neoplasm Staging Radiotherapy, Adjuvant Recurrence Survival |
| title | Recurrence and survival after laparoscopy versus laparotomy without lymphadenectomy in early-stage endometrial cancer: Long-term outcomes of a randomised trial |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-22T06%3A49%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Recurrence%20and%20survival%20after%20laparoscopy%20versus%20laparotomy%20without%20lymphadenectomy%20in%20early-stage%20endometrial%20cancer:%20Long-term%20outcomes%20of%20a%20randomised%20trial&rft.jtitle=Gynecologic%20oncology&rft.au=Reijntjes,%20Bianca&rft.date=2022-02&rft.volume=164&rft.issue=2&rft.spage=265&rft.epage=270&rft.pages=265-270&rft.issn=0090-8258&rft.eissn=1095-6859&rft_id=info:doi/10.1016/j.ygyno.2021.12.019&rft_dat=%3Cproquest_cross%3E2614757214%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2614757214&rft_id=info:pmid/34955237&rft_els_id=S0090825821016760&rfr_iscdi=true |