Browsing by Author "Garrido, Marcelo"
Now showing 1 - 5 of 5
Results Per Page
Sort Options
Item A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer(2021) Cordova-Delgado, Miguel; Bravo, María Loreto; Cumsille, Elisa; Hill, Charlotte N.; Muñoz-Medel, Matías; Pinto, Mauricio P.; Retamal, Ignacio N.; Lavanderos, María A.; Miquel, Juan Francisco; Rodriguez-Fernandez, Maria; Liao, Yuwei; Li, Zhiguang; Corvalán, Alejandro H.; Armisén, Ricardo; Garrido, Marcelo; Quiñones, Luis A.; Owen, Gareth I.Background: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3–4 toxicity. Methods: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. Results: Reported grade ≤ 2 and 3–4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70–10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19–1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. Conclusion: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.Item A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability(MDPI, Basel Sz., 2020) Pinto, Mauricio; Córdova-Delgado, Miguel; Retamal, Ignacio; Muñoz-Medel, Matías; Bravo, Loreto; Durán, Doris; Villanueva, Francisco; Sánchez, César; Acevedo, Francisco; Mondaca, Sebastián; Érica, Koch; Ibáñez, Carolina; Galindo, Héctor; Madrid, Jorge; Nervi, Bruno; Peña, José; Torres, Javiera; Garrido, Marcelo; Owen, Gareth I.; Corvalán, Alejandro H.; Armisén, RicardoGastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinicPublication Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers(2024) Garrido, Javiera; Bernal, Yanara; González, Evelin; Blanco, Alejandro; Sepúlveda, Gonzalo; Freire, Matías; Oróstica, Karen; Rivas, Solange; Marcelain, Katherine; Owen, Gareth; Ibañez, Carolina; Corvalan, Alejandro; Garrido, Marcelo; Assar, Rodrigo; Lizana, Rodrigo; Cáceres, Javier; Ampuero, Diego; Ramos, Liliana; Pérez, Paola; Aren, Osvaldo; Chernilo, Sara; Fernández, Cristina; Spencer, María; Flores, Jacqueline; Bernal, Giuliano; Ahumada, Mónica; Rasse, Germán; Sánchez, Carolina; De Amorim, Maria; Bartelli, Thais; Noronha, Diana; Dias, Emmanuel; Freitas, Helano; Armisén, RicardoBackground: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. Methods: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. Results: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. Conclusions: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.Publication Methylated Reprimo Cell-Free DNA as a Non-Invasive Biomarker for Gastric Cancer(2025) Maturana, María; Padilla, Oslando; Santoro, Pablo; Alarcón, Maria; Olivares, Wilda; Blanco, Alejandro; Armisen, Ricardo; Garrido, Marcelo; Aravena, Edmundo; Barrientos, Carlos; Calvo, Alfonso; Corvalán, AlejandroRestrictions resulting from the COVID-19 pandemic abruptly reversed the slow decline of the diagnosis and mortality rates of gastric cancer (GC). This scenario highlights the importance of developing cost-effective methods for mass screening and evaluation of treatment response. In this study, we evaluated a non-invasive method based on the circulating methylated cell-free DNA (cfDNA) of Reprimo (RPRM), a tumor suppressor gene associated with the development of GC. Methylated RPRM cfDNA was analyzed in three de-identified cohorts: Cohort 1 comprised 81 participants with GC and 137 healthy donors (HDs); Cohort 2 comprised 27 participants with GC undergoing gastrectomy and/or chemotherapy analyzed at the beginning and after three months of treatment; and Cohort 3 comprised 1105 population-based participants in a secondary prevention program who underwent esophagogastroduodenal (EGD) endoscopy. This cohort includes 180 normal participants, 845 participants with premalignant conditions (692 with chronic atrophic gastritis [AG] and 153 with gastric intestinal metaplasia/low-grade dysplasia [GIM/LGD]), 21 with high-grade dysplasia/early GC [HGD/eGC], and 59 with advanced GC [aGC]). A nested case-control substudy was performed using a combination of methylated RPRM cfDNA and pepsinogens (PG)-I/II ratio. The dense CpG island of the promoter region of the RPRM gene was bisulfite sequenced and analyzed to develop a fluorescence-based real-time PCR assay (MethyLight). This assay allows the determination of the absolute number of copies of methylated RPRM cfDNA. A targeted sequence of PCR amplicon products confirmed the gastric origin of the plasma-isolated samples. In Cohort 1, the mean value of GCs (32,240.00 copies/mL) was higher than that of the HD controls (139.00 copies/mL) (p < 0.0001). After dividing this cohort into training–validation subcohorts, we identified an area under the curve of 0.764 (95% confidence interval (CI) = 0.683–0.845) in the training group. This resulted in a cut-off value of 87.37 copies/mL (sensitivity 70.0% and specificity 80.2%). The validation subcohort predicted sensitivity of 66.67% and a specificity of 83.33%. In Cohort 2 (monitoring treatment response), RPRM levels significantly decreased in responders (p = 0.0042) compared to non-responders. In Cohort 3 (population-based participants), 18.9% %, 24.1%, 30.7%, 47.0%, and 71.2% of normal, AG, GIM/LGD, HGD/eGC, and aGC participants tested positive for methylated RPRM cfDNA, respectively. Overall sensitivity and specificity in distinguishing normal/premalignant conditions vs. GC were 65.0% (95% CI 53.52% to 75.33%) and 75.9% (95% CI 73.16% to 78.49%), respectively, with an accuracy of 75.11% (95% CI 72.45% to 77.64%). Logistic regression analyses revealed an OR of 1.85 (95% CI 1.11–3.07, p = 0.02) and an odds ratio (OR) of 3.9 (95% CI 1.53–9.93, p = 0.004) for the risk of developing GIM/LGD and HGD/eGC, respectively. The combined methylated RPRM cfDNA and PG-I/II ratio reached a sensitivity of 78.9% (95% CI 54.43% to 93.95%) and specificity of 63.04% (95% CI 52.34% to 72.88%) for detecting HGD/eGC vs. three to six age- and sex-matched participants with premalignant conditions. Our results demonstrate that methylated RPRM cfDNA should be considered a direct biomarker for the non-invasive detection of GC and a predictive biomarker for treatment response.Publication Quadruple therapies show a higher eradication rate compared to standard triple therapy for Helicobacter pylori infection within the LEGACy consortium. A multicenter observational study in European and Latin American countries(2024) Medel-Jara, Patricio; Reyes Placencia, Diego; Fuentes-López, Eduardo; Corsi, Oscar; Latorre, Gonzalo; Antón, Rosario; Jiménez, Elena; Miralles-Marco, Ana; Caballero, Carmelo; Boggino, Hugo; Cantero, Daniel; Barros, Rita; Santos-Antunes, João; Díez, Marc; Quiñones, Luis A.; Riquelme, Erick; Rollan, Antonio; Cerpa, Leslie C.; Valdés, Ivania; Nyssen, Olga P.; Moreira, Leticia; Gisbert, Javier P.; Camargo, M. Constanza; Ortiz-Olvera, Nayeli; Leon‐Takahashi, Alberto, M.; Ruiz-Garcia, Erika; Fernández-Figueroa, Edith A.; Garrido, Marcelo; Owen, Gareth I.; Cervantes, Andrés; Fleita, Tania; Riquelme, ArnoldoIntroduction: Gastric cancer (GC) is one of the most lethal malignancies worldwide.Helicobacter pylori is the primary cause of GC; therefore, its eradication reduces therisk of developing this neoplasia. There is extensive evidence regarding quadrupletherapy with relevance to the European population. However, in Latin America, dataare scarce. Furthermore, there is limited information about the eradication ratesachieved by antibiotic schemes in European and Latin American populations.Objective: To compare the effectiveness of standard triple therapy (STT), quadrupleconcomitant therapy (QCT), and bismuth quadruple therapy (QBT) in six centers inEurope and Latin America.Methods: A retrospective study was carried out based on the LEGACy registry from2017 to 2022. Data from adult patients recruited in Portugal, Spain, Chile, Mexico,and Paraguay with confirmed H. pylori infection who received eradication therapyand confirmatory tests at least 1 month apart were included. Treatment success by each scheme was compared using a mixed multilevel Poisson regression, adjustingfor patient sex and age, together with country‐specific variables, including preva-lence of H. pylori antibiotic resistance (clarithromycin, metronidazole, and amoxi-cillin), and CYP2C19 polymorphisms.Results: 772 patients were incorporated (64.64% females; mean age of 52.93 years).The total H. pylori eradication rates were 75.20% (255/339) with STT, 88.70% (159/178) with QCT, and 91.30% (191/209) with QBT. Both quadruple therapies (QCT‐QBT) showed significantly higher eradication rates compared with STT, with anadjusted incidence risk ratio (IRR) of 1.25 (p: <0.05); and 1.24 (p: <0.05), respectively.The antibiotic‐resistance prevalence by country, but not the prevalence of CYP2C19polymorphism, showed a statistically significant impact on eradication success.Conclusions: Both QCT and QBT are superior to STT for H. pylori eradication whenadjusted for country‐specific antibiotic resistance and CYP2C19 polymorphism in asample of individuals residing in five countries within two continents.