Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma
The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contrib...
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| Veröffentlicht in: | Gynecologic oncology 2019-05, Vol.153 (2), p.217-222 |
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| creator | Morse, Christopher B. Toukatly, Mirna N. Kilgore, Mark R. Agnew, Kathy J. Bernards, Sarah S. Norquist, Barbara M. Pennington, Kathryn P. Garcia, Rochelle L. Liao, John B. Swisher, Elizabeth M. |
| description | The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival.
Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C.
Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25–0.59)).
Patients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.
•Homologous recombination deficient (HRD) ovarian carcinoma (OC) is enriched for CD3+ tumor infiltrating lymphocytes (TIL).•Patients with both CD3+ TILs and HRD OC have the greatest overall survival, which may have therapeutic implications.•These findings highlight differences in the tumor microenvironment that could contribute to differential responses.•This is especially relevant as novel immunotherapies are being tested for the treatment of ovarian carcinoma. |
| doi_str_mv | 10.1016/j.ygyno.2019.02.011 |
| format | Article |
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Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C.
Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25–0.59)).
Patients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.
•Homologous recombination deficient (HRD) ovarian carcinoma (OC) is enriched for CD3+ tumor infiltrating lymphocytes (TIL).•Patients with both CD3+ TILs and HRD OC have the greatest overall survival, which may have therapeutic implications.•These findings highlight differences in the tumor microenvironment that could contribute to differential responses.•This is especially relevant as novel immunotherapies are being tested for the treatment of ovarian carcinoma.</description><identifier>ISSN: 0090-8258</identifier><identifier>ISSN: 1095-6859</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2019.02.011</identifier><identifier>PMID: 30803719</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; Carcinoma - genetics ; Carcinoma - immunology ; Carcinoma - mortality ; Carcinoma - surgery ; CD3 Complex - metabolism ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Lymphocytes, Tumor-Infiltrating - immunology ; Macrophages - immunology ; Middle Aged ; Mutation ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms - mortality ; Ovarian Neoplasms - surgery ; Ovary - pathology ; Ovary - surgery ; Prospective Studies ; Recombinational DNA Repair - genetics ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism</subject><ispartof>Gynecologic oncology, 2019-05, Vol.153 (2), p.217-222</ispartof><rights>2019 Elsevier Inc.</rights><rights>Copyright © 2019 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-3365cb296a252f23975ed746875ec59dd05021b369d53e2de84d3f8a8511431b3</citedby><cites>FETCH-LOGICAL-c459t-3365cb296a252f23975ed746875ec59dd05021b369d53e2de84d3f8a8511431b3</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.2019.02.011$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,777,781,882,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30803719$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morse, Christopher B.</creatorcontrib><creatorcontrib>Toukatly, Mirna N.</creatorcontrib><creatorcontrib>Kilgore, Mark R.</creatorcontrib><creatorcontrib>Agnew, Kathy J.</creatorcontrib><creatorcontrib>Bernards, Sarah S.</creatorcontrib><creatorcontrib>Norquist, Barbara M.</creatorcontrib><creatorcontrib>Pennington, Kathryn P.</creatorcontrib><creatorcontrib>Garcia, Rochelle L.</creatorcontrib><creatorcontrib>Liao, John B.</creatorcontrib><creatorcontrib>Swisher, Elizabeth M.</creatorcontrib><title>Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma</title><title>Gynecologic oncology</title><addtitle>Gynecol Oncol</addtitle><description>The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival.
Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C.
Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25–0.59)).
Patients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.
•Homologous recombination deficient (HRD) ovarian carcinoma (OC) is enriched for CD3+ tumor infiltrating lymphocytes (TIL).•Patients with both CD3+ TILs and HRD OC have the greatest overall survival, which may have therapeutic implications.•These findings highlight differences in the tumor microenvironment that could contribute to differential responses.•This is especially relevant as novel immunotherapies are being tested for the treatment of ovarian carcinoma.</description><subject>Aged</subject><subject>Carcinoma - genetics</subject><subject>Carcinoma - immunology</subject><subject>Carcinoma - mortality</subject><subject>Carcinoma - surgery</subject><subject>CD3 Complex - metabolism</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Humans</subject><subject>Kaplan-Meier Estimate</subject><subject>Lymphocytes, Tumor-Infiltrating - immunology</subject><subject>Macrophages - immunology</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Ovarian Neoplasms - mortality</subject><subject>Ovarian Neoplasms - surgery</subject><subject>Ovary - pathology</subject><subject>Ovary - surgery</subject><subject>Prospective Studies</subject><subject>Recombinational DNA Repair - genetics</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><issn>0090-8258</issn><issn>1095-6859</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1v1DAQhi0EokvhFyAhH7kk-CP22geQUMWXVIlLOVtee7LrVWIHO5sqv4K_jNstFVy4eOSZd94ZzYPQa0paSqh8d2zX_RpTywjVLWEtofQJ2lCiRSOV0E_RhhBNGsWEukAvSjkSQjih7Dm64EQRvqV6g37dnMaUcYh9GOZs5xD3eFjH6ZDcOkPBNnp8SGMa0j6dCs7g0rgLsQpTxB764AJEt2KboZp4mKA-cR5qppTkgp3B49swH3AYp5yW-iunvITFDlWP02JzsBE7m12IabQv0bPeDgVePcRL9OPzp5urr8319y_frj5eN64Tem44l8LtmJaWCdYzrrcC_LaTqkYntPdEEEZ3XGovODAPqvO8V1YJSjteC5fow9l3Ou1G8K7unO1gphxGm1eTbDD_VmI4mH1ajOyUVFxXg7cPBjn9PEGZzRiKg2GwEeqlDKNK0k5K3lUpP0tdTqVk6B_HUGLuUJqjuUdp7lAawkxFWbve_L3hY88fdlXw_iyAeqclQDblHgb4UDHNxqfw3wG_AWBetqE</recordid><startdate>20190501</startdate><enddate>20190501</enddate><creator>Morse, Christopher B.</creator><creator>Toukatly, Mirna N.</creator><creator>Kilgore, Mark R.</creator><creator>Agnew, Kathy J.</creator><creator>Bernards, Sarah S.</creator><creator>Norquist, Barbara M.</creator><creator>Pennington, Kathryn P.</creator><creator>Garcia, Rochelle L.</creator><creator>Liao, John B.</creator><creator>Swisher, Elizabeth M.</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><scope>5PM</scope></search><sort><creationdate>20190501</creationdate><title>Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma</title><author>Morse, Christopher B. ; Toukatly, Mirna N. ; Kilgore, Mark R. ; Agnew, Kathy J. ; Bernards, Sarah S. ; Norquist, Barbara M. ; Pennington, Kathryn P. ; Garcia, Rochelle L. ; Liao, John B. ; Swisher, Elizabeth M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-3365cb296a252f23975ed746875ec59dd05021b369d53e2de84d3f8a8511431b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Aged</topic><topic>Carcinoma - genetics</topic><topic>Carcinoma - immunology</topic><topic>Carcinoma - mortality</topic><topic>Carcinoma - surgery</topic><topic>CD3 Complex - metabolism</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Humans</topic><topic>Kaplan-Meier Estimate</topic><topic>Lymphocytes, Tumor-Infiltrating - immunology</topic><topic>Macrophages - immunology</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Ovarian Neoplasms - mortality</topic><topic>Ovarian Neoplasms - surgery</topic><topic>Ovary - pathology</topic><topic>Ovary - surgery</topic><topic>Prospective Studies</topic><topic>Recombinational DNA Repair - genetics</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Morse, Christopher B.</creatorcontrib><creatorcontrib>Toukatly, Mirna N.</creatorcontrib><creatorcontrib>Kilgore, Mark R.</creatorcontrib><creatorcontrib>Agnew, Kathy J.</creatorcontrib><creatorcontrib>Bernards, Sarah S.</creatorcontrib><creatorcontrib>Norquist, Barbara M.</creatorcontrib><creatorcontrib>Pennington, Kathryn P.</creatorcontrib><creatorcontrib>Garcia, Rochelle L.</creatorcontrib><creatorcontrib>Liao, John B.</creatorcontrib><creatorcontrib>Swisher, Elizabeth M.</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Morse, Christopher B.</au><au>Toukatly, Mirna N.</au><au>Kilgore, Mark R.</au><au>Agnew, Kathy J.</au><au>Bernards, Sarah S.</au><au>Norquist, Barbara M.</au><au>Pennington, Kathryn P.</au><au>Garcia, Rochelle L.</au><au>Liao, John B.</au><au>Swisher, Elizabeth M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma</atitle><jtitle>Gynecologic oncology</jtitle><addtitle>Gynecol Oncol</addtitle><date>2019-05-01</date><risdate>2019</risdate><volume>153</volume><issue>2</issue><spage>217</spage><epage>222</epage><pages>217-222</pages><issn>0090-8258</issn><issn>1095-6859</issn><eissn>1095-6859</eissn><abstract>The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival.
Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C.
Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25–0.59)).
Patients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies.
•Homologous recombination deficient (HRD) ovarian carcinoma (OC) is enriched for CD3+ tumor infiltrating lymphocytes (TIL).•Patients with both CD3+ TILs and HRD OC have the greatest overall survival, which may have therapeutic implications.•These findings highlight differences in the tumor microenvironment that could contribute to differential responses.•This is especially relevant as novel immunotherapies are being tested for the treatment of ovarian carcinoma.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30803719</pmid><doi>10.1016/j.ygyno.2019.02.011</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Aged Carcinoma - genetics Carcinoma - immunology Carcinoma - mortality Carcinoma - surgery CD3 Complex - metabolism Female Follow-Up Studies Humans Kaplan-Meier Estimate Lymphocytes, Tumor-Infiltrating - immunology Macrophages - immunology Middle Aged Mutation Ovarian Neoplasms - genetics Ovarian Neoplasms - immunology Ovarian Neoplasms - mortality Ovarian Neoplasms - surgery Ovary - pathology Ovary - surgery Prospective Studies Recombinational DNA Repair - genetics T-Lymphocytes - immunology T-Lymphocytes - metabolism |
| title | Tumor infiltrating lymphocytes and homologous recombination deficiency are independently associated with improved survival in ovarian carcinoma |
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