Browsing by Author "Roa, Juan Carlos"
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- ItemEnvironmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer(2022) Pérez Moreno, Pablo; Riquelme, Ismael; García Cañete, Patricia; Brebi, Priscilla; Roa, Juan CarlosGallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet. Other risk factors such as autoimmune disorders and bacterial, parasitic and fungal infections have also been described. All these factors can generate a long-term inflammatory state characterized by the persistent activation of the immune system, the frequent release of pro-inflammatory cytokines, and the constant production of reactive oxygen species that result in a chronic damage/repair cycle, subsequently inducing the loss of the normal architecture of the gallbladder mucosa that leads to the development of GBC. This review addresses how the different risk factors could promote a chronic inflammatory state essential to the development of gallbladder carcinogenesis, which will make it possible to define some strategies such as anti-inflammatory drugs or public health proposals in the prevention of GBC.
- ItemEvaluación de la respuesta inmune anti-tumoral mediada por linfocitos T en organoides derivados de pacientes con cáncer de vesícula biliar(2024) Obreque Castro, Javiera Constanza; Bizama, Carolina; Roa, Juan Carlos; Montecinos Acuña, Viviana; Pontificia Universidad Católica de Chile. Escuela de MedicinaEl cáncer de vesícula biliar (GBC) es una de las neoplasias más comunes y agresivas dentro del tracto biliar. Particularmente en nuestro país, el GBC se ha reportado como un problema de salud pública, especialmente en mujeres donde contribuye como la quinta causa de muerte por cáncer. Actualmente, el único tratamiento efectivo es la resección quirúrgica de la vesícula en estadios temprano. Sin embargo, la mayoría de los pacientes son diagnosticados en estadios avanzados, donde la única alternativa terapéutica es la quimioterapia con gemcitabina y cisplatino, la cual presenta muy baja respuesta. Es por esto, que la búsqueda de nuevos blancos de terapia y de modelos preclínicos que representen fielmente la respuesta a terapias ha cobrado gran interés en la investigación biomédica con enfoques en medicina personalizada. En los tumores de GBC se ha descrito la presencia de las células iniciadoras de tumor (TICs) o cancer stem cells (CSC), caracterizadas por la expresión doble positiva de los marcadores CD44 y CD133. Una de las características de las TICs, es la evasión de la respuesta inmune antitumoral, a través, de la expresión de los immune checkpoint (o puntos de control inmune) desencadenando la supresión de los linfocitos T citotóxicos, encargados de orquestar la respuesta inmune antitumoral. En los últimos años, la inmunoterapia ha revolucionado el tratamiento del cáncer y actualmente se utiliza con resultados favorables en el tratamiento de diferentes tipos de tumores. Dentro de las inmunoterapias aprobadas por la FDA, se encuentran los inhibidores de los inmune checkpoint, PD-L1/PD-1, CTLA4 y LAG-3. Inicialmente estas terapias fueron aprobados para su uso en melanoma, pero en la actualidad los dos primeros se utilizan en variados tipos de cáncer incluido el gástrico. Por lo tanto, para el análisis de la respuesta y predicción a estas nuevas inmunoterapias se requiere de nuevos modelos in vitro de cáncer, que sean capaces de recapitular la interacción de las células del cáncer con el componente inmune. Dentro de estos modelos, se propone el uso de los cultivos 3D de organoides tumorales derivados de pacientes (PDOs) como una poderosa herramienta que imita las características histológicas, genéticas y fisiopatológicas del tumor del cual derivan. Sin embargo, el principal desafío es enriquecer este modelo de PDOs tumorales con células del componente inmune para poder estudiar la respuesta de los pacientes a la inmunoterapia. Actualmente, el uso de co-cultivo entre organoides y células inmunes, se ha utilizado para generar linfocitos TCD8 reactivos y evaluar la capacidad citotóxica TCD8 en contra de las células tumorales. Tomando todo esto en consideración, el presente proyecto de tesis tuvo como hipótesis: “La interacción directa entre organoides derivados de pacientes con cáncer de vesícula biliar y células inmunes, permite evaluar la respuesta antitumoral mediada por linfocitos T y el efecto de inhibidores de PD-1”.
- ItemPathologic staging of pancreatic, ampullary, biliary, and gallbladder cancers: pitfalls and practical limitations of the current AJCC/UICC TNM staging system and opportunities for improvement(W B SAUNDERS CO-ELSEVIER INC, 2012) Adsay, N. Volkan; Bagci, Pelin; Tajiri, Takuma; Oliva, Irma; Ohike, Nobuyuki; Balci, Serdar; Gonzalez, Raul S.; Basturk, Olca; Jang, Kee Taek; Roa, Juan CarlosTumors of the ampulla-pancreatobiliary tract are encountered increasingly; however, their staging can be highly challenging due to lack of familiarity. In this review article, the various issues encountered in staging of these tumors at the pathologic level are evaluated and possible solutions for daily practice as well as potential improvements for future staging protocols are discussed. While N-stage parameters have now been well established (the number of lymph nodes required in pancreatoduodenectomies is 12), the T-staging has several issues: for the pancreas, the discovery of small cancers arising in intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs) necessitates the creation of substages of T1 (as T1a, b, and c); lack of proper definition of "peripancreatic soft tissue" and "common bile duct involvement" (as to which part is meant) makes T3 highly subjective. Increasing resectability of main vessels (portal vein) brings the need to redefine a "T" for such cases. For the ampulla, due to factors like anatomic complexity of the region and the under-appreciation of three-dimensional spread of the tumors in this area (in particular, the frequent extension into periduodenal soft tissues and duodenal serosa, which are not addressed in the current system and which require specific grossing approaches to document), the current T-staging lacks reproducibility and clinical relevance, and therefore, major revisions are needed. Recently proposed refined definition and site-specific subclassification of ampullary tumors highlight the areas for improvement. For the extrahepatic bile ducts, the staging schemes that use the depth of invasion may be more practical to circumvent the inconsistencies in the histologic layering of the ducts; better definition of terms like "periductal spread" is needed. For the gallbladder, since many gallbladder cancers are "unapparent" (found in clinically and grossly unsuspected cholecystectomies), establishing proper grossing protocols and adequate sampling are crucial. Since the
- ItemProspective 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, ArnoldoBackground. 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.