Detección de alteraciones genéticas mediante análisis citogenéticos moleculares, en una serie de casos de pacientes pediátricos con glioma en Colombia: un estudio piloto

Autores/as

DOI:

https://doi.org/10.35509/01239015.1112

Palabras clave:

glioma, childhood cancer, in situ hybridization

Resumen

Objetivo: determinar la presencia de alteraciones genéticas en vías clave de crecimiento y proliferación celular en pacientes pediátricos con gliomas en Colombia, mediante hibridación in situ fluorescente (FISH) e inmunohistoquímica.

Metodología: se realizó un estudio observacional descriptivo de una serie de casos, conformado por 50 pacientes pediátricos diagnosticados con glioma. Sobre tejido tumoral embebido en parafina remanente de los estudios diagnósticos, se emplearon microarreglos de tejido y FISH para detectar la fusión KIAA1549::BRAF, la deleción de CDKN2A, las amplificaciones de EGFR y N-Myc, y la codeleción 1p/19q. La expresión de H3K27me3 se determinó mediante inmunohistoquímica.

Resultados: la edad media al diagnóstico fue de 8,05 años, el 54 % eran niñas, el 44 % tenía gliomas de alto grado y el 56 % eran de bajo grado. El 18 % de los tumores presentaron alguna de las alteraciones genéticas, siendo la más frecuente la fusión KIAA1549::BRAF (12 %). Se detectaron alteraciones en la expresión de H3K27me3 (8 %), alteraciones en EGFR (4 %), deleción homocigota de CDKN2A (2 %) y pérdida heterocigota de 1p (2 %). No se evidenció amplificación de N-Myc en ningún caso.

Conclusiones: esta metodología resulta útil y de bajo costo para el estudio de gliomas pediátricos. Los hallazgos sugieren la presencia de un perfil genético, principalmente asociado a gliomas infantiles. Futuras investigaciones deberían explorar alteraciones características de gliomas de tipo adulto y paneles de estudio de esta naturaleza podrían incorporarse a la práctica de rutina en entornos de recursos limitados, con el fin de mejorar la clasificación de los gliomas pediátricos y su elección terapéutica.

Biografía del autor/a

Maria Fernanda Guerrero-Criollo, Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

1. Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

Diana Marcela Mendoza-Urbano, Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

2. Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

Julia Samanda Martínez-Rico, Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

1. Morfología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

Edna Margarita Quintero-Canasto, Patología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

3. Patología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

Esteban Felipe Patiño-Calderón, Patología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

3. Patología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

Pablo Andrés Aux-Chaves, Residente de la Especialización en Radiología, Universidad Nacional de Colombia (Seccional Bogotá), Bogotá, D. C., Colombia.

4. Residente de la Especialización en Radiología, Universidad Nacional de Colombia (Seccional Bogotá), Bogotá, D. C., Colombia.

Nelson Hernando Aponte-Barrios, Hemato-Oncología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

5. Hemato-Oncología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

6. Epidemiología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

Orlando Faber Peláez-Rincón, Neurocirugía Pediátrica, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

7. Neurocirugía Pediátrica, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

Edgar Cabrera-Bernal, Hemato-Oncología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

5. Hemato-Oncología, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

8. Hemato-Oncología Pediátrica, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

Luz Angela Moreno-Gómez, Radiología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

9. Radiología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

10. Radiología Pediátrica, Fundación Hospital Pediátrico la Misericordia, Bogotá, D. C., Colombia.

Natalia Olaya, Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

2. Patología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D. C., Colombia.

Referencias bibliográficas

Zong H, Verhaak RGW, Canoll P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert Rev Mol Diagn. 2012;12(4):383–94. https://doi.org/10.1586/erm.12.30

Johnston WT, Erdmann F, Newton R, Steliarova-Foucher E, Schüz J, Roman E. Childhood cancer: Estimating regional and global incidence. Cancer Epidemiol. 2021;71:101662. https://doi.org/10.1016/j.canep.2019.101662

Funakoshi Y, Hata N, Kuga D, Hatae R, Sangatsuda Y, Fujioka Y, et al. Pediatric glioma: An update of diagnosis, biology, and treatment. Cancers (Basel). 2021;13(4):1–17. https://doi.org/10.3390/cancers13040758

Bhakta N, Force LM, Allemani C, Atun R, Bray F, Coleman MP, et al. Childhood cancer burden: a review of global estimates. Lancet Oncol. 2019;20(1):e42–53. https://doi.org/10.1016/S1470-2045(18)30761-7

Blionas A, Giakoumettis D, Klonou A, Neromyliotis E, Karydakis P, Themistocleous MS. Paediatric gliomas: diagnosis, molecular biology and management. Ann Transl Med. 2018;6(12):251. https://doi.org/10.21037/atm.2018.05.11

Appay R, Fina F, Macagno N, Padovani L, Colin C, Barets D, et al. Duplications of KIAA1549 and BRAF screening by Droplet Digital PCR from formalin-fixed paraffin-embedded DNA is an accurate alternative for KIAA1549-BRAF fusion detection in pilocytic astrocytomas. Mod Pathol. 2018;31(10):1490–501. https://doi.org/10.1038/s41379-018-0050-6

Sievers P, Sill M, Schrimpf D, Stichel D, Reuss DE, Sturm D, et al. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro Oncol. 2021;23(1):34–43. https://doi.org/10.1093/neuonc/noaa251

Tauziède-Espariat A, Debily MA, Castel D, Grill J, Puget S, Roux A, et al. The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts. Acta Neuropathol Commun. 2020;8(1):104. https://doi.org/10.1186/s40478-020-00974-x

Mistry M, Zhukova N, Merico D, Rakopoulos P, Krishnatry R, Shago M, et al. BRAF mutation and CDKN2A deletion define a clinically distinct subgroup of childhood secondary high-grade glioma. J Clin Oncol. 2015;33(9):1015–22. https://doi.org/10.1200/JCO.2014.58.3922

Pandith AA, Zahoor W, Manzoor U, Nisar S, Guru FR, Naikoo NA, et al. Evaluation of chromosome 1p/19q deletion by Fluorescence in Situ Hybridization (FISH) as prognostic factors in malignant glioma patients on treatment with alkylating chemotherapy. Cancer Genet. 2023;278–279:55–61. https://doi.org/10.1016/j.cancergen.2023.08.005

Vallero SG, Bertero L, Morana G, Sciortino P, Bertin D, Mussano A, et al. Pediatric diffuse midline glioma H3K27-altered: A complex clinical and biological landscape behind a neatly defined tumor type. Front Oncol. 2023;12:1082062. https://doi.org/10.3389/fonc.2022.1082062

Seyedmirzaei H, Shobeiri P, Turgut M, Hanaei S, Rezaei N. VEGF levels in patients with glioma: a systematic review and meta-analysis. Rev Neurosci. 2020;32(2):191–202. https://doi.org/10.1515/revneuro-2020-0062

Frederico SC, Sharma N, Darling C, Taori S, Dubinsky AC, Zhang X, et al. Myeloid cells as potential targets for immunotherapy in pediatric gliomas. Front Pediatr. 2024;12:1346493. https://doi.org/10.3389/fped.2024.1346493

Ministerio de Salud y Protección Social. Situación del cáncer en la población pediátrica atendida en el SGSSS de Colombia 2023. Bogotá; 2023 [cited 2024 Sep 17]. Available from: https://cuentadealtocosto.org/site/publicaciones/situacion-del-cancer-en-la-poblacion-pediatrica-atendida-en-el-sgsss-de-colombia-2021/?1675388137385

Koo M, Squires JM, Ying D, Huang J. Making a Tissue Microarray. In: Yong WH, editor. Biobanking: Methods and Protocols. New York: Springer New York; 2019. p. 313–23. https://doi.org/10.1007/978-1-4939-8935-5_27

Ammendola S, Caldonazzi N, Simbolo M, Piredda ML, Brunelli M, Poliani PL, et al. H3K27me3 immunostaining is diagnostic and prognostic in diffuse gliomas with oligodendroglial or mixed oligoastrocytic morphology. Virchows Arch. 2021;479(5):987–96. https://doi.org/10.1007/s00428-021-03134-1

Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: A summary. Neuro Oncol. 2021;23(8):1231–51. https://doi.org/10.1093/neuonc/noab106

AlRayahi J, Alwalid O, Mubarak W, Maaz AUR, Mifsud W. Pediatric Brain Tumors in the Molecular Era: Updates for the Radiologist. Semin Roentgenol. 2023;58(1):47–66. https://doi.org/10.1053/j.ro.2022.09.004

Colli SL, Cardoso N, Massone CA, Cores M, García Lombardi M, De Matteo EN, et al. Molecular alterations in the integrated diagnosis of pediatric glial and glioneuronal tumors: A single center experience. PLoS One. 2022;17(4):e0266466. https://doi.org/10.1371/journal.pone.0266466

Cabral de Carvalho Corrêa D, Tesser-Gamba F, Dias Oliveira I, Saba da Silva N, Capellano AM, de Seixas Alves MT, et al. Gliomas in children and adolescents: investigation of molecular alterations with a potential prognostic and therapeutic impact. J Cancer Res Clin Oncol. 2022;148(1):107–19. https://doi.org/10.1007/s00432-021-03813-1

Yang W, Cai Y, Chen J, Yang P, Ying Z, Liang Y, et al. Epidemiological characteristics, clinical presentations, and prognoses of pediatric brain tumors: Experiences of national center for children’s health. Front Oncol. 2023;13:1067858. https://doi.org/10.3389/fonc.2023.1067858

Ramirez O, Piedrahita V, Ardila J, Pardo C, Cabrera-Bernal E, Lopera J, et al. Primary central nervous system tumors survival in children in ten Colombian cities: a VIGICANCER report. Front Oncol. 2024;13:1326788. https://doi.org/10.3389/fonc.2023.1326788

Mackay A, Burford A, Carvalho D, Izquierdo E, Fazal-Salom J, Taylor KR, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell. 2017;32(4):520–37.e5. https://doi.org/10.1016/j.ccell.2017.08.017

Venneti S, Garimella MT, Sullivan LM, Martinez D, Huse JT, Heguy A, et al. Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol. 2013;23(5):558–64. https://doi.org/10.1111/bpa.12042

Mohammad F, Weissmann S, Leblanc B, Pandey DP, Højfeldt JW, Comet I, et al. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas. Nat Med. 2017;23(4):483–92. https://doi.org/10.1038/nm.4293

Mosaab A, El-Ayadi M, Khorshed EN, Amer N, Refaat A, El-Beltagy M, et al. Histone H3K27M mutation overrides histological grading in pediatric gliomas. Sci Rep. 2020;10(1):8368. https://doi.org/10.1038/s41598-020-65272-x

Saratsis AM, Knowles T, Petrovic A, Nazarian J. H3K27M mutant glioma: Disease definition and biological underpinnings. Neuro Oncol. 2024;26(Supplement_2):S92–100. https://doi.org/10.1093/neuonc/noad164

Pratt D, Natarajan SK, Banda A, Giannini C, Vats P, Koschmann C, et al. Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas. Acta Neuropathol. 2018;135(2):299–301. https://doi.org/10.1007/s00401-018-1805-3

Bjerke L, Mackay A, Nandhabalan M, Burford A, Jury A, Popov S, et al. Histone H3.3 mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov. 2013;3(5):512–9. https://doi.org/10.1158/2159-8290.CD-12-0426

Korshunov A, Capper D, Jones DTW, Leske H, Orr BA, Rodriguez FJ, et al. Diffuse hemispheric glioma, H3 G34-mutant. In: WHO Classification of Tumours Editorial Board, editor. WHO Classification of Tumours Central Nervous System Tumours. Lyon (France): International Agency for Research on Cancer; 2021. p. 74–6. https://doi.org/10.1093/neuonc/noab184

Wang H, Zhang X, Liu J, Chen W, Guo X, Wang Y, et al. Clinical roles of EGFR amplification in diffuse gliomas: a real-world study using the 2021 WHO classification of CNS tumors. Front Neurosci. 2024;18:1308627. https://doi.org/10.3389/fnins.2024.1308627

Pereira R, Mackay A, Grabovska Y, Bradley A, Bloom T, Nicoll J, et al. The spectrum of IDH- and H3-wildtype high-grade glioma subgroups occurring across teenage and young adult patient populations. Clin Cancer Res. 2025;31(15):3259–75. https://doi.org/10.1158/1078-0432.CCR-24-1256

Korshunov A, Schrimpf D, Ryzhova M, Sturm D, Chavez L, Hovestadt V, et al. H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol. 2017;134(3):507–16. https://doi.org/10.1007/s00401-017-1710-1

Rodriguez FJ, Tihan T, Lin D, McDonald W, Nigro J, Feuerstein B, et al. Clinicopathologic features of pediatric oligodendrogliomas: A series of 50 patients. Am J Surg Pathol. 2014;38(8):1058–70. https://doi.org/10.1097/PAS.0000000000000221

Pollack IF, Finkelstein SD, Burnham J, Hamilton RL, Yates AJ, Holmes EJ, et al. Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: Results from the CCG-945 cohort. Pediatr Neurosurg. 2003;39(3):114–21. https://doi.org/10.1159/000071647

Yeo KK, Alexandrescu S, Cotter JA, Vogelzang J, Bhave V, Li MM, et al. Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics. Neuro Oncol. 2023;25(1):199–210. https://doi.org/10.1093/neuonc/noac132

Lim-Fat MJ, Cotter JA, Touat M, Vogelzang J, Sousa C, Pisano W, et al. A comparative analysis of IDH-mutant glioma in pediatric, young adult, and older adult patients. Neuro Oncol. 2024;26(12):2364–76. https://doi.org/10.1093/neuonc/noae142

Trinder SM, McKay C, Power P, Topp M, Chan B, Valvi S, et al. BRAF-mediated brain tumors in adults and children: A review and the Australian and New Zealand experience. Front Oncol. 2023;13:1154246. https://doi.org/10.3389/fonc.2023.1154246

Tabouret E, Fina F, Vincentelli F, Nanni I, Figarella-Branger D. New IDH1 I113T mutation associated with BRAFV600E mutation: New driver of gliomagenesis? J Neurol Sci. 2014;342(1):204–6. https://doi.org/10.1016/j.jns.2014.05.010

Patel K, Zhao G, Huang SM, Karakousi T, Nicolaides T, Papagiannakopoulos T. LGG-07. Novel CRISPR/Cas9 induced KIAA1549:BRAF fusion model for preclinical studies of pediatric gliomas. Neuro Oncol. 2022 Jun 1;24(Supplement_1):i88. https://doi.org/10.1093/neuonc/noac079.323

Ryall S, Zapotocky M, Fukuoka K, Nobre L, Guerreiro Stucklin A, Bennett J, et al. Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. Cancer Cell. 2020;37(4):569–83.e5. https://doi.org/10.1016/j.ccell.2020.03.011

Srinivasa K, Cross KA, Dahiya S. BRAF Alteration in central and peripheral nervous system tumors. Front Oncol. 2020;10:574974. https://doi.org/10.3389/fonc.2020.574974

Comba A, Faisal SM, Varela ML, Hollon T, Al-Holou WN, Umemura Y, et al. Uncovering spatiotemporal heterogeneity of high-grade gliomas: From disease biology to therapeutic implications. Front Oncol. 2021;11:703764. https://doi.org/10.3389/fonc.2021.703764

Hennani S, Dehbi H, Nadifi S, Karkouri M. Detection of KIAA1549/BRAF fusion in Moroccan patients with pediatric low-grade gliomas. Gene Rep. 2020;19:100634. https://doi.org/10.1016/j.genrep.2020.100634

Yamashita S, Takeshima H, Matsumoto F, Yamasaki K, Fukushima T, Sakoda H, et al. Detection of the KIAA1549-BRAF fusion gene in cells forming microvascular proliferations in pilocytic astrocytoma. PLoS One. 2019;14(7):e0220146. https://doi.org/10.1371/journal.pone.0220146

Umehara T, Arita H, Miya F, Achiha T, Shofuda T, Yoshioka E, et al. Revisiting the definition of glioma recurrence based on a phylogenetic investigation of primary and re-emerging tumor samples: a case report. Brain Tumor Pathol. 2022;39(4):218–24. https://doi.org/10.1007/s10014-022-00438-1

Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol. 2012;14(6):777–89. https://doi.org/10.1093/neuonc/nos077

Lee SH, Kim TG, Ryu KH, Kim SH, Kim YZ. CDKN2A homozygous deletion is a stronger predictor of outcome than IDH1/2-mutation in CNS WHO Grade 4 gliomas. Biomedicines. 2024;12(10):2256. https://doi.org/10.3390/biomedicines12102256

Antonelli M, Badiali M, Moi L, Buttarelli FR, Baldi C, Massimino M, et al. KIAA1549:BRAF fusion gene in pediatric brain tumors of various histogenesis. Pediatr Blood Cancer. 2015;62(4):724–7. https://doi.org/10.1002/pbc.25272

Villani V, Casini B, Tanzilli A, Lecce M, Rasile F, Telera S, et al. The Glioma-IRE project − Molecular profiling in patients with glioma: steps toward an individualized diagnostic and therapeutic approach. J Transl Med. 2023;21(1):215. https://doi.org/10.1186/s12967-023-04057-y

Giunti L, Pantaleo M, Sardi I, Provenzano A, Magi A, Cardellicchio S, et al. Genome-wide copy number analysis in pediatric glioblastoma multiforme. Am J Cancer Res. 2014;4:293–303. PMID: 24959384

Badiali M, Gleize V, Paris S, Moi L, Elhouadani S, Arcella A, et al. KIAA1549-BRAF fusions and IDH mutations can coexist in diffuse gliomas of adults. Brain Pathol. 2012;22(6):841–7. https://doi.org/10.1111/j.1750-3639.2012.00603.x

Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, et al. Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol. 2009;27(10):1627–36. https://doi.org/10.1200/JCO.2008.17.9432

French PJ, Eoli M, Sepulveda JM, De Heer I, Kros JM, Walenkamp A, et al. Defining EGFR amplification status for clinical trial inclusion. Neuro Oncol. 2019;21(10):1263–72. https://doi.org/10.1093/neuonc/noz096

Marker DF, Pearce TM. Homozygous deletion of CDKN2A by fluorescence in situ hybridization is prognostic in grade 4, but not grade 2 or 3, IDH-mutant astrocytomas. Acta Neuropathol Commun. 2020;8(1):169. https://doi.org/10.1186/s40478-020-01044-y

Pinkham MB, Telford N, Whitfield GA, Colaco RJ, O’Neill F, McBain CA. FISHing tips: What every clinician should know about 1p19q analysis in gliomas using fluorescence in situ hybridisation. Clin Oncol. 2015;27(8):445–53. https://doi.org/10.1016/j.clon.2015.04.008

Hawkins C, Walker E, Mohamed N, Zhang C, Jacob K, Shirinian M, et al. BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res. 2011;17(14):4790–8. https://doi.org/10.1158/1078-0432.CCR-11-0034

Induni S, Soderholm H, Pointer KB. Prognostic factors in H3K7M-mutant diffuse midline gliomas. Int J Radiat Oncol Biol Phys. 2024;120(2, Supplement):e691. https://doi.org/10.1016/j.ijrobp.2024.07.1518

Speirs CK, Simpson JR, Robinson CG, DeWees TA, Tran DD, Linette G, et al. Impact of 1p/19q codeletion and histology on outcomes of anaplastic gliomas treated with radiation therapy and temozolomide. Int J Radiat Oncol Biol Phys. 2015;91(2):268–76. https://doi.org/10.1016/j.ijrobp.2014.10.027

Saadeh Fadi S, Mahfouz Rami, Assi Hazem I. EGFR as a clinical marker in glioblastomas and other gliomas. Int J Biol Markers. 2017;33(1):22–32. https://doi.org/10.5301/ijbm.5000301

Liu R, Shi P, Wang Z, Yuan C, Cui H. Molecular mechanisms of MYCN dysregulation in cancers. Front Oncol. 2021;10:625332. https://doi.org/10.3389/fonc.2020.625332

Hutter S, Bolin S, Weishaupt H, Swartling FJ. Modeling and targeting MYC genes in childhood brain tumors. Genes (Basel). 2017;8(4):107. https://doi.org/10.3390/genes8040107

Zhuang D, Han T, Guo D, Kong R, Chen S, Dong Y, et al. Prevalence and characteristics analysis of CDKN2A/B deletion in glioma. J Clin Oncol. 2023;41(16_suppl):e14026. https://doi.org/10.1200/JCO.2023.41.16_suppl.e14026

Cómo citar

[1]
Guerrero Criollo, M.F. et al. 2025. Detección de alteraciones genéticas mediante análisis citogenéticos moleculares, en una serie de casos de pacientes pediátricos con glioma en Colombia: un estudio piloto. Revista Colombiana de Cancerología. 29, 4 (dic. 2025), 146–161. DOI:https://doi.org/10.35509/01239015.1112.

Descargas

Los datos de descargas todavía no están disponibles.

Publicado

12-12-2025

Número

Sección

Artículos de investigación/originales
Estadísticas de artículo
Vistas de resúmenes
Vistas de PDF
Descargas de PDF
Vistas de HTML
Otras vistas
Crossref Cited-by logo