Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
Purpose: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous malignancy with poor prognosis. The optimal timing of chemotherapy-neoadjuvant (NACT) versus adjuvant (ACT)-remains controversial. This study assessed real-world outcomes in non-metastatic TNBC patients according to chemot...
- Autores:
-
Rodríguez Jaramillo, Carlos Andrés
Zapata Muñoz, Maycos Leandro
González Ramírez, Diego Mauricio
Graciano, Noiver
López, Lucelly
Montoya, Katherine
Gómez, Luis Rodolfo
Cortés, Javier
- Tipo de recurso:
- Article of investigation
- Fecha de publicación:
- 2025
- Institución:
- Universidad de Antioquia
- Repositorio:
- Repositorio UdeA
- Idioma:
- eng
- OAI Identifier:
- oai:bibliotecadigital.udea.edu.co:10495/46272
- Acceso en línea:
- https://hdl.handle.net/10495/46272
- Palabra clave:
- Quimioterapia
Antineoplastic Combined Chemotherapy Protocols
Protocolos de Quimioterapia Combinada Antineoplásica
Chemotherapy
Quimioterapia
Neoadjuvant Therapy
Terapia Neoadyuvante
Neoplasm Staging
Estadificación de Neoplasias
Prognosis
Pronóstico
Retrospective Studies
Estudios Retrospectivos
Time Factors
Factores de Tiempo
Triple Negative Breast Neoplasms
Neoplasias de la Mama Triple Negativas
https://id.nlm.nih.gov/mesh/D000971
https://id.nlm.nih.gov/mesh/D004358
https://id.nlm.nih.gov/mesh/D020360
https://id.nlm.nih.gov/mesh/D009367
https://id.nlm.nih.gov/mesh/D011379
https://id.nlm.nih.gov/mesh/D012189
https://id.nlm.nih.gov/mesh/D013997
https://id.nlm.nih.gov/mesh/D064726
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
- Rights
- openAccess
- License
- http://creativecommons.org/licenses/by/4.0/
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| dc.title.eng.fl_str_mv |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study |
| title |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study |
| spellingShingle |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study Quimioterapia Antineoplastic Combined Chemotherapy Protocols Protocolos de Quimioterapia Combinada Antineoplásica Chemotherapy Quimioterapia Neoadjuvant Therapy Terapia Neoadyuvante Neoplasm Staging Estadificación de Neoplasias Prognosis Pronóstico Retrospective Studies Estudios Retrospectivos Time Factors Factores de Tiempo Triple Negative Breast Neoplasms Neoplasias de la Mama Triple Negativas https://id.nlm.nih.gov/mesh/D000971 https://id.nlm.nih.gov/mesh/D004358 https://id.nlm.nih.gov/mesh/D020360 https://id.nlm.nih.gov/mesh/D009367 https://id.nlm.nih.gov/mesh/D011379 https://id.nlm.nih.gov/mesh/D012189 https://id.nlm.nih.gov/mesh/D013997 https://id.nlm.nih.gov/mesh/D064726 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| title_short |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study |
| title_full |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study |
| title_fullStr |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study |
| title_full_unstemmed |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study |
| title_sort |
Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study |
| dc.creator.fl_str_mv |
Rodríguez Jaramillo, Carlos Andrés Zapata Muñoz, Maycos Leandro González Ramírez, Diego Mauricio Graciano, Noiver López, Lucelly Montoya, Katherine Gómez, Luis Rodolfo Cortés, Javier |
| dc.contributor.author.none.fl_str_mv |
Rodríguez Jaramillo, Carlos Andrés Zapata Muñoz, Maycos Leandro González Ramírez, Diego Mauricio Graciano, Noiver López, Lucelly Montoya, Katherine Gómez, Luis Rodolfo Cortés, Javier |
| dc.contributor.researchgroup.none.fl_str_mv |
Grupo de Investigación en Farmacología y Toxicología |
| dc.subject.mesh.none.fl_str_mv |
Quimioterapia |
| topic |
Quimioterapia Antineoplastic Combined Chemotherapy Protocols Protocolos de Quimioterapia Combinada Antineoplásica Chemotherapy Quimioterapia Neoadjuvant Therapy Terapia Neoadyuvante Neoplasm Staging Estadificación de Neoplasias Prognosis Pronóstico Retrospective Studies Estudios Retrospectivos Time Factors Factores de Tiempo Triple Negative Breast Neoplasms Neoplasias de la Mama Triple Negativas https://id.nlm.nih.gov/mesh/D000971 https://id.nlm.nih.gov/mesh/D004358 https://id.nlm.nih.gov/mesh/D020360 https://id.nlm.nih.gov/mesh/D009367 https://id.nlm.nih.gov/mesh/D011379 https://id.nlm.nih.gov/mesh/D012189 https://id.nlm.nih.gov/mesh/D013997 https://id.nlm.nih.gov/mesh/D064726 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| dc.subject.decs.none.fl_str_mv |
Antineoplastic Combined Chemotherapy Protocols Protocolos de Quimioterapia Combinada Antineoplásica Chemotherapy Quimioterapia Neoadjuvant Therapy Terapia Neoadyuvante Neoplasm Staging Estadificación de Neoplasias Prognosis Pronóstico Retrospective Studies Estudios Retrospectivos Time Factors Factores de Tiempo Triple Negative Breast Neoplasms Neoplasias de la Mama Triple Negativas |
| dc.subject.meshuri.none.fl_str_mv |
https://id.nlm.nih.gov/mesh/D000971 https://id.nlm.nih.gov/mesh/D004358 https://id.nlm.nih.gov/mesh/D020360 https://id.nlm.nih.gov/mesh/D009367 https://id.nlm.nih.gov/mesh/D011379 https://id.nlm.nih.gov/mesh/D012189 https://id.nlm.nih.gov/mesh/D013997 https://id.nlm.nih.gov/mesh/D064726 |
| dc.subject.ods.none.fl_str_mv |
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| description |
Purpose: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous malignancy with poor prognosis. The optimal timing of chemotherapy-neoadjuvant (NACT) versus adjuvant (ACT)-remains controversial. This study assessed real-world outcomes in non-metastatic TNBC patients according to chemotherapy timing. Methods: This retrospective study (2008-2023) evaluated the impact of chemotherapy timing on overall survival (OS) and event-free survival (EFS) in a cohort of 711 patients. Propensity score (PS) matching with preoperative variables was used to adjust for baseline imbalances, and Cox regression models were applied to account for treatment-related variables. Results: NACT was administered to 525 patients (73.8%), with a 37.3% pathological complete response (pCR) rate. PS matching yielded 177 patient pairs; tumor stage, age and histologic grade remained unbalanced. In the unadjusted analysis, NACT was associated with worse OS (HR 1.56, 95% CI1.08-2.25, p = 0.018). However, multivariate analysis adjusting for unmatched and postoperative variables showed a potential benefit of NACT for OS (HR 0.53, 95% CI 0.07-4.13, p = 0.545) and EFS (HR 0.94, 95% CI 0.21-4.17, p = 0.932). Tumor stage acted as an effect modifier, and stratified analyses revealed that NACT was superior to ACT in patients with advanced-stage disease who achieved pCR (HR 0.22, 95% CI 0.07-0.7, p < 0.010). Conclusions: In our TNBC cohort, chemotherapy timing significantly influenced OS and EFS, particularly in relation to initial tumor stage and pCR status. NACT was more beneficial than ACT in patients with advanced disease who achieve pCR, underscoring its role in both prognostic stratification and therapeutic decision-making. |
| publishDate |
2025 |
| dc.date.accessioned.none.fl_str_mv |
2025-06-06T22:53:26Z |
| dc.date.issued.none.fl_str_mv |
2025-07 |
| dc.type.none.fl_str_mv |
Artículo de investigación |
| dc.type.coar.none.fl_str_mv |
http://purl.org/coar/resource_type/c_2df8fbb1 |
| dc.type.redcol.none.fl_str_mv |
http://purl.org/redcol/resource_type/ART |
| dc.type.content.none.fl_str_mv |
Text |
| dc.type.coarversion.none.fl_str_mv |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.driver.none.fl_str_mv |
info:eu-repo/semantics/article |
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info:eu-repo/semantics/publishedVersion |
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http://purl.org/coar/resource_type/c_2df8fbb1 |
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publishedVersion |
| dc.identifier.citation.none.fl_str_mv |
Graciano N, López L, Rodriguez CA, Montoya K, González DM, Gómez LR, Zapata ML, Cortés J. Effect of chemotherapy timing in triple-negative breast cancer: a real-world evidence study. Breast Cancer Res Treat. 2025 Jul;212(2):225-236. doi: 10.1007/s10549-025-07716-4. |
| dc.identifier.issn.none.fl_str_mv |
0167-6806 |
| dc.identifier.uri.none.fl_str_mv |
https://hdl.handle.net/10495/46272 |
| dc.identifier.eissn.none.fl_str_mv |
1573-7217 |
| dc.identifier.pmid.none.fl_str_mv |
40399665 |
| identifier_str_mv |
Graciano N, López L, Rodriguez CA, Montoya K, González DM, Gómez LR, Zapata ML, Cortés J. Effect of chemotherapy timing in triple-negative breast cancer: a real-world evidence study. Breast Cancer Res Treat. 2025 Jul;212(2):225-236. doi: 10.1007/s10549-025-07716-4. 0167-6806 1573-7217 40399665 |
| url |
https://hdl.handle.net/10495/46272 |
| dc.language.iso.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.ispartofjournalabbrev.none.fl_str_mv |
Breast. Cancer. Res. Treat. |
| dc.relation.citationedition.none.fl_str_mv |
12 páginas |
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236 |
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2 |
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225 |
| dc.relation.citationvolume.none.fl_str_mv |
212 |
| dc.relation.ispartofjournal.none.fl_str_mv |
Breast Cancer Research and Treatment |
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http://creativecommons.org/licenses/by/4.0/ |
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info:eu-repo/semantics/openAccess |
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Attribution 4.0 International |
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http://creativecommons.org/licenses/by/4.0/ Attribution 4.0 International http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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12 páginas |
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application/pdf |
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Springer |
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Dordrecht, Países Bajos |
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Springer |
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Universidad de Antioquia |
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Rodríguez Jaramillo, Carlos AndrésZapata Muñoz, Maycos LeandroGonzález Ramírez, Diego MauricioGraciano, NoiverLópez, LucellyMontoya, KatherineGómez, Luis RodolfoCortés, JavierGrupo de Investigación en Farmacología y Toxicología2025-06-06T22:53:26Z2025-07Graciano N, López L, Rodriguez CA, Montoya K, González DM, Gómez LR, Zapata ML, Cortés J. Effect of chemotherapy timing in triple-negative breast cancer: a real-world evidence study. Breast Cancer Res Treat. 2025 Jul;212(2):225-236. doi: 10.1007/s10549-025-07716-4.0167-6806https://hdl.handle.net/10495/462721573-721740399665Purpose: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous malignancy with poor prognosis. The optimal timing of chemotherapy-neoadjuvant (NACT) versus adjuvant (ACT)-remains controversial. This study assessed real-world outcomes in non-metastatic TNBC patients according to chemotherapy timing. Methods: This retrospective study (2008-2023) evaluated the impact of chemotherapy timing on overall survival (OS) and event-free survival (EFS) in a cohort of 711 patients. Propensity score (PS) matching with preoperative variables was used to adjust for baseline imbalances, and Cox regression models were applied to account for treatment-related variables. Results: NACT was administered to 525 patients (73.8%), with a 37.3% pathological complete response (pCR) rate. PS matching yielded 177 patient pairs; tumor stage, age and histologic grade remained unbalanced. In the unadjusted analysis, NACT was associated with worse OS (HR 1.56, 95% CI1.08-2.25, p = 0.018). However, multivariate analysis adjusting for unmatched and postoperative variables showed a potential benefit of NACT for OS (HR 0.53, 95% CI 0.07-4.13, p = 0.545) and EFS (HR 0.94, 95% CI 0.21-4.17, p = 0.932). Tumor stage acted as an effect modifier, and stratified analyses revealed that NACT was superior to ACT in patients with advanced-stage disease who achieved pCR (HR 0.22, 95% CI 0.07-0.7, p < 0.010). Conclusions: In our TNBC cohort, chemotherapy timing significantly influenced OS and EFS, particularly in relation to initial tumor stage and pCR status. NACT was more beneficial than ACT in patients with advanced disease who achieve pCR, underscoring its role in both prognostic stratification and therapeutic decision-making.COL003990212 páginasapplication/pdfengSpringerDordrecht, Países Bajoshttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessAttribution 4.0 Internationalhttp://purl.org/coar/access_right/c_abf2QuimioterapiaAntineoplastic Combined Chemotherapy ProtocolsProtocolos de Quimioterapia Combinada AntineoplásicaChemotherapyQuimioterapiaNeoadjuvant TherapyTerapia NeoadyuvanteNeoplasm StagingEstadificación de NeoplasiasPrognosisPronósticoRetrospective StudiesEstudios RetrospectivosTime FactorsFactores de TiempoTriple Negative Breast NeoplasmsNeoplasias de la Mama Triple Negativashttps://id.nlm.nih.gov/mesh/D000971https://id.nlm.nih.gov/mesh/D004358https://id.nlm.nih.gov/mesh/D020360https://id.nlm.nih.gov/mesh/D009367https://id.nlm.nih.gov/mesh/D011379https://id.nlm.nih.gov/mesh/D012189https://id.nlm.nih.gov/mesh/D013997https://id.nlm.nih.gov/mesh/D064726ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edadesEfect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence studyArtículo de investigaciónhttp://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/redcol/resource_type/ARTTexthttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionBreast. Cancer. Res. 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ltbywgc2kgZnVlcmUgYXBsaWNhYmxlKSwgeS9vIChpaSkgZWwgbm9tYnJlIGRlIGxhIHBhcnRlIG8gbGFzIHBhcnRlcyBxdWUgZWwgQXV0b3IgT3JpZ2luYWwgeS9vIGVsIExpY2VuY2lhbnRlIGh1YmllcmVuIGRlc2lnbmFkbyBwYXJhIGxhIGF0cmlidWNpw7NuICh2LmcuLCB1biBpbnN0aXR1dG8gcGF0cm9jaW5hZG9yLCBlZGl0b3JpYWwsIHB1YmxpY2FjacOzbikgZW4gbGEgaW5mb3JtYWNpw7NuIGRlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBkZWwgTGljZW5jaWFudGUsIHTDqXJtaW5vcyBkZSBzZXJ2aWNpb3MgbyBkZSBvdHJhcyBmb3JtYXMgcmF6b25hYmxlczsgZWwgdMOtdHVsbyBkZSBsYSBPYnJhIHNpIGVzdMOhIHByb3Zpc3RvOyBlbiBsYSBtZWRpZGEgZGUgbG8gcmF6b25hYmxlbWVudGUgZmFjdGlibGUgeSwgc2kgZXN0w6EgcHJvdmlzdG8sIGVsIElkZW50aWZpY2Fkb3IgVW5pZm9ybWUgZGUgUmVjdXJzb3MgKFVuaWZvcm0gUmVzb3VyY2UgSWRlbnRpZmllcikgcXVlIGVsIExpY2VuY2lhbnRlIGVzcGVjaWZpY2EgcGFyYSBzZXIgYXNvY2lhZG8gY29uIGxhIE9icmEsIHNhbHZvIHF1ZSB0YWwgVVJJIG5vIHNlIHJlZmllcmEgYSBsYSBub3RhIHNvYnJlIGxvcyBkZXJlY2hvcyBkZSBhdXRvciBvIGEgbGEgaW5mb3JtYWNpw7NuIHNvYnJlIGVsIGxpY2VuY2lhbWllbnRvIGRlIGxhIE9icmE7IHkgZW4gZWwgY2FzbyBkZSB1bmEgT2JyYSBEZXJpdmFkYSwgYXRyaWJ1aXIgZWwgY3LDqWRpdG8gaWRlbnRpZmljYW5kbyBlbCB1c28gZGUgbGEgT2JyYSBlbiBsYSBPYnJhIERlcml2YWRhICh2LmcuLCAiVHJhZHVjY2nDs24gRnJhbmNlc2EgZGUgbGEgT2JyYSBkZWwgQXV0b3IgT3JpZ2luYWwsIiBvICJHdWnDs24gQ2luZW1hdG9ncsOhZmljbyBiYXNhZG8gZW4gbGEgT2JyYSBvcmlnaW5hbCBkZWwgQXV0b3IgT3JpZ2luYWwiKS4gVGFsIGNyw6lkaXRvIHB1ZWRlIHNlciBpbXBsZW1lbnRhZG8gZGUgY3VhbHF1aWVyIGZvcm1hIHJhem9uYWJsZTsgZW4gZWwgY2Fzbywgc2luIGVtYmFyZ28sIGRlIE9icmFzIERlcml2YWRhcyB1IE9icmFzIENvbGVjdGl2YXMsIHRhbCBjcsOpZGl0byBhcGFyZWNlcsOhLCBjb21vIG3DrW5pbW8sIGRvbmRlIGFwYXJlY2UgZWwgY3LDqWRpdG8gZGUgY3VhbHF1aWVyIG90cm8gYXV0b3IgY29tcGFyYWJsZSB5IGRlIHVuYSBtYW5lcmEsIGFsIG1lbm9zLCB0YW4gZGVzdGFjYWRhIGNvbW8gZWwgY3LDqWRpdG8gZGUgb3RybyBhdXRvciBjb21wYXJhYmxlLiAgCmQuIFBhcmEgZXZpdGFyIHRvZGEgY29uZnVzacOzbiwgZWwgTGljZW5jaWFudGUgYWNsYXJhIHF1ZSwgY3VhbmRvIGxhIG9icmEgZXMgdW5hIGNvbXBvc2ljacOzbiBtdXNpY2FsOgoKaS4gUmVnYWzDrWFzIHBvciBpbnRlcnByZXRhY2nDs24geSBlamVjdWNpw7NuIGJham8gbGljZW5jaWFzIGdlbmVyYWxlcy4gRWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSBhdXRvcml6YXIgbGEgZWplY3VjacOzbiBww7pibGljYSBvIGxhIGVqZWN1Y2nDs24gcMO6YmxpY2EgZGlnaXRhbCBkZSBsYSBvYnJhIHkgZGUgcmVjb2xlY3Rhciwgc2VhIGluZGl2aWR1YWxtZW50ZSBvIGEgdHJhdsOpcyBkZSB1bmEgc29jaWVkYWQgZGUgZ2VzdGnDs24gY29sZWN0aXZhIGRlIGRlcmVjaG9zIGRlIGF1dG9yIHkgZGVyZWNob3MgY29uZXhvcyAocG9yIGVqZW1wbG8sIFNBWUNPKSwgbGFzIHJlZ2Fsw61hcyBwb3IgbGEgZWplY3VjacOzbiBww7pibGljYSBvIHBvciBsYSBlamVjdWNpw7NuIHDDumJsaWNhIGRpZ2l0YWwgZGUgbGEgb2JyYSAocG9yIGVqZW1wbG8gV2ViY2FzdCkgbGljZW5jaWFkYSBiYWpvIGxpY2VuY2lhcyBnZW5lcmFsZXMsIHNpIGxhIGludGVycHJldGFjacOzbiBvIGVqZWN1Y2nDs24gZGUgbGEgb2JyYSBlc3TDoSBwcmltb3JkaWFsbWVudGUgb3JpZW50YWRhIHBvciBvIGRpcmlnaWRhIGEgbGEgb2J0ZW5jacOzbiBkZSB1bmEgdmVudGFqYSBjb21lcmNpYWwgbyB1bmEgY29tcGVuc2FjacOzbiBtb25ldGFyaWEgcHJpdmFkYS4KaWkuIFJlZ2Fsw61hcyBwb3IgRm9ub2dyYW1hcy4gRWwgTGljZW5jaWFudGUgc2UgcmVzZXJ2YSBlbCBkZXJlY2hvIGV4Y2x1c2l2byBkZSByZWNvbGVjdGFyLCBpbmRpdmlkdWFsbWVudGUgbyBhIHRyYXbDqXMgZGUgdW5hIHNvY2llZGFkIGRlIGdlc3Rpw7NuIGNvbGVjdGl2YSBkZSBkZXJlY2hvcyBkZSBhdXRvciB5IGRlcmVjaG9zIGNvbmV4b3MgKHBvciBlamVtcGxvLCBsb3MgY29uc2FncmFkb3MgcG9yIGxhIFNBWUNPKSwgdW5hIGFnZW5jaWEgZGUgZGVyZWNob3MgbXVzaWNhbGVzIG8gYWxnw7puIGFnZW50ZSBkZXNpZ25hZG8sIGxhcyByZWdhbMOtYXMgcG9yIGN1YWxxdWllciBmb25vZ3JhbWEgcXVlIFVzdGVkIGNyZWUgYSBwYXJ0aXIgZGUgbGEgb2JyYSAo4oCcdmVyc2nDs24gY292ZXLigJ0pIHkgZGlzdHJpYnV5YSwgZW4gbG9zIHTDqXJtaW5vcyBkZWwgcsOpZ2ltZW4gZGUgZGVyZWNob3MgZGUgYXV0b3IsIHNpIGxhIGNyZWFjacOzbiBvIGRpc3RyaWJ1Y2nDs24gZGUgZXNhIHZlcnNpw7NuIGNvdmVyIGVzdMOhIHByaW1vcmRpYWxtZW50ZSBkZXN0aW5hZGEgbyBkaXJpZ2lkYSBhIG9idGVuZXIgdW5hIHZlbnRhamEgY29tZXJjaWFsIG8gdW5hIGNvbXBlbnNhY2nDs24gbW9uZXRhcmlhIHByaXZhZGEuCiAgICAgIAplLiBHZXN0acOzbiBkZSBEZXJlY2hvcyBkZSBBdXRvciBzb2JyZSBJbnRlcnByZXRhY2lvbmVzIHkgRWplY3VjaW9uZXMgRGlnaXRhbGVzIChXZWJDYXN0aW5nKS4gUGFyYSBldml0YXIgdG9kYSBjb25mdXNpw7NuLCBlbCBMaWNlbmNpYW50ZSBhY2xhcmEgcXVlLCBjdWFuZG8gbGEgb2JyYSBzZWEgdW4gZm9ub2dyYW1hLCBlbCBMaWNlbmNpYW50ZSBzZSByZXNlcnZhIGVsIGRlcmVjaG8gZXhjbHVzaXZvIGRlIGF1dG9yaXphciBsYSBlamVjdWNpw7NuIHDDumJsaWNhIGRpZ2l0YWwgZGUgbGEgb2JyYSAocG9yIGVqZW1wbG8sIHdlYmNhc3QpIHkgZGUgcmVjb2xlY3RhciwgaW5kaXZpZHVhbG1lbnRlIG8gYSB0cmF2w6lzIGRlIHVuYSBzb2NpZWRhZCBkZSBnZXN0acOzbiBjb2xlY3RpdmEgZGUgZGVyZWNob3MgZGUgYXV0b3IgeSBkZXJlY2hvcyBjb25leG9zIChwb3IgZWplbXBsbywgQUNJTlBSTyksIGxhcyByZWdhbMOtYXMgcG9yIGxhIGVqZWN1Y2nDs24gcMO6YmxpY2EgZGlnaXRhbCBkZSBsYSBvYnJhIChwb3IgZWplbXBsbywgd2ViY2FzdCksIHN1amV0YSBhIGxhcyBkaXNwb3NpY2lvbmVzIGFwbGljYWJsZXMgZGVsIHLDqWdpbWVuIGRlIERlcmVjaG8gZGUgQXV0b3IsIHNpIGVzdGEgZWplY3VjacOzbiBww7pibGljYSBkaWdpdGFsIGVzdMOhIHByaW1vcmRpYWxtZW50ZSBkaXJpZ2lkYSBhIG9idGVuZXIgdW5hIHZlbnRhamEgY29tZXJjaWFsIG8gdW5hIGNvbXBlbnNhY2nDs24gbW9uZXRhcmlhIHByaXZhZGEuCiAgCjUuIFJlcHJlc2VudGFjaW9uZXMsIEdhcmFudMOtYXMgeSBMaW1pdGFjaW9uZXMgZGUgUmVzcG9uc2FiaWxpZGFkLgpBIE1FTk9TIFFVRSBMQVMgUEFSVEVTIExPIEFDT1JEQVJBTiBERSBPVFJBIEZPUk1BIFBPUiBFU0NSSVRPLCBFTCBMSUNFTkNJQU5URSBPRlJFQ0UgTEEgT0JSQSAoRU4gRUwgRVNUQURPIEVOIEVMIFFVRSBTRSBFTkNVRU5UUkEpIOKAnFRBTCBDVUFM4oCdLCBTSU4gQlJJTkRBUiBHQVJBTlTDjUFTIERFIENMQVNFIEFMR1VOQSBSRVNQRUNUTyBERSBMQSBPQlJBLCBZQSBTRUEgRVhQUkVTQSwgSU1QTMONQ0lUQSwgTEVHQUwgTyBDVUFMUVVJRVJBIE9UUkEsIElOQ0xVWUVORE8sIFNJTiBMSU1JVEFSU0UgQSBFTExBUywgR0FSQU5Uw41BUyBERSBUSVRVTEFSSURBRCwgQ09NRVJDSUFCSUxJREFELCBBREFQVEFCSUxJREFEIE8gQURFQ1VBQ0nDk04gQSBQUk9Qw5NTSVRPIERFVEVSTUlOQURPLCBBVVNFTkNJQSBERSBJTkZSQUNDScOTTiwgREUgQVVTRU5DSUEgREUgREVGRUNUT1MgTEFURU5URVMgTyBERSBPVFJPIFRJUE8sIE8gTEEgUFJFU0VOQ0lBIE8gQVVTRU5DSUEgREUgRVJST1JFUywgU0VBTiBPIE5PIERFU0NVQlJJQkxFUyAoUFVFREFOIE8gTk8gU0VSIEVTVE9TIERFU0NVQklFUlRPUykuIEFMR1VOQVMgSlVSSVNESUNDSU9ORVMgTk8gUEVSTUlURU4gTEEgRVhDTFVTScOTTiBERSBHQVJBTlTDjUFTIElNUEzDjUNJVEFTLCBFTiBDVVlPIENBU08gRVNUQSBFWENMVVNJw5NOIFBVRURFIE5PIEFQTElDQVJTRSBBIFVTVEVELgogIAo2LiBMaW1pdGFjacOzbiBkZSByZXNwb25zYWJpbGlkYWQuCkEgTUVOT1MgUVVFIExPIEVYSUpBIEVYUFJFU0FNRU5URSBMQSBMRVkgQVBMSUNBQkxFLCBFTCBMSUNFTkNJQU5URSBOTyBTRVLDgSBSRVNQT05TQUJMRSBBTlRFIFVTVEVEIFBPUiBEQcORTyBBTEdVTk8sIFNFQSBQT1IgUkVTUE9OU0FCSUxJREFEIEVYVFJBQ09OVFJBQ1RVQUwsIFBSRUNPTlRSQUNUVUFMIE8gQ09OVFJBQ1RVQUwsIE9CSkVUSVZBIE8gU1VCSkVUSVZBLCBTRSBUUkFURSBERSBEQcORT1MgTU9SQUxFUyBPIFBBVFJJTU9OSUFMRVMsIERJUkVDVE9TIE8gSU5ESVJFQ1RPUywgUFJFVklTVE9TIE8gSU1QUkVWSVNUT1MgUFJPRFVDSURPUyBQT1IgRUwgVVNPIERFIEVTVEEgTElDRU5DSUEgTyBERSBMQSBPQlJBLCBBVU4gQ1VBTkRPIEVMIExJQ0VOQ0lBTlRFIEhBWUEgU0lETyBBRFZFUlRJRE8gREUgTEEgUE9TSUJJTElEQUQgREUgRElDSE9TIERBw5FPUy4gQUxHVU5BUyBMRVlFUyBOTyBQRVJNSVRFTiBMQSBFWENMVVNJw5NOIERFIENJRVJUQSBSRVNQT05TQUJJTElEQUQsIEVOIENVWU8gQ0FTTyBFU1RBIEVYQ0xVU0nDk04gUFVFREUgTk8gQVBMSUNBUlNFIEEgVVNURUQuCiAgCjcuIFTDqXJtaW5vLgkKYS4gRXN0YSBMaWNlbmNpYSB5IGxvcyBkZXJlY2hvcyBvdG9yZ2Fkb3MgZW4gdmlydHVkIGRlIGVsbGEgdGVybWluYXLDoW4gYXV0b23DoXRpY2FtZW50ZSBzaSBVc3RlZCBpbmZyaW5nZSBhbGd1bmEgY29uZGljacOzbiBlc3RhYmxlY2lkYSBlbiBlbGxhLiBTaW4gZW1iYXJnbywgbG9zIGluZGl2aWR1b3MgbyBlbnRpZGFkZXMgcXVlIGhhbiByZWNpYmlkbyBPYnJhcyBEZXJpdmFkYXMgbyBDb2xlY3RpdmFzIGRlIFVzdGVkIGRlIGNvbmZvcm1pZGFkIGNvbiBlc3RhIExpY2VuY2lhLCBubyB2ZXLDoW4gdGVybWluYWRhcyBzdXMgbGljZW5jaWFzLCBzaWVtcHJlIHF1ZSBlc3RvcyBpbmRpdmlkdW9zIG8gZW50aWRhZGVzIHNpZ2FuIGN1bXBsaWVuZG8gw61udGVncmFtZW50ZSBsYXMgY29uZGljaW9uZXMgZGUgZXN0YXMgbGljZW5jaWFzLiBMYXMgU2VjY2lvbmVzIDEsIDIsIDUsIDYsIDcsIHkgOCBzdWJzaXN0aXLDoW4gYSBjdWFscXVpZXIgdGVybWluYWNpw7NuIGRlIGVzdGEgTGljZW5jaWEuCmIuIFN1amV0YSBhIGxhcyBjb25kaWNpb25lcyB5IHTDqXJtaW5vcyBhbnRlcmlvcmVzLCBsYSBsaWNlbmNpYSBvdG9yZ2FkYSBhcXXDrSBlcyBwZXJwZXR1YSAoZHVyYW50ZSBlbCBwZXLDrW9kbyBkZSB2aWdlbmNpYSBkZSBsb3MgZGVyZWNob3MgZGUgYXV0b3IgZGUgbGEgb2JyYSkuIE5vIG9ic3RhbnRlIGxvIGFudGVyaW9yLCBlbCBMaWNlbmNpYW50ZSBzZSByZXNlcnZhIGVsIGRlcmVjaG8gYSBwdWJsaWNhciB5L28gZXN0cmVuYXIgbGEgT2JyYSBiYWpvIGNvbmRpY2lvbmVzIGRlIGxpY2VuY2lhIGRpZmVyZW50ZXMgbyBhIGRlamFyIGRlIGRpc3RyaWJ1aXJsYSBlbiBsb3MgdMOpcm1pbm9zIGRlIGVzdGEgTGljZW5jaWEgZW4gY3VhbHF1aWVyIG1vbWVudG87IGVuIGVsIGVudGVuZGlkbywgc2luIGVtYmFyZ28sIHF1ZSBlc2EgZWxlY2Npw7NuIG5vIHNlcnZpcsOhIHBhcmEgcmV2b2NhciBlc3RhIGxpY2VuY2lhIG8gcXVlIGRlYmEgc2VyIG90b3JnYWRhICwgYmFqbyBsb3MgdMOpcm1pbm9zIGRlIGVzdGEgbGljZW5jaWEpLCB5IGVzdGEgbGljZW5jaWEgY29udGludWFyw6EgZW4gcGxlbm8gdmlnb3IgeSBlZmVjdG8gYSBtZW5vcyBxdWUgc2VhIHRlcm1pbmFkYSBjb21vIHNlIGV4cHJlc2EgYXRyw6FzLiBMYSBMaWNlbmNpYSByZXZvY2FkYSBjb250aW51YXLDoSBzaWVuZG8gcGxlbmFtZW50ZSB2aWdlbnRlIHkgZWZlY3RpdmEgc2kgbm8gc2UgbGUgZGEgdMOpcm1pbm8gZW4gbGFzIGNvbmRpY2lvbmVzIGluZGljYWRhcyBhbnRlcmlvcm1lbnRlLgogIAo4LiBWYXJpb3MuCmEuIENhZGEgdmV6IHF1ZSBVc3RlZCBkaXN0cmlidXlhIG8gcG9uZ2EgYSBkaXNwb3NpY2nDs24gcMO6YmxpY2EgbGEgT2JyYSBvIHVuYSBPYnJhIENvbGVjdGl2YSwgZWwgTGljZW5jaWFudGUgb2ZyZWNlcsOhIGFsIGRlc3RpbmF0YXJpbyB1bmEgbGljZW5jaWEgZW4gbG9zIG1pc21vcyB0w6lybWlub3MgeSBjb25kaWNpb25lcyBxdWUgbGEgbGljZW5jaWEgb3RvcmdhZGEgYSBVc3RlZCBiYWpvIGVzdGEgTGljZW5jaWEuCmIuIFNpIGFsZ3VuYSBkaXNwb3NpY2nDs24gZGUgZXN0YSBMaWNlbmNpYSByZXN1bHRhIGludmFsaWRhZGEgbyBubyBleGlnaWJsZSwgc2Vnw7puIGxhIGxlZ2lzbGFjacOzbiB2aWdlbnRlLCBlc3RvIG5vIGFmZWN0YXLDoSBuaSBsYSB2YWxpZGV6IG5pIGxhIGFwbGljYWJpbGlkYWQgZGVsIHJlc3RvIGRlIGNvbmRpY2lvbmVzIGRlIGVzdGEgTGljZW5jaWEgeSwgc2luIGFjY2nDs24gYWRpY2lvbmFsIHBvciBwYXJ0ZSBkZSBsb3Mgc3VqZXRvcyBkZSBlc3RlIGFjdWVyZG8sIGFxdcOpbGxhIHNlIGVudGVuZGVyw6EgcmVmb3JtYWRhIGxvIG3DrW5pbW8gbmVjZXNhcmlvIHBhcmEgaGFjZXIgcXVlIGRpY2hhIGRpc3Bvc2ljacOzbiBzZWEgdsOhbGlkYSB5IGV4aWdpYmxlLgpjLiBOaW5nw7puIHTDqXJtaW5vIG8gZGlzcG9zaWNpw7NuIGRlIGVzdGEgTGljZW5jaWEgc2UgZXN0aW1hcsOhIHJlbnVuY2lhZGEgeSBuaW5ndW5hIHZpb2xhY2nDs24gZGUgZWxsYSBzZXLDoSBjb25zZW50aWRhIGEgbWVub3MgcXVlIGVzYSByZW51bmNpYSBvIGNvbnNlbnRpbWllbnRvIHNlYSBvdG9yZ2FkbyBwb3IgZXNjcml0byB5IGZpcm1hZG8gcG9yIGxhIHBhcnRlIHF1ZSByZW51bmNpZSBvIGNvbnNpZW50YS4KZC4gRXN0YSBMaWNlbmNpYSByZWZsZWphIGVsIGFjdWVyZG8gcGxlbm8gZW50cmUgbGFzIHBhcnRlcyByZXNwZWN0byBhIGxhIE9icmEgYXF1w60gbGljZW5jaWFkYS4gTm8gaGF5IGFycmVnbG9zLCBhY3VlcmRvcyBvIGRlY2xhcmFjaW9uZXMgcmVzcGVjdG8gYSBsYSBPYnJhIHF1ZSBubyBlc3TDqW4gZXNwZWNpZmljYWRvcyBlbiBlc3RlIGRvY3VtZW50by4gRWwgTGljZW5jaWFudGUgbm8gc2UgdmVyw6EgbGltaXRhZG8gcG9yIG5pbmd1bmEgZGlzcG9zaWNpw7NuIGFkaWNpb25hbCBxdWUgcHVlZGEgc3VyZ2lyIGVuIGFsZ3VuYSBjb211bmljYWNpw7NuIGVtYW5hZGEgZGUgVXN0ZWQuIEVzdGEgTGljZW5jaWEgbm8gcHVlZGUgc2VyIG1vZGlmaWNhZGEgc2luIGVsIGNvbnNlbnRpbWllbnRvIG11dHVvIHBvciBlc2NyaXRvIGRlbCBMaWNlbmNpYW50ZSB5IFVzdGVkLgo= 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