Gastric adenocarcinoma with high‑level microsatellite instability: A case report

Alfaro,Alejandro; Zanabria,Daniel; Aguilar,Alfredo; Jimenez‑Solano,Sergio A.; Zevallos,Alejandra; Fajardo,Williams

doi:10.3892/mco.2023.2612

Gastric adenocarcinoma with high‑level microsatellite instability: A case report

Authors:
- Alejandro Alfaro
- Daniel Zanabria
- Alfredo Aguilar
- Sergio A. Jimenez‑Solano
- Alejandra Zevallos
- Williams Fajardo
View Affiliations

Affiliations: Department of Pathology, Hospital Nacional Dos de Mayo, Lima 15003, Peru, Department of Pathology, Oncosalud‑AUNA, Lima 15036, Peru, Basic and Translational Research Unit, Oncosalud‑AUNA, Lima 15036, Peru, Faculty of Natural Sciences and Mathematics, Universidad Nacional Federico Villarreal, Lima 15007, Peru, School of Medicine, Universidad Privada San Juan Bautista, Lima 15067, Peru
Published online on: January 26, 2023 https://doi.org/10.3892/mco.2023.2612
Article Number: 16
Copyright : © Alfaro et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Gastric cancer (GC) ranks fifth on the list of the most common malignancies worldwide. In Peru, gastric neoplasms are considered the second leading cause of mortality among males. Among the molecular subgroups of GC, microsatellite instability presents a favorable prognosis due to its hypermutated phenotype, which activates immunosurveillance. The present study describes the case of a 75‑year‑old patient, who was admitted in the hospital with a history of upper gastrointestinal bleeding and recurrent hospital admission, due to severe anemia. The patient presented with pale skin, normal vital functions, slight swelling of the lower extremities, and abdominal distention and bloating upon a physical examination. An endoscopic examination revealed an infiltrating circular ulcerated lesion. The histopathological analysis identified a moderately differentiated intestinal‑type adenocarcinoma with pathological stage T3N0M0. Tumor genomic profiling demonstrated alterations in 15 different genes with a tumor mutational burden of 28 mutations/Mb. Finally, the patient underwent a partial gastrectomy without pre‑operative chemotherapy. After 4 days, the patient presented with post‑operative complications for which he was re‑operated on. The patient did not survive. To the best of our knowledge, in the present case, pernicious anemia was an early sign of GC and a gastroscopy had to be performed. Furthermore, MutS homolog 3 alterations probably conditioned the presence of multiple frame‑shift mutations.

View Figures

View References

1	Rawla P and Barsouk A: Epidemiology of gastric cancer: Global trends, risk factors and prevention. Prz Gastroenterol. 14:26–38. 2019.PubMed/NCBI View Article : Google Scholar
2	International Agency for Research on Cancer; World Health Organization: World Source: Globocan 2020. Available from: https://gco.iarc.fr/today/data/factsheets/populations/900-wolrd-fact-sheet.pdf. Accessed on February 20, 2022.
3	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021.PubMed/NCBI View Article : Google Scholar
4	Castaneda CA, Castillo M, Chavez I, Barreda F, Suarez N, Nieves J, Bernabe LA, Valdivia D, Ruiz E, Dias-Neto E, et al: Prevalence of helicobacter pylori infection, its virulent genotypes, and Epstein-Barr virus in peruvian patients with chronic gastritis and gastric cancer. J Glob Oncol. 2019:1–9. 2019.PubMed/NCBI View Article : Google Scholar
5	Nelen SD, Bosscha K, Lemmens VEPP, Hartgrink HH, Verhoeven RHA and de Wilt JHW: Morbidity and mortality according to age following gastrectomy for gastric cancer. Br J Surg. 105:1163–1170. 2018.PubMed/NCBI View Article : Google Scholar
6	Jeong JR, Choi JW, Ryu SY and Choe YR: Relationship between frailty and mortality after gastrectomy in older patients with gastric cancer. J Geriatr Oncol. 13:67–73. 2022.PubMed/NCBI View Article : Google Scholar
7	Lee KG, Lee HJ, Yang JY, Oh SY, Bard S, Suh YS, Kong SH and Yang HK: Risk factors associated with complication following gastrectomy for gastric cancer: Retrospective analysis of prospectively collected data based on the Clavien-Dindo system. J Gastrointest Surg. 18:1269–1277. 2014.PubMed/NCBI View Article : Google Scholar
8	David H and Ilson MP: Microsatellite instability: A biomarker in gastric cancer. NEJM J Watch: Sep 12, 2019 (Epub ahead of print).
9	Mohanty S, Rosenthal RA, Russell MM, Neuman MD, Ko CY and Esnaola NF: Optimal perioperative management of the geriatric patient: A best practices guideline from the American college of surgeons NSQIP and the American geriatrics society. J Am Coll Surg. 222:930–947. 2016.PubMed/NCBI View Article : Google Scholar
10	Feldman AT and Wolfe D: Tissue processing and hematoxylin and eosin staining. Methods Mol Biol. 1180:31–43. 2014.PubMed/NCBI View Article : Google Scholar
11	Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, Schnall-Levin M, White J, Sanford EM, An P, et al: Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 31:1023–1031. 2013.PubMed/NCBI View Article : Google Scholar
12	Choi YY, Kim H, Shin SJ, Kim HY, Lee J, Yang HK, Kim WH, Kim YW, Kook MC, Park YK, et al: Microsatellite instability and programmed cell death-ligand 1 expression in stage II/III gastric cancer: Post hoc analysis of the classic randomized controlled study. Ann Surg. 270:309–316. 2019.PubMed/NCBI View Article : Google Scholar
13	Haag GM, Czink E, Ahadova A, Schmidt T, Sisic L, Blank S, Heger U, Apostolidis L, Berger AK, Springfeld C, et al: Prognostic significance of microsatellite-instability in gastric and gastroesophageal junction cancer patients undergoing neoadjuvant chemotherapy. Int J Cancer. 144:1697–1703. 2019.PubMed/NCBI View Article : Google Scholar
14	Hashimoto T, Kurokawa Y, Takahashi T, Miyazaki Y, Tanaka K, Makino T, Yamasaki M, Nakajima K, Ikeda JI, Mori M and Doki Y: Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer. Gastric Cancer. 22:785–792. 2019.PubMed/NCBI View Article : Google Scholar
15	Kim SY, Choi YY, An JY, Shin HB, Jo A, Choi H, Seo SH, Bang HJ, Cheong JH, Hyung WJ and Noh SH: The benefit of microsatellite instability is attenuated by chemotherapy in stage II and stage III gastric cancer: Results from a large cohort with subgroup analyses. Int J Cancer. 137:819–825. 2015.PubMed/NCBI View Article : Google Scholar
16	Smyth EC, Wotherspoon A, Peckitt C, Gonzalez D, Hulkki-Wilson S, Eltahir Z, Fassan M, Rugge M, Valeri N, Okines A, et al: Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol. 3:1197–1203. 2017.PubMed/NCBI View Article : Google Scholar
17	Ellegren H: Microsatellites: Simple sequences with complex evolution. Nat Rev Genet. 5:435–445. 2004.PubMed/NCBI View Article : Google Scholar
18	Ratti M, Lampis A, Hahne JC, Passalacqua R and Valeri N: Microsatellite instability in gastric cancer: Molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci. 75:4151–4162. 2018.PubMed/NCBI View Article : Google Scholar
19	Hudler P: Genetic aspects of gastric cancer instability. ScientificWorldJournal. 2012(761909)2012.PubMed/NCBI View Article : Google Scholar
20	Harfe BD and Jinks-Robertson S: DNA mismatch repair and genetic instability. Annu Rev Genet. 34:359–399. 2000.PubMed/NCBI View Article : Google Scholar
21	Genschel J, Littman SJ, Drummond JT and Modrich P: Isolation of MutSbeta from human cells and comparison of the mismatch repair specificities of MutSbeta and MutSalpha. J Biol Chem. 273:19895–19901. 1998.PubMed/NCBI View Article : Google Scholar
22	De Wind N, Dekker M, Claij N, Jansen L, van Klink Y, Radman M, Riggins G, van der Valk M, van't Wout K and te Riele H: HNPCC-like cancer predisposition in mice through simultaneous loss of Msh3 and Msh6 mismatch-repair protein functions. Nat Genet. 23:359–362. 1999.PubMed/NCBI View Article : Google Scholar
23	Miao HK, Chen LP, Cai DP, Kong WJ, Xiao L and Lin J: MSH3 rs26279 polymorphism increases cancer risk: A meta-analysis. Int J Clin Exp Pathol. 8:11060–11067. 2015.PubMed/NCBI
24	Ni H, Jiang B, Zhou Z, Yuan X, Cao X, Huang G and Li Y: Inactivation of MSH3 by promoter methylation correlates with primary tumor stage in nasopharyngeal carcinoma. Int J Mol Med. 40:673–678. 2017.PubMed/NCBI View Article : Google Scholar
25	Van Oers JMM, Edwards Y, Chahwan R, Zhang W, Smith C, Pechuan X, Schaetzlein S, Jin B, Wang Y, Bergman A, et al: The MutSβ complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double strand break repair and mismatch repair. Oncogene. 33:3939–3946. 2014.PubMed/NCBI View Article : Google Scholar
26	Haugen AC, Goel A, Yamada K, Marra G, Nguyen TP, Nagasaka T, Kanazawa S, Koike J, Kikuchi Y, Zhong X, et al: Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. Cancer Res. 68:8465–8472. 2008.PubMed/NCBI View Article : Google Scholar
27	Lee S, Chung H, Devaraj B, Iwaizumi M, Han HS, Hwang DY, Seong MK, Jung BH and Carethers JM: Microsatellite alterations at selected tetranucleotide repeats are associated with morphologies of colorectal neoplasias. Gastroenterology. 139:1519–1525. 2010.PubMed/NCBI View Article : Google Scholar
28	Wang K, Yuen ST, Xu J, Lee SP, Yan HHN, Shi ST, Siu HC, Deng S, Chu KM, Law S, et al: Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer. Nat Genet. 46:573–582. 2014.PubMed/NCBI View Article : Google Scholar
29	Guo YA, Chang MM, Huang W, Ooi WF, Xing M, Tan P and Skanderup AJ: Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers. Nat Commun. 9(1520)2018.PubMed/NCBI View Article : Google Scholar
30	Zhu L, Li Z, Wang Y, Zhang C, Liu Y and Qu X: Microsatellite instability and survival in gastric cancer: A systematic review and meta-analysis. Mol Clin Oncol. 3:699–705. 2015.PubMed/NCBI View Article : Google Scholar
31	Seo JY, Jin EH, Jo HJ, Yoon H, Shin CM, Park YS, Kim N, Jung HC and Lee DH: Clinicopathologic and molecular features associated with patient age in gastric cancer. World J Gastroenterol. 21:6905–6913. 2015.PubMed/NCBI View Article : Google Scholar
32	Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 513:202–209. 2014.PubMed/NCBI View Article : Google Scholar
33	Angell HK, Lee J, Kim KM, Kim K, Kim ST, Park SH, Kang WK, Sharpe A, Ogden J, Davenpor A, et al: PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer. Oncoimmunology. 8(e1544442)2019.PubMed/NCBI View Article : Google Scholar
34	van Velzen MJM, Derks S, van Grieken NCT, Mohammad NH and van Laarhoven HWM: MSI as a predictive factor for treatment outcome of gastroesophageal adenocarcinoma. Cancer Treat Rev. 86(102024)2020.PubMed/NCBI View Article : Google Scholar
35	Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 372:2018–2028. 2015.PubMed/NCBI View Article : Google Scholar
36	Gogas H, Dréno B, Larkin J, Demidov L, Stroyakovskiy D, Eroglu Z, Ferrucci PF, Pigozzo J, Rutkowski P, Mackiewicz J, et al: Cobimetinib plus atezolizumab in BRAF^V600 wild-type melanoma: Primary results from the randomized phase III IMspire170 study. Ann Oncol. 32:384–394. 2021.PubMed/NCBI View Article : Google Scholar
37	Barroso-Sousa R, Keenan TE, Pernas S, Exman P, Jain E, Garrido-Castro AC, Hughes M, Bychkovsky B, Umeton R, Files JL, et al: Tumor mutational burden and PTEN alterations as molecular correlates of response to PD-1/L1 blockade in metastatic triple-negative breast cancer. Clin Cancer Res. 26:2565–2572. 2020.PubMed/NCBI View Article : Google Scholar
38	Kim J, Kim B, Kang SY, Heo YJ, Park SH, Kim ST, Kang WK, Lee J and Kim KM: Tumor mutational burden determined by panel sequencing predicts survival after immunotherapy in patients with advanced gastric cancer. Front Oncol. 10(314)2020.PubMed/NCBI View Article : Google Scholar
39	Rizzo A, Ricci AD and Brandi G: PD-L1, TMB, MSI, and other predictors of response to immune checkpoint inhibitors in biliary tract cancer. Cancers (Basel). 13(558)2021.PubMed/NCBI View Article : Google Scholar
40	Kim JY, Kronbichler A, Eisenhut M, Hong SH, van der Vliet HJ, Kang J, Shin JI and Gamerith G: Tumor mutational burden and efficacy of immune checkpoint inhibitors: A systematic review and meta-analysis. Cancers (Basel). 11(1798)2019.PubMed/NCBI View Article : Google Scholar
41	Wang F, Wei XL, Wang FH, Xu N, Shen L, Dai GH, Yuan XL, Chen Y, Yang SJ, Shi JH, et al: Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432. Ann Oncol. 30:1479–1486. 2019.PubMed/NCBI View Article : Google Scholar
42	Guo X, Liang X, Wang Y, Cheng A, Zhang H, Qin C and Wang Z: Significance of tumor mutation burden combined with immune infiltrates in the progression and prognosis of advanced gastric cancer. Front Genet. 12(642608)2021.PubMed/NCBI View Article : Google Scholar
43	Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, Liu XQ, Sher X, Jung H, Lee M, et al: Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 24:1449–1458. 2018.PubMed/NCBI View Article : Google Scholar
44	Takeda M, Takahama T, Sakai K, Shimizu S, Watanabe S, Kawakami H, Tanaka K, Sato C, Hayashi H, Nonagase Y, et al: Clinical application of the foundationone CDx assay to therapeutic decision-making for patients with advanced solid tumors. Oncologist. 26:e588–e596. 2021.PubMed/NCBI View Article : Google Scholar
45	Sunami K, Ichikawa H, Kubo T, Kato M, Fujiwara Y, Shimomura A, Koyama T, Kakishima H, Kitami M, Matsushita H, et al: Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study. Cancer Sci. 110:1480–1490. 2019.PubMed/NCBI View Article : Google Scholar
46	Bilkey GA, Burns BL, Coles EP, Mahede T, Baynam G and Nowak KJ: Optimizing precision medicine for public health. Front Public Health. 7(42)2019.PubMed/NCBI View Article : Google Scholar
47	Medrano-Guzmán R, Valencia-Mercado D, Luna-Castillo M, García-Ríos LE and González-Rodríguez D: Prognostic factors for survival in patients with resectable advanced gastric adenocarcinoma. Cir Cir. 84:469–476. 2016.PubMed/NCBI View Article : Google Scholar : (In Spanish).
48	Garcia-Arispe JE, Loo-Valverde M, Chanduví W, Vela-Ruiz JM, Guillen-Ponce R and Cruz-Vargas DL: Anemia y supervivencia en pacientes con cáncer, un estudio peruano con seguimiento de 5 años. Rev Fac Med Hum Enero. 21:90–100. 2021.(In Spain).
49	Littlewood T: The impact of hemoglobin levels on treatment outcomes in patients with cancer. Semin Oncol. 28:49–53. 2001.PubMed/NCBI View Article : Google Scholar
50	Kim JJ, Tao H, Carloni E, Leung WK, Graham DY and Sepulveda AR: Helicobacter pylori impairs DNA mismatch repair in gastric epithelial cells. Gastroenterology. 123:542–553. 2002.PubMed/NCBI View Article : Google Scholar
51	Silva-Fernandes IJDL, de Oliveira ES, Santos JC, Ribeiro ML, Ferrasi AC, Pardini MI, Burbano RMR and Rabenhorst SHB: The intricate interplay between MSI and polymorphisms of DNA repair enzymes in gastric cancer H.pylori associated. Mutagenesis. 32:471–478. 2017.PubMed/NCBI View Article : Google Scholar
52	Machado AMD, Figueiredo C, Touati E, Máximo V, Sousa S, Michel V, Carneiro F, Nielsen FC, Seruca R and Rasmussen LJ: Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clin Cancer Res. 15:2995–3002. 2009.PubMed/NCBI View Article : Google Scholar
53	Koh FH, Chua JM, Tan JL, Foo FJ, Tan WJ, Sivarajah SS, Ho LML, Teh BT and Chew MH: Paradigm shift in gastrointestinal surgery-combating sarcopenia with prehabilitation: Multimodal review of clinical and scientific data. World J Gastrointest Surg. 13:734–755. 2021.PubMed/NCBI View Article : Google Scholar
54	Kanda M: Preoperative predictors of postoperative complications after gastric cancer resection. Surg Today. 50:3–11. 2020.PubMed/NCBI View Article : Google Scholar
55	Kanda M, Tanaka C, Murotani K, Kobayashi D, Ito S, Mochizuki Y, Ishigure K, Ishiyama A, Teramoto H, Murai T, et al: <Editors' Choice> Efficacy of enteral nutrients containing β-hydroxy-β-methylbutyrate, glutamine, and arginine for the patients with anastomotic leakage after gastrectomy: Study protocol of a multicenter phase II clinical trial. Nagoya J Med Sci. 80:351–355. 2018.PubMed/NCBI View Article : Google Scholar
56	Sasahara M, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, et al: The preoperative prognostic nutritional index predicts short-term and long-term outcomes of patients with stage II/III gastric cancer: Analysis of a multi-institution dataset. Dig Surg. 37:135–144. 2020.PubMed/NCBI View Article : Google Scholar
57	Xue DD, Cheng Y, Wu M and Zhang Y: Comprehensive geriatric assessment prediction of postoperative complications in gastrointestinal cancer patients: A meta-analysis. Clin Interv Aging. 13:723–736. 2018.PubMed/NCBI View Article : Google Scholar
58	Suwa K, Ushigome T, Ohtsu M, Narihiro S, Ryu S, Shimoyama Y, Okamoto T and Yanaga K: Risk factors for early postoperative small bowel obstruction after anterior resection for rectal cancer. World J Surg. 42:233–238. 2018.PubMed/NCBI View Article : Google Scholar
59	Barmparas G, Branco BC, Schnüriger B, Oliver M, Konstantinidis A, Lustenberger T, Eberle BM, Inaba K and Demetriades D: In-hospital small bowel obstruction after exploratory laparotomy for trauma. J Trauma. 71:486–490. 2011.PubMed/NCBI View Article : Google Scholar
60	Ellozy SH, Harris MT, Bauer JJ, Gorfine SR and Kreel I: Early postoperative small-bowel obstruction: A prospective evaluation in 242 consecutive abdominal operations. Dis Colon Rectum. 45:1214–1217. 2002.PubMed/NCBI View Article : Google Scholar
61	Khoraki J, Mazzini GS, Shah AS, Del Prado PAR, Wolfe LG and Campos GM: Early small bowel obstruction after laparoscopic gastric bypass: A surgical emergency. Surg Obes Relat Dis. 14:1118–1125. 2018.PubMed/NCBI View Article : Google Scholar
62	Nakamura T, Sato T, Naito M, Ogura N, Yamanashi T, Miura H, Tsutsui A, Yamashita K and Watanabe M: Laparoscopic surgery is useful for preventing recurrence of small bowel obstruction after surgery for postoperative small bowel obstruction. Surg Laparosc Endosc Percutan Tech. 26:e1–e4. 2016.PubMed/NCBI View Article : Google Scholar
63	Badia-Tahull MB, Llop-Talaveron J, Fort-Casamartina E, Farran-Teixidor L, Ramon-Torrel JM and Jódar-Masanés R: Preoperative albumin as a predictor of outcome in gastrointestinal surgery. E Spen Eur E J Clin Nutr Metab. 4:e248–e251. 2009.
64	Alberda C, Graf A and McCargar L: Malnutrition: Etiology, consequences, and assessment of a patient at risk. Best Pract Res Clin Gastroenterol. 20:419–439. 2006.PubMed/NCBI View Article : Google Scholar
65	Morse BC, Simpson JP, Jones YR, Johnson BL, Knott BM and Kotrady JA: Determination of independent predictive factors for anastomotic leak: Analysis of 682 intestinal anastomoses. Am J Surg. 206:950–956. 2013.PubMed/NCBI View Article : Google Scholar
66	Meza JN, Ortiz FM and Segura ER: Hospital malnutrition in a low-resources country: A survey and critique of the status of the published available literature. Clin Nutr. 34:330–331. 2015.PubMed/NCBI View Article : Google Scholar
67	Baca DA, Rego FR, Lazo MS, Rique IA and Kano PL: Estado nutricional y morbi-mortalidad en pacientes con anastomosis gastrointestinales en el hospital nacional hipolito unanue (HNHU). Rev Gastroenterol Perú. 32:273–280. 2012.PubMed/NCBI
68	Robles Valcárcel P and Seclén MPT: Nutritional status morbility and mortality in patients with gastrointestinal anastomosis in the ‘Hospital Nacional Hipolito Unanue’ (HNHU). Rev Gastroenterol Peru. 32:273–280. 2012.PubMed/NCBI(In Spanish).
69	Pinto JA, Pinillos L, Villarreal-Garza C, Morante Z, Villarán MV, Mejía G, Caglevic C, Aguilar A, Fajardo W, Usuga F, et al: Barriers in Latin America for the management of locally advanced breast cancer. Ecancermedicalscience. 13(897)2019.PubMed/NCBI View Article : Google Scholar
70	Li WH, Zhang JY, Liu WH and Chen XX: Role of the initial degree of anaemia and treatment model in the prognosis of gastric cancer patients treated by chemotherapy: A retrospective analysis. BMC Cancer. 20(414)2020.PubMed/NCBI View Article : Google Scholar
71	Puliga E, Corso S, Pietrantonio F and Giordano S: Microsatellite instability in gastric cancer: Between lights and shadows. Cancer Treat Rev. 95(102175)2021.PubMed/NCBI View Article : Google Scholar