Browsing by Author "Corvalan, Alejandro H."

Now showing 1 - 20 of 20
  • No Thumbnail Available
    Item
    Comparison of OLGA and OLGIM as predictors of gastric cancer in a Latin American population: the ECHOS Study
    (2024) Latorre Selvat, Gonzalo Ignacio; Silva Peña, Felipe Andres; Montero Jaras, Isabella; Bustamante Cartagena, Miguel Alonso; Dukes Berry, Eitan Ariel; Uribe Monasterio, Javier Andres; Corsi Sotelo, Oscar Felipe; Reyes Placencia, Diego Armando; Fuentes López, Eduardo; Pizarro Rojas, Margarita Alicia; Medel Jara, Patricio Andres; Torres, Javiera; Roa, Juan Carlos; Pizarro, Sebastian; Achurra Tirado, Pablo Andres; Donoso, Andres; Wichmann Pérez, Ignacio Alberto; Corvalan, Alejandro H.; Chahuan Abde, Javier Nicolas; Candia Balboa, Roberto Andres; Aguero, Carlos; Gonzalez, Robinson; Vargas, Jose Ignacio; Espino, Alberto; Camargo, M. Constanza; Shah, Shailja C.; Riquelme, Arnoldo
  • No Thumbnail Available
    Item
    Epstein-Barr Virus BARF1 Is Expressed in Lung Cancer and Is Associated with Cancer Progression
    (2024) Osorio, Julio C.; Armijo, Alvaro; Carvajal, Francisco J.; Corvalan, Alejandro H.; Castillo, Andres; Fuentes-Panana, Ezequiel M.; Moreno-Leon, Carolina; Romero, Carmen; Aguayo, Francisco
    Background: Epstein-Barr virus (EBV) is involved in the development of lymphomas, nasopharyngeal carcinomas (NPC), and a subgroup of gastric carcinomas (GC), and has also been detected in lung carcinomas, even though the role of the virus in this malignancy has not yet been established. BamH1-A Rightward Frame 1 (BARF1), a suggested exclusive epithelial EBV oncoprotein, is detected in both EBV-associated GCs (EBVaGC) and NPC. The expression and role of BARF1 in lung cancer is unknown. Methods: A total of 158 lung carcinomas including 80 adenocarcinomas (AdCs) and 78 squamous cell carcinomas (SQCs) from Chilean patients were analyzed for EBV presence via polymerase chain reaction (PCR), Immunohistochemistry (IHC), or chromogenic in situ hybridization (CISH). The expression of BARF1 was evaluated using Reverse Transcription Real-Time PCR (RT-qPCR). Additionally, A549 and BEAS-2B lung epithelial cells were transfected with a construct for ectopic BARF1 expression. Cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) were evaluated. Results: We found that EBV was present in 37 out of 158 (23%) lung carcinomas using PCR. Considering EBV-positive specimens using PCR, IHC for Epstein-Barr nuclear antigen 1 (EBNA1) detected EBV in 24 out of 30 (80%) cases, while EBERs were detected using CISH in 13 out of 16 (81%) cases. Overall, 13 out of 158 (8%) lung carcinomas were shown to be EBV-positive using PCR/IHC/CISH. BARF1 transcripts were detected in 6 out of 13 (46%) EBV-positive lung carcinomas using RT qPCR. Finally, lung cells ectopically expressing BARF1 showed increased migration, invasion, and EMT. Conclusions. EBV is frequently found in lung carcinomas from Chile with the expression of BARF1 in a significant subset of cases, suggesting that this viral protein may be involved in EBV-associated lung cancer progression.
  • Thumbnail Image
    Item
    Epstein–Barr Virus Infection in Lung Cancer: Insights and Perspectives
    (MDPI, 2022) Osorio, Julio C.; Blanco, Rancés; Corvalan, Alejandro H.; Muñoz, Juan P.; Calaf, Gloria M.; Aguayo, Francisco
    © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Lung cancer (LC) is the leading cause of cancer death worldwide. Tobacco smoke is the most frequent risk factor etiologically associated with LC, although exposures to other environmental factors such as arsenic, radon or asbestos are also involved. Additionally, the involvement of some viral infections such as high-risk human papillomaviruses (HR-HPVs), Merkel cell polyomavirus (MCPyV), Jaagsiekte Sheep Retrovirus (JSRV), John Cunningham Virus (JCV), and Epstein– Barr virus (EBV) has been suggested in LC, though an etiological relationship has not yet been established. EBV is a ubiquitous gamma herpesvirus causing persistent infections and some lymphoid and epithelial tumors. Since EBV is heterogeneously detected in LCs from different parts of the world, in this review we address the epidemiological and experimental evidence of a potential role of EBV. Considering this evidence, we propose mechanisms potentially involved in EBV-associated lung carcinogenesis. Additional studies are warranted to dissect the role of EBV in this very frequent malignancy.
  • No Thumbnail Available
    Item
    Extracellular vesicles from gastric epithelial GES-1 cells infected with Helicobacter pylori promote changes in recipient cells associated with malignancy
    (2022) Fernanda Gonzalez, Maria; Burgos-Ravanal, Renato; Shao, Baohai; Heinecke, Jay; Valenzuela-Valderrama, Manuel; Corvalan, Alejandro H.; Quest, Andrew F. G.
    Chronic Helicobacter pylori (H. pylori) infection is considered the main risk factor for the development of gastric cancer. Pathophysiological changes in the gastric mucosa initiated by this bacterium can persist even after pharmacological eradication and are likely attributable also to changes induced in non-infected cells as a consequence of intercellular communication via extracellular vesicles (EVs). To better understand what such changes might entail, we isolated EVs from immortalized normal gastric GES-1 cells infected (EVHp+) or not with H. pylori (EVHp-) by ultracentrifugation and characterized them. Infection of GES-1 cells with H. pylori significantly increased the release of EVs and slightly decreased the EV mean size. Incubation with EVHp+ for 24 h decreased the viability of GES-1 cells, but increased the levels of IL-23 in GES-1 cells, as well as the migration of GES-1 and gastric cancer AGS cells. Furthermore, incubation of GES-1 and AGS cells with EVHp+, but not with EVHp-, promoted cell invasion and trans-endothelial migration in vitro. Moreover, stimulation of endothelial EA.hy926 cells for 16 h with EVHp+ promoted the formation of linked networks. Finally, analysis by mass spectrometry identified proteins uniquely present and others enriched in EVHp+ compared to EVHp-, several of which are known targets of hypoxia induced factor-1 alpha (HIF-1 alpha) that may promote the acquisition of traits important for the genesis/progression of gastric pre-neoplastic changes associated with H. pylori infection. In conclusion, the harmful effects of H. pylori infection associated with the development of gastric malignancies may spread via EVs to non-infected areas in the early and later stages of gastric carcinogenesis.
  • Thumbnail Image
    Item
    Functional Interaction between Human Papillomavirus Type 16 E6 and E7 Oncoproteins and Cigarette Smoke Components in Lung Epithelial Cells
    (PUBLIC LIBRARY SCIENCE, 2012) Pablo Munoz, Juan; Gonzalez, Carolina; Parra, Barbara; Corvalan, Alejandro H.; Tornesello, Maria Lina; Eizuru, Yoshito; Aguayo, Francisco
    The smoking habit is the most important, but not a sufficient cause for lung cancer development. Several studies have reported the human papillomavirus type 16 (HPV16) presence and E6 and E7 transcripts expression in lung carcinoma cases from different geographical regions. The possible interaction between HPV infection and smoke carcinogens, however, remains unclear. In this study we address a potential cooperation between tobacco smoke and HPV16 E6 and E7 oncoproteins for alterations in proliferative and tumorigenic properties of lung epithelial cells. A549 (alveolar, tumoral) and BEAS-2B (bronchial, non-tumoral) cell lines were stably transfected with recombinant pLXSN vectors expressing HPV16 E6 and E7 oncoproteins and exposed to cigarette smoke condensate (CSC) at different concentrations. HPV16 E6 and E7 expression was associated with loss of p53 stability, telomerase (hTERT) and p16(INK4A) overexpression in BEAS-2B cells as demonstrated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). In A549 cells we observed downregulation of p53 but not a significant increase of hTERT transcripts. In addition, the HPV16 E6/E7 transfected cell lines showed an increased proliferation rate and anchorage-independent growth in a HPV16 E6 and E7 expression-dependent manner. Moreover, both HPV16 E6/E7 and mock transfected cells showed an increased proliferation rate and anchorage-independent growth in the presence of 0.1 and 10 mu g/mL CSC. However, this increase was significantly greater in HPV16 E6/E7 transfected cells (p<0.001). Data were confirmed by FCSE proliferation assay. The results obtained in this study are suggestive of a functional interaction between tobacco smoke and HPV16 E6/E7 oncoproteins for malignant transformation and tumorigenesis of lung epithelial cells. More studies are warranted in order to dissect the molecular mechanisms involved in this cooperation.
  • No Thumbnail Available
    Item
    Gold@Silica Nanoparticles Functionalized with Oligonucleotides: A Prominent Tool for the Detection of the Methylated Reprimo Gene in Gastric Cancer by Dynamic Light Scattering
    (2019) Jose Marchant, Maria; Guzman, Leda; Corvalan, Alejandro H.; Kogan, Marcelo J.
    Reprimo (RPRM) is a tumor suppressor gene involved in the development of gastric cancer. Hypermethylation of the RPRM promoter region has been found in tumor tissue and plasma samples from patients with gastric cancer. These findings suggest that circulating methylated DNA of RPRM could be a candidate for a noninvasive detection of gastric cancer. We designed a nanosystem based on the functionalization of silica coated gold nanoparticles with oligonucleotides that recognize a specific DNA fragment of the RPRM promoter region. The functionality of the oligonucleotide on the surface of the nanoparticle was confirmed by polymerase chain reaction (PCR). The nanoparticles were incubated with a synthetic DNA fragment of methylated DNA of RPRM and changes in the size distribution after hybridization were evaluated by dynamic light scattering (DLS). A difference in the size distribution of nanoparticles hybridized with genomic DNA from the KATO III gastric cancer cell line was observed when was compared with DNA from the GES-1 normal cell line. These results showed that this nanosystem may be a useful tool for the specific and sensitive detection of methylated DNA of RPRM in patients at risk of developing gastric cancer.
  • Thumbnail Image
    Item
    Helicobacter pylori-Induced Loss of the Inhibitor-of-Apoptosis Protein Survivin Is Linked to Gastritis and Death of Human Gastric Cells
    (OXFORD UNIV PRESS INC, 2010) Valenzuela, Manuel; Perez Perez, Guillermo; Corvalan, Alejandro H.; Carrasco, Gonzalo; Urra, Hery; Bravo, Denisse; Toledo, Hector; Quest, Andrew F. G.
    Helicobacter pylori infects the human stomach and modifies signaling pathways that affect gastric epithelial cell proliferation and viability. Chronic exposure to this pathogen contributes to the onset of gastric atrophy, an early event in the genesis of gastric cancer associated with H. pylori infection. Susceptibility to H. pylori-induced cell death ultimately depends on the presence of protective host cell factors. Although expression of the inhibitor-of-apoptosis protein survivin in adults is frequently linked to the development of cancer, evidence indicating that the protein is present in normal gastric mucosa is also available. Thus, we investigated in human gastric tissue samples and cell lines whether H. pylori infection is linked to loss of survivin and increased cell death. Our results show that infection with H. pylori decreased survivin protein levels in the mucosa of patients with gastritis. Furthermore, survivin down-regulation correlated with apoptosis and loss of cell viability in gastrointestinal cells cocultured with different H. pylori strains. Finally, overexpression of survivin in human gastric cells was sufficient to reduce cell death after infection. Taken together, these findings implicate survivin as an important survival factor in the gastric mucosa of humans.
  • No Thumbnail Available
    Item
    High-Risk Human Papillomavirus and Epstein-Barr Virus Coinfection: A Potential Role in Head and Neck Carcinogenesis
    (2021) Blanco, Rances; Carrillo-Beltran, Diego; Corvalan, Alejandro H.; Aguayo, Francisco
    Simple Summary A subset of carcinomas that arise in the head and neck region show a viral etiology. In fact, a subgroup of oropharyngeal cancers are caused by some types of human papillomavirus (HPV), so-called high-risk (HR)-HPVs, whereas undifferentiated nasopharyngeal carcinomas are etiologically related to Epstein-Barr virus (EBV). However, studies have reported the presence of both HR-HPV and EBV in some types of head and neck cancers. In this review, we discuss the potential contribution and role of HR-HPV/EBV coinfection in head and neck carcinogenesis, as well as the mechanisms that are potentially involved. In addition, HR-HPV/EBV interaction models are proposed. High-risk human papillomaviruses (HR-HPVs) and Epstein-Barr virus (EBV) are recognized oncogenic viruses involved in the development of a subset of head and neck cancers (HNCs). HR-HPVs are etiologically associated with a subset of oropharyngeal carcinomas (OPCs), whereas EBV is a recognized etiological agent of undifferentiated nasopharyngeal carcinomas (NPCs). In this review, we address epidemiological and mechanistic evidence regarding a potential cooperation between HR-HPV and EBV for HNC development. Considering that: (1) both HR-HPV and EBV infections require cofactors for carcinogenesis; and (2) both oropharyngeal and oral epithelium can be directly exposed to carcinogens, such as alcohol or tobacco smoke, we hypothesize possible interaction mechanisms. The epidemiological and experimental evidence suggests that HR-HPV/EBV cooperation for developing a subset of HNCs is plausible and warrants further investigation.
  • No Thumbnail Available
    Item
    Identification of anti-Helicobacter pylori antibody signatures in gastric intestinal metaplasia
    (2023) Song, Lusheng; Song, Minkyo; Rabkin, Charles S.; Chung, Yunro; Williams, Stacy; Torres, Javier; Corvalan, Alejandro H.; Gonzalez, Robinson; Bellolio, Enrique; Shome, Mahasish; LaBaer, Joshua; Qiu, Ji; Camargo, M. Constanza
    Background Chronic Helicobacter pylori infection may induce gastric intestinal metaplasia (IM). We compared anti-H. pylori antibody profiles between IM cases and non-atrophic gastritis (NAG) controls. Methods We evaluated humoral responses to 1528 H. pylori proteins among a discovery set of 50 IM and 50 NAG using H. pylori protein arrays. Antibodies with >= 20% sensitivity at 90% specificity for either group were selected and further validated in an independent set of 100 IM and 100 NAG using odds ratios (OR). A validated multi-signature was evaluated using the area under the receiver operating characteristics curve (AUC) and net reclassification improvement (NRI). Results Sixty-two immunoglobulin (Ig) G and 11 IgA antibodies were detected in > 10%. Among them, 22 IgG and 6 IgA antibodies were different between IM and NAG in the discovery set. Validated antibodies included 11 IgG (anti-HP1177/Omp27/HopQ [OR = 8.1, p < 0.001], anti-HP0547/CagA [4.6, p < 0.001], anti-HP0596/Tip alpha [4.0, p = 0.002], anti-HP0103/TlpB [3.8, p = 0.001], anti-HP1125/PalA/Omp18 [3.1, p = 0.001], anti-HP0153/RecA [0.48, p = 0.03], anti-HP0385 [0.41, p = 0.006], anti-HP0243/TlpB [0.39, p = 0.016], anti-HP0371/FabE [0.37, p = 0.017], anti-HP0900/HypB/AccB [0.35, p = 0.048], and anti-HP0709 [0.30, p = 0.003]), and 2 IgA (anti-HP1125/PalA/Omp18 [2.7, p = 0.03] and anti-HP0596/Tip alpha [2.5, p = 0.027]). A model including all 11 IgG antibodies (AUC = 0.81) had better discriminated IM and NAG compared with an anti-CagA only (AUC = 0.77) model (NRI = 0.44; p = 0.001). Conclusions Our study represents the most comprehensive assessment of anti-H. pylori antibody profiles in IM. The target antigens for these novel antibodies may act together with CagA in the progression to IM. Along with other biomarkers, specific H. pylori antibodies may identify IM patients, who would benefit from surveillance.
  • Thumbnail Image
    Item
    Identification of The Distinctive Type i/XhoI plus Strain of Epstein-Barr Virus in Gastric Carcinoma in Peru
    (INT INST ANTICANCER RESEARCH, 2011) Ordonez, Paula; Koriyama, Chihaya; Ding, Shan; Yoshiwara, Elena; Corvalan, Alejandro H.; Takano, Juan; Chirinos, Jesus L.; Watanabe, Jose; Miyagui, Juan; Hidalgo, Heriberto; Chacon, Pedro; Linares, Victor; Eizuru, Yoshito; Akiba, Suminori
    Aim: To clarify the reason for the low frequency of Epstein-Barr virus-associated gastric carcinoma (EBVaGC) in Peru, despite the high frequency reported in neighboring countries, the distribution of the distinctive EBV (type i/XhoI+) strain in EBVaGC and a healthy population was examined. Materials and Methods: EBV polymorphisms in BamHI W1/I1 and XhoI restriction site of the latent membrane protein 1 gene (LMP1) were examined among 11 EBVaGCs and 172 healthy controls from Peru, and these frequencies were compared with those in a previous study of Chile and Colombia (n=303). Results: The frequency of the distinctive EBV strain in EBVaGCs (55%) was significantly higher than that in controls (7%). Furthermore, the frequency of this EBV type in Peruvian controls was significantly lower than that in controls from Chile and Colombia (27%, p<0.001). Conclusion: The low frequency of the distinctive EBV strain among the Peruvian population might be a reason for the lower incidence of EBVaGC in Peru, as compared with neighboring countries.
  • No Thumbnail Available
    Item
    Implementation of the updated Sydney system biopsy protocol improves the diagnostic yield of gastric preneoplastic conditions: Results from a real-world study
    (2024) Latorre, Gonzalo; Vargas, Jose Ignacio; Shah, Shailja C.; Ivanovic-Zuvic, Danisa; Achurra, Pablo; Fritzsche, Martin; Leung, Jai-Sen; Ramos, Bernardita; Jensen, Elisa; Uribe, Javier; Montero, Isabella; Gandara, Vicente; Robles, Camila; Bustamante, Miguel; Silva, Felipe; Dukes, Eitan; Corsi, Oscar; Martinez, Francisca; Binder, Victoria; Candia, Roberto; Espino, Alberto; Agueero, Carlos; Sharp, Allan; Torres, Javiera; Roa, Juan Carlos; Pizarro, Margarita; Corvalan, Alejandro H.; Rabkin, Charles S.; Camargo, M. Constanza; Riquelme, Arnoldo
    Background: The updated Sydney system biopsy protocol (USSBP) standardizes the sampling of gastric biopsies for the detection of preneoplastic conditions ( e.g. , gastric intestinal metaplasia [GIM]), but the real-world diagnostic yield is not well-described. Aim: To determine whether regular application of USSBP is associated with higher detection of chronic atrophic gastritis (CAG), GIM and autoimmune gastritis (AIG). Methods: We performed a real-world retrospective study at an academic urban tertiary hospital in Chile. We manually reviewed medical records from consecutive patients undergoing esophagogastroduodenoscopy (EGD) from January to December 2017. Seven endoscopists who performed EGDs were categorized into two groups (USSBP 'regular' and USSBP 'infrequent') based on USSBP adherence, using minimum 20% adherence as the prespecified threshold. Multivariable logistic regression models were used to estimate the odds ratios (aOR) and 95% confidence intervals (CI) for the association between endoscopist groups and the likelihood of diagnosing CAG, GIM or AIG. Results: 1206 patients were included in the study (mean age: 58.5; 65.3% female). The USSBP regular group demonstrated a higher likelihood of detecting CAG (20% vs . 5.3%; aOR 4.03, 95%CI: 2.69-6.03), GIM (12.2% vs. 3.4%; aOR 3.91, 95%CI: 2.39-6.42) and AIG (2.9% vs. 0.8%; aOR 6.52, 95%CI: 1.87-22.74) compared to infrequent group. Detection of advanced-stage CAG (Operative Link for Gastritis Assessment stage III/IV) was significantly higher in the USSBP regular vs. infrequent group (aOR 5.84, 95%CI: 2.23-15.31). Conclusions: Routine adherence to USSBP increases the detection rates of preneoplastic conditions, including CAG, GIM and AIG. Standardized implementation of USSBP should be considered in high gastric cancer risk populations. (c) 2023 Elsevier Espana, S.L.U. All rights reserved.
  • No Thumbnail Available
    Item
    Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis
    (2014) Camargo, M. Constanza; Kim, Woo-Ho; Chiaravalli, Anna Maria; Kim, Kyoung-Mee; Corvalan, Alejandro H.; Matsuo, Keitaro; Yu, Jun; Sung, Joseph J. Y.; Herrera-Goepfert, Roberto; Meneses-Gonzalez, Fernando; Kijima, Yuko; Natsugoe, Shoji; Liao, Linda M.; Lissowska, Jolanta; Kim, Sung; Hu, Nan; Gonzalez, Carlos A.; Yatabe, Yashushi; Koriyama, Chihaya; Hewitt, Stephen M.; Akiba, Suminori; Gulley, Margaret L.; Taylor, Philip R.; Rabkin, Charles S.
    Background and objective About 9% of gastric carcinomas have Epstein-Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors.
  • Thumbnail Image
    Item
    Merkel cell polyomavirus in non-small cell lung carcinomas from Chile
    (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2012) Gheit, Tarik; Pablo Munoz, Juan; Levican, Jorge; Gonzalez, Carolina; Ampuero, Sandra; Parra, Barbara; Gaggero, Aldo; Corvalan, Alejandro H.; Meneses, Manuel; Tommasino, Massimo; Aguayo, Francisco
    Lung cancer is a leading pathology strongly associated with the smoking habit. However, a viral etiology for a subset of patients developing lung cancer has been suggested. Polyomaviruses (PyVs) are small double stranded DNA viruses associated with the development of some human diseases. However, a causal role of these viruses in human cancer has been difficult to demonstrate. In this study, eighty-six non-small cell lung carcinomas (NSCLCs), including adenocarcinomas (AdCs) and squamous cell lung carcinomas (SQCs) from Chile were analyzed for the presence of PyVs using polymerase chain reaction (PCR). All of the specimens were positive for a fragment of the betaglobin gene. We found that 4/86 (4.7%) of lung carcinomas were positive for PyVs. After sequencing and BlastN alignment, all four cases were identified as Merkel cell polyomaviruses (MCV) that corresponded to two AdCs and two SQCs. A non-significant statistical association was found between the presence of MCV and clinic-pathological features of the patients and tumors. In addition, 1/4 (25%) of the carcinomas were actively expressing large T antigen (LT) transcripts, as demonstrated by reverse-transcriptase PCR (RT-PCR). Thus a possible role of MCV in a very small subset of patients with lung cancer cannot be ruled out and warrants more investigation. (C) 2012 Elsevier Inc. All rights reserved.
  • Thumbnail Image
    Item
    Overexpression of p73 as a Tissue Marker for High-Risk Gastritis
    (AMER ASSOC CANCER RESEARCH, 2010) Carrasco, Gonzalo; Diaz, Jose; Valbuena, Jose R.; Ibanez, Paulina; Rodriguez, Paz; Araya, Gabriela; Rodriguez, Carolina; Torres, Javiera; Duarte, Ignacio; Aravena, Edmundo; Mena, Fernando; Barrientos, Carlos; Corvalan, Alejandro H.
    Purpose: Histologic assessment of high-risk gastritis for the development of gastric cancer is not well defined. The identification of tissue markers together with the integration of histologic features will be required for this assessment.
  • No Thumbnail Available
    Item
    Perioperative chemotherapy in locally advanced gastric cancer in Chile: from evidence to daily practice
    (2021) Muller, Bettina; Garcia, Carlos; Sola, Jose A.; Fernandez, Wanda; Werner, Patrick; Cerda, Mauricio; Slater, Jeannie; Benavides, Carlos; Arancibia, Jorge; Ascui, Rodrigo; Reyes, Felipe; Anne Stevens, Mary; Pablo Miranda, Juan; Buchholtz, Martin; Corvalan, Alejandro H.
    Gastric cancer (GC) is a leading cause of cancer death in Chile. Although recommended in international guidelines since 2006, perioperative chemotherapy was not available to patients in the public health system in Chile until 2016. We conducted an observational study to assess the feasibility of this strategy in public hospitals in Chile (Observational Study of Perioperative Chemotherapy in Locally Advanced Gastric Cancer - PRECISO). Patients with locally advanced, operable GC were offered to receive preoperative chemotherapy with Epirubicin + Cisplatin + Capecitabine (ECX) for three cycles followed by curative surgery. Staging included abdominal CT scan and laparoscopy if peritoneal carcinomatosis was suspected. Postoperative ECX for three cycles was recommended. Between August 2010 and March 2013, 110 patients were screened and 61 enrolled. Median age was 62 years (23-76 years) and most patients had good performance status at baseline (Eastern Cooperative Oncology Group performance status score (ECOG) 0: 42, ECOG 1: 19). Tumour site was proximal in 32 (52%) and medial and distal in 29 (48%) patients. All but four patients (n = 57, 93%) completed three cycles of preoperative chemotherapy. Fifty-six patients were operated and 54 (89%) had a curative resection. Thirty-three patients (54%) had pT0-2, and 18 (30%) had pN0 tumours, with two patients achieving a complete response. As of 20 December 2020, 39 patients died, 32 due to GC, one within 30 days of surgery, two due to intestinal obstruction at 5 and 3 months after surgery and four due to other causes. Five-year survival rate was 38%. We conclude that perioperative chemotherapy is feasible in public hospitals in Chile and should be offered to patients with locally advanced GC.
  • No Thumbnail Available
    Item
    Prospective follow-up of chronic atrophic gastritis in a high-risk population for gastric cancer in latin america
    (2022) Latorre, Gonzalo; Silva, Felipe; Montero, Isabella; Bustamante, Miguel; Dukes, Eitan; Gandara, Vicente; Robles, Camila; Uribe, Javier; Corsi, Oscar; Crispi, Francisca; Espinoza Sepúlveda, Manuel Antonio; Cuadrado, Cristobal; Fuentes-Lopez, Eduardo; Shah, Shailja; Camargo, M. Constanza; Torres, Javiera; Roa, Juan Carlos; Corvalan, Alejandro H.; Candia, Roberto; Aguero, Carlos; Gonzalez, Robinson G.; Vargas Domínguez, José Ignacio; Espino, Alberto; Riquelme, Arnoldo
    Background. Gastric adenocarcinoma (GA) is preceded by premalignant conditions such as chronic atrophic gastritis (CAG) with or without gastric intestinal metaplasia (GIM). Endoscopic follow-up of these conditions has been proposed as a strategy for the detection of early-stage GA. Aim. To describe the risk of progression to gastric dysplasia (GD) and early-stage GA of patients who underwent esophagogastroduodenoscopy (EGD) with gastric biopsies obtained following the updated Sydney System biopsy protocol (USSBP). Methods. We conducted a real-world, multicenter, prospective cohort study. Patients undergoing EGD surveillance with USSBP were enrolled between 2015 and 2021 from three endoscopy units at Santiago, Chile. Patients with prior history of GA or gastric resection were excluded. Follow-up surveillance schedule was determined by gastroenterologist in accordance with the Chilean Digestive Endoscopy Association Guidelines. CAG was confirmed by two expert GI pathologists and categorized by the Operative Link on Gastritis Assessment as stage 0 (normal) through stage IV (advanced stage). The primary endpoint was a composite of GD (low-grade, LGD or high-grade, HGD) or GA, while secondary endpoints were progression in OLGA and separate outcomes of LGD, HGD or GA. Multivariable Cox regression analysis was used to estimate the association between CAG +/- GIM and the outcomes, adjusted for age, sex and Helicobacter pylori (Hp) infection. Results. 600 patients were included in the cohort (64% female; mean age 58 years). At baseline 32.3% (n=194) had active Hp infection. OLGA stage was: 31% (n=184) OLGA 0, 48% (n=291) OLGA I-II and 21% (125) OLGA III-IV. GIM was identified in 52% (n=312) and autoimmune gastritis in 6.2% (n=37). Median follow-up was 28 months (IQR 17-42). During follow-up, 6 early-stage GA, 3 HGD and 6 LGD were observed. No advanced-stage GA was diagnosed. Only 19% (n=35) of baseline OLGA 0 patients progressed to OLGA I-IV, with <2% progressing to OLGA III/IV (Figure 1). Persistence of Hp infection (aOR 2.1; 95%CI 1.1-4.0) was independently associated with increase of at least 1 point in the OLGA scale during follow-up. GA/GD free survival at 3- years for OLGA 0, I-II and III-IV was 99.4%, 97.1% and 91.7%, respectively (p=0.0015) (Figure 2). Based on multivariable Cox regression, OLGA III-IV (vs. OLGA 0) was associated with a 12.1-fold (95%CI 1.5-97.4) higher risk of GA, while GIM was associated with a 13.0-fold (95%CI 1.7-101.2) higher risk, although the CI was wide; this was particularly between 2 and 3 years of follow-up. Discussion: These findings, including the observation that all GAs were early-stage, support endoscopic/histologic surveillance for patients with advanced OLGA stages or GIM, which is a common finding in patients with advanced CAG. Further studies are needed to determine the optimal time interval for surveillance.
  • Thumbnail Image
    Item
    Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer
    (AMER ASSOC CANCER RESEARCH, 2008) Bernal, Carolina; Aguayo, Francisco; Villarroel, Cynthia; Vargas, Macarena; Diaz, Ignacio; Ossandon, Francisco J.; Santibanez, Eudocia; Palma, Mariana; Aravena, Edmundo; Barrientos, Carlos; Corvalan, Alejandro H.
    Purpose: Gastric cancer is a curable disease if diagnosed at early stage. However, most cases are diagnosed at advanced stage because of the lack of screening programs. Therefore, the identification of plasma biomarkers for early detection is necessary.
  • No Thumbnail Available
    Item
    The Cervical and Meningeal Lymphatic Network as a Pathway for Retrograde Nanoparticle Transport to the Brain
    (2024) Ramos-Zaldivar, Hector; Polakovicova, Iva; Salas-Huenuleo, Edison; Yefi, Claudia P.; Silva-Ancahuail, David; Jara-Guajardo, Pedro; Oyarzun, Juan Esteban; Neira-Troncoso, Alvaro; Burgos, Patricia, V; Cavieres, Viviana A.; Arias-Munoz, Eloisa; Martinez, Carlos; Riveros, Ana L.; Corvalan, Alejandro H.; Kogan, Marcelo J.; Andia, Marcelo E.
    Introduction: The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain. Methods: We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for post-mortem and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis. Results: Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes post-mortem and in vivo, exclusively through lymphatic structures. Discussion: The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain.
  • No Thumbnail Available
    Item
    Volatilomic Signatures of AGS and SNU-1 Gastric Cancer Cell Lines
    (2022) Slefarska-Wolak, Dania; Heinzle, Christine; Leiherer, Andreas; Ager, Clemens; Muendlein, Axel; Mezmale, Linda; Leja, Marcis; Corvalan, Alejandro H.; Drexel, Heinz; Krolicka, Agnieszka; Shani, Gidi; Mayhew, Christopher A.; Haick, Hossam; Mochalski, Pawel
    In vitro studies can help reveal the biochemical pathways underlying the origin of volatile indicators of numerous diseases. The key objective of this study is to identify the potential biomarkers of gastric cancer. For this purpose, the volatilomic signatures of two human gastric cancer cell lines, AGS (human gastric adenocarcinoma) and SNU-1 (human gastric carcinoma), and one normal gastric mucosa cell line (GES-1) were investigated. More specifically, gas chromatography mass spectrometry has been applied to pinpoint changes in cell metabolism triggered by cancer. In total, ten volatiles were found to be metabolized, and thirty-five were produced by cells under study. The volatiles consumed were mainly six aldehydes and two heterocyclics, whereas the volatiles released embraced twelve ketones, eight alcohols, six hydrocarbons, three esters, three ethers, and three aromatic compounds. The SNU-1 cell line was found to have significantly altered metabolism in comparison to normal GES-1 cells. This was manifested by the decreased production of alcohols and ketones and the upregulated emission of esters. The AGS cells exhibited the increased production of methyl ketones containing an odd number of carbons, namely 2-tridecanone, 2-pentadecanone, and 2-heptadecanone. This study provides evidence that the cancer state modifies the volatilome of human cells.
  • No Thumbnail Available
    Item
    Volatilomic signatures of different strains of Helicobacter pylori
    (2024) Vangravs, Reinis; Mezmale, Linda; Slefarska-Wolak, Daria; Dauss, Edgars; Ager, Clemens; Corvalan, Alejandro H.; Fernandez, Elmer Andres; Mayhew, Chris A.; Leja, Marcis; Mochalski, Pawel
    Background: Helicobacter pylori (H. pylori) infection is the most extensively studied risk factor for gastric cancer. As with any bacteria, H. pylori will release distinctive odors that result from an emission of volatile metabolic byproducts in unique combinations and proportions. Effectively capturing and identifying these volatiles can pave the way for the development of innovative and non-invasive diagnostic methods for determining infection. Here we characterize the H. pylori volatilomic signature, pinpoint potential biomarkers of its presence, and evaluate the variability of volatilomic signatures between different H. pylori isolates. Materials and Methods: Using needle trap extraction, volatiles in the headspace above H. pylori cultures were collected and, following thermal desorption at 290 degrees C in a splitless mode, were analyzed using gas chromatography-mass spectrometry. The resulting volatilomic signatures of H. pylori cultures were compared to those obtained from an analysis of the volatiles in the headspace above the cultivating medium only. Results: Amongst the volatiles detected, 21 showed consistent differences between the bacteria cultures and the cultivation medium, with 11 compounds being elevated and 10 showing decreased levels in the culture's headspace. The 11 elevated volatiles are four ketones (2-pentanone, 5-methyl-3-heptanone, 2-heptanone, and 2-nonanone), three alcohols (2-methyl-1-propanol, 3-methyl-1-butanol, and 1 butanol), one aromatic (styrene), one aldehyde (2-ethyl-hexanal), one hydrocarbon (n-octane), and one sulfur compound (dimethyl disulfide). The 10 volatiles with lower levels in the headspace of the cultures are four aldehydes (2-methylpropanal, benzaldehyde, 3-methylbutanal, and butanal), two heterocyclic compounds (2-ethylfuran and 2-pentylfuran), one ketone (2-butanone), one aromatic (benzene), one alcohol (2-butanol) and bromodichloromethane. Of the volatile species showing increased levels, the highest emissions are found to be for 3-methyl-1-butanol, 1-butanol and dimethyl disulfide. Qualitative variations in their emissions from the different isolates was observed. Conclusions: The volatiles emitted by H. pylori provide a characteristic volatilome signature that has the potential of being developed as a tool for monitoring infections caused by this pathogen. Furthermore, using the volatilome signature, we are able to differentiate different isolates of H. pylori. However, the volatiles also represent potential confounders for the recognition of gastric cancer volatile markers.