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Ramirez Mahaluf, Juan PabloAuthorMartínez Romero, AnabelAuthorMartínez-Romero AAuthorRamírez JAuthorReguart NAuthor
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Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer

Publicated to:Lung Cancer. 135 151-160 - 2019-09-01 135(), DOI: 10.1016/j.lungcan.2019.07.020

Authors: Alcaraz, Jordi; Lluis Carrasco, Josep; Millares, Laura; Luis, Iuliana-Cristiana; Fernandez-Porras, Francisco J; Martinez-Romero, Anabel; Diaz-Valdivia, Natalia; Sanchez De Cos, Julio; Rami-Porta, Ramon; Seijo, Luis; Ramirez, Josep; Jose Pajares, Maria; Reguart, Noemi; Barreiro, Esther; Monso, Eduard

Affiliations

BIST, Inst Bioengn Catalonia IBEC, Barcelona, Spain - Author
Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias - Author
Centro de Investigacion Medica Aplicada - Author
CIBERONC, Grp Colaborat Canc Pulmon CIBERES, Plataforma Biobanco Pulmonar, SEPAR, Pamplona, Spain - Author
CIBERONC, Pamplona, Spain - Author
Ctr Appl Med Res CIMA, Program Solid Tumors & Biomarkers, Pamplona, Spain - Author
Fdn Jimenez Diaz, Madrid, Spain - Author
Grupo Colaborativo en Cáncer de Pulmón CIBERES-CIBERONC-SEPAR-Plataforma Biobanco Pulmonar - Author
Hosp Clin Barcelona, Anatomopathol Dept, Barcelona, Spain - Author
Hosp Clin Barcelona, Med Oncol Dept, IDIBAPS, Barcelona, Spain - Author
Hosp San Pedro Alcantara, Caceres, Spain - Author
Hosp Univ Mutua Terrassa, Terrassa, Spain - Author
Hosp Univ Parc Tauli, Resp Med, Sabadell, Spain - Author
Hospital Clinic Barcelona - Author
Hospital del Mar - Author
Hospital San Pedro de Alcántara - Author
Hospital Universitari Mútua Terrassa - Author
Hospital Universitari Parc Taulí - Author
Hospital Universitario Fundacion Jimenez Diaz - Author
IMIM Hosp del Mar, CEXS, Muscle Wasting & Cachexia Chron Resp Dis & Lung C, UPF,PRBB, Barcelona, Spain - Author
Inst Salud Carlos HI, CIBER Enfermedades Resp CIBERES, Madrid, Spain - Author
Instituto de Bioingeniería de Cataluña - Author
UAB, Dept Med, Barcelona, Spain - Author
Univ Barcelona, Sch Med & Hlth Sci, Dept Basic Clin Practice, Unit Biostat, Barcelona, Spain - Author
Univ Barcelona, Sch Med & Hlth Sci, Dept Biomed, Unit Biophys & Bioengn, Barcelona, Spain - Author
Universidad Autonoma de Barcelona, Facultad de Medicina - Author
Universitat de Barcelona - Author
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Abstract

© 2019 The Authors Objectives: Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear. Material and Methods: We conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient. Results: Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia. Conclusions: Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA + TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy.

Keywords
cancer associated fibroblastcollagenlung cancernecrosissurvival8th edition?-smaAgedAged, 80 and overAlpha-smaBiomarkers, tumorBreast-cancerCancer associated fibroblastCancer-associated fibroblastsCarcinoma, non-small-cell lungCarcinoma-associated-fibroblastsCollagenExpressionFemaleGene expressionHumansHypoxiaImmunohistochemistryKaplan-meier estimateLung cancerLung neoplasmsMaleMicroenvironmentMiddle agedNecrosisNeoplasm stagingPrognosisProgressionStaging projectSurvivalTnm classificationΑ-sma

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Lung Cancer due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2019, it was in position 15/64, thus managing to position itself as a Q1 (Primer Cuartil), in the category Respiratory System.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 1.7. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

  • Weighted Average of Normalized Impact by the Scopus agency: 1.63 (source consulted: FECYT Feb 2024)
  • Field Citation Ratio (FCR) from Dimensions: 9.12 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-02, the following number of citations:

  • WoS: 38
  • Scopus: 41
  • Europe PMC: 21
  • OpenCitations: 40
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 46.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 46 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 0.25.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.