Browsing by Author "Roa, Juan Carlos"

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    Adenomyomas of the Gallbladder An Analysis of Frequency, Clinicopathologic Associations, and Relationship to Carcinoma of a Malformative Lesion
    (2024) Dursun, Nevra; Memis, Bahar; Pehlivanoglu, Burcin; Taskin, Orhun Cig; Okcu, Oguzhan; Akkas, Gizem; Bagci, Pelin; Balci, Serdar; Saka, Burcu; Araya, Juan Carlos; Bellolio, Enrique; Roa, Juan Carlos; Jang, Kee-Taek; Losada, Hector; Maithel, Shishir K.; Sarmiento, Juan; Reid, Michelle D.; Jang, Jin-Young; Cheng, Jeanette D.; Basturk, Olca; Koshiol, Jill; Adsay, N. Volkan
    Context.-The nature and associations of gallbladder (GB) "adenomyoma"(AM) remain controversial. Some studies have attributed up to 26% of GB carcinoma to AMs. Objective.-To examine the true frequency, clinicopathologic characteristics, and neoplastic changes in GB AM. Design.-Cholecystectomy cohorts analyzed were 1953 consecutive cases, prospectively with specific attention to AM; 2347 consecutive archival cases; 203 totally embedded GBs; 207 GBs with carcinoma; and archival search of institutions for all cases diagnosed as AM. Results.-Frequency of AM was 9.3% (19 of 203) in totally submitted cases but 3.3% (77 of 2347) in routinely sampled archival tissue. A total of 283 AMs were identified, with a female to male ratio =1.9 (177:94) and mean size = 1.3 cm (range, 0.3-5.9). Most (96%, 203 of 210) were fundic, with formed nodular trabeculated submucosal thickening, and were difficult to appreciate from the mucosal surface. Four of 257 were multifocal (1.6%), and 3 of 257 (1.2%) were extensive ("adenomyomatosis"). Dilated glands (up to 14 mm), often radially converging to a point in the mucosa, were typical. Muscle was often minimal, confined to the upper segment. Nine of 225 (4%) revealed features of a duplication. No specific associations with inflammation, cholesterolosis, intestinal metaplasia, or thickening of the uninvolved GB wall were identified. Neoplastic change arising in AM was seen in 9.9% (28 of 283). Sixteen of 283 (5.6%) had mural intracholecystic neoplasm; 7 of 283 (2.5%) had flat -type high-grade dysplasia/carcinoma in situ. Thirteen of 283 cases had both AM and invasive carcinoma (4.6%), but in only 5 of 283 (1.8%), carcinoma arose from AM (invasion was confined to AM, and dysplasia was predominantly in AM). Conclusions.-AMs have all the features of a malformative developmental lesion, and may not show a significant muscle component (ie, the name "adeno-myoma"is partly a misnomer). While most are innocuous, some pathologies may arise in AMs, including intracholecystic neoplasms, flattype high-grade dysplasia or carcinoma in situ, and invasive carcinoma (1.8%, 5 of 283). It is recommended that gross examination of GBs include serial slicing of the fundus for AM detection and total submission if one is found.
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    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
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    Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer
    (2022) Pérez Moreno, Pablo; Riquelme, Ismael; García Cañete, Patricia; Brebi, Priscilla; Roa, Juan Carlos
    Gallbladder 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.
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    Eosinophilic Cholecystitis and Eosinophils in Gallbladder Injuries: A Clinicopathological Analysis of 1050 Cholecystectomies
    (2023) Memis, Bahar; Saka, Burcu; Roa, Juan Carlos; Bandyopadhyay, Sudeshna; Reid, Michelle; Bagci, Pelin; Aktas, Berk Kaan; Armutlu, Ayse; Basturk, Olca; Adsay, N. Volkan
    "Eosinophilic cholecystitis" has been an elusive concept. Around 1050 consecutive cholecystectomies with chronic (CC, n = 895), subacute (SAC, n = 100), and acute cholecystitis (AC, n = 55) were reviewed for eosinophilic infiltration. Eosinophilic hot spots (>40 eosinophils/HPF) were seen in 63% of SAC and 35% of AC (vs. 6% of CC, p < 0.001). Eosinophils were mostly encountered in areas of wall thickening, revealing edema with early collagenization and young tissue-culture-type fibroblasts. However, in ten chronic cholecystitis patients (<1%), prominent eosinophilia with eosinophil-rich foci (>100 eosinophils/HPF) was noted. These ten cases, classified as "eosinophilic cholecystitis", were analyzed further: The patients were relatively young (mean age = 43 years), with a 9:1 female:male ratio. None had blood eosinophilia/eosinophilia syndromes. Although one had ulcerative colitis, others did not have any autoimmune diseases. The mean gallbladder wall thickness was 3.5 mm (vs. 4.2 mm in ordinary CC). In conclusion, eosinophils are a part of especially subacute injuries in the gallbladder. They are typically condensed in the areas of healing and appear to signify a distinctive state of injury in which there are erosions leading to slow/sustained exposure of the mural tissues to the bile contents that induce chemical injury/recruit eosinophils. Eosinophilic cholecystitis is a very uncommon occurrence and appears to be an exaggerated response in allergic patients who are prone to recruit eosinophils in reaction to injury.
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    Epigallocatechin Gallate Enhances MAL-PDT Cytotoxic Effect on PDT-Resistant Skin Cancer Squamous Cells
    (2020) Leon, Daniela; Buchegger, Kurt; Silva, Ramon; Riquelme, Ismael; Viscarra, Tamara; Mora-Lagos, Barbara; Zanella, Louise; Schafer, Fabiola; Kurachi, Cristina; Roa, Juan Carlos; Ili, Carmen; Brebi, Priscilla
    Photodynamic therapy (PDT) has been used to treat certain types of non-melanoma skin cancer with promising results. However, some skin lesions have not fully responded to this treatment, suggesting a potential PDT-resistant phenotype. Therefore, novel therapeutic alternatives must be identified that improve PDT in resistant skin cancer. In this study, we analyzed the cell viability, intracellular protoporphyrin IX (PpIX) content and subcellular localization, proliferation profile, cell death, reactive oxygen species (ROS) detection and relative gene expression in PDT-resistant HSC-1 cells. PDT-resistant HSC-1 cells show a low quantity of protoporphyrin IX and low levels of ROS, and thus a low rate of death cell. Furthermore, the resistant phenotype showed a downregulation of HSPB1, SLC15A2, FECH, SOD2 and an upregulation of HMBS and BIRC5 genes. On the other hand, epigallocatechin gallate catechin enhanced the MAL-PDT effect, increasing levels of protoporphyrin IX and ROS, and killing 100% of resistant cells. The resistant MAL-PDT model of skin cancer squamous cells (HSC-1) is a reliable and useful tool to understand PDT cytotoxicity and cellular response. These resistant cells were successfully sensitized with epigallocatechin gallate catechin. The in vitro epigallocatechin gallate catechin effect as an enhancer of MAL-PDT in resistant cells is promising in the treatment of difficult skin cancer lesions.
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    Epigenetic reprogramming of cell cycle genes by ACK1 promotes breast cancer resistance to CDK4/6 inhibitor
    (2023) Sawant, Mithila; Wilson, Audrey; Sridaran, Dhivya; Mahajan, Kiran; O'Conor, Christopher J.; Hagemann, Ian S.; Luo, Jingqin; Weimholt, Cody; Li, Tiandao; Roa, Juan Carlos; Pandey, Akhilesh; Wu, Xinyan; Mahajan, Nupam P.
    Hormone receptor-positive, HER2-negative advanced breast cancers exhibit high sensitivity to CDK4/6 inhibitors such as palbociclib. However, most patients inevitably develop resistance, thus identification of new actionable therapeutic targets to overcome the recurrent disease is an urgent need. Immunohistochemical studies of tissue microarray revealed increased activation of non-receptor tyrosine kinase, ACK1 (also known as TNK2) in most of the breast cancer subtypes, independent of their hormone receptor status. Chromatin immunoprecipitation studies demonstrated that the nuclear target of activated ACK1, pY88-H4 epigenetic marks, were deposited at cell cycle genes, CCNB1, CCNB2 and CDC20, which in turn initiated their efficient transcription. Pharmacological inhibition of ACK1 using its inhibitor, (R)-9b dampened CCNB1, CCNB2 and CDC20 expression, caused G2/M arrest, culminating in regression of palbociclib-resistant breast tumor growth. Further, (R)-9b suppressed expression of CXCR4 receptor, which resulted in significant impairment of metastasis of breast cancer cells to lung. Overall, our pre-clinical data identifies activated ACK1 as an oncogene that epigenetically controls the cell cycle genes governing the G2/M transition in breast cancer cells. ACK1 inhibitor, (R)-9b could be a novel therapeutic option for the breast cancer patients that have developed resistance to CDK4/6 inhibitors.
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    Evaluación 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 Medicina
    El 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”.
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    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.
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    Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes
    (2021) Nepal, Chirag; Zhu, Bin; O'Rourke, Colm J.; Bhatt, Deepak Kumar; Lee, Donghyuk; Song, Lei; Wang, Difei; Van Dyke, Alison L.; Choo-Wosoba, Hyoyoung; Liu, Zhiwei; Hildesheim, Allan; Goldstein, Alisa M.; Dean, Michael; LaFuente-Barquero, Juan; Lawrence, Scott; Mutreja, Karun; Olanich, Mary E.; Bermejo, Justo Lorenzo; Ferreccio, Catterina; Roa, Juan Carlos; Rashid, Asif; Hsing, Ann W.; Gao, Yu-Tang; Chanock, Stephen J.; Araya, Juan Carlos; Andersen, Jesper B.; Koshiol, Jill
    Background & Aims: Gallbladder cancer (GBC) is the most common type of biliary tract cancer, but the molecular mechanisms involved in gallbladder carcinogenesis remain poorly understood. In this study, we applied integrative genomics approaches to characterise GBC and explore molecular subtypes associated with patient survival. Methods: We profiled the mutational landscape of GBC tumours (whole-exome sequencing on 92, targeted sequencing on 98, in total 190 patients). In a subset (n = 45), we interrogated the matched transcriptomes, DNA methylomes, and somatic copy number alterations. We explored molecular subtypes identified through clustering tumours by genes whose expression was associated with survival in 47 tumours and validated subtypes on 34 publicly available GBC cases. Results: Exome analysis revealed TP53was themostmutated gene. The overallmutation ratewas low(median 0.82Mut/Mb). APOBECmediated mutational signatures were more common in tumours with higher mutational burden. Aflatoxin-related signatures tended to be highly clonal (present in >-50% of cancer cells). Transcriptome-wide survival association analysis revealed a 95gene signature that stratified all GBC patients into 3 subtypes that suggested an association with overall survival post-resection. The 2 poor-survival subtypes were associated with adverse clinicopathologic features (advanced stage, pN1, pM1), immunosuppressive micro-environments (myeloid-derived suppressor cell accumulation, extensive desmoplasia, hypoxia) and T cell dysfunction, whereas the good-survival subtype showed the opposite features. Conclusion: These data suggest that the tumour microenvironment and immune profiles could play an important role in gallbladder carcinogenesis and should be evaluated in future clinical studies, along with mutational profiles. Lay summary: Gallbladder cancer is highly fatal, and its causes are poorly understood. We evaluated gallbladder tumours to see if there were differences between tumours in genetic information such as DNA and RNA. We found evidence of aflatoxin exposure in these tumours, and immune cells surrounding the tumours were associated with survival. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
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    Mucocutaneous Manifestations in Autoimmune Gastritis: A Prospective Case-Control Study
    (2021) Gonzalez, Agustin; Latorre, Gonzalo; Paredes, Loreto; Montoya, Lorena; Maquilon, Sara; Shah, Shailja C.; Espino, Alberto; Sabatini, Natalia; Torres, Javiera; Roa, Juan Carlos; Riquelme, Arnoldo; Kolbach, Marianne
    INTRODUCTION: Autoimmune gastritis (AIG) is associated with nutritional deficiencies, autoimmune diseases, and gastric malignancies. The aims of the study were to test the hypothesis that mucocutaneous (MC) manifestations occur more often in patients with vs without AIG and to delineate patterns of MC manifestations in AIG.
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    Pathologic 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 Carlos
    Tumors 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
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    PIM1 kinase promotes gallbladder cancer cell proliferation via inhibition of proline-rich Akt substrate of 40kDa (PRAS40)
    (2019) Subbannayya, Tejaswini; Leal-Rojas, Pamela; Zhavoronkov, Alex; Ozerov, Ivan, V; Korzinkin, Mikhail; Babu, Niraj; Radhakrishnan, Aneesha; Chavan, Sandip; Raja, Remya; Pinto, Sneha M.; Patil, Arun H.; Barbhuiya, Mustafa A.; Kumar, Prashant; Guerrero-Preston, Rafael; Navani, Sanjay; Tiwari, Pramod K.; Kumar, Rekha Vijay; Prasad, T. S. Keshava; Roa, Juan Carlos; Pandey, Akhilesh; Sidransky, David; Gowda, Harsha; Izumchenko, Evgeny; Chatterjee, Aditi
    Gallbladder cancer (GBC) is a rare malignancy, associated with poor disease prognosis with a 5-year survival of only 20%. This has been attributed to late presentation of the disease, lack of early diagnostic markers and limited efficacy of therapeutic interventions. Elucidation of molecular events in GBC can contribute to better management of the disease by aiding in the identification of therapeutic targets. To identify aberrantly activated signaling events in GBC, tandem mass tag-based quantitative phosphoproteomic analysis of five GBC cell lines was carried out. Proline-rich Akt substrate 40kDa (PRAS40) was one of the proteins found to be hyperphosphorylated in all the invasive GBC cell lines. Tissue microarray-based immunohistochemical labeling of phospho-PRAS40 (T246) revealed moderate to strong staining in 77% of the primary gallbladder adenocarcinoma cases. Regulation of PRAS40 activity by inhibiting its upstream kinase PIM1 resulted in a significant decrease in cell proliferation, colony forming and invasive ability of GBC cells. Our results support the role of PRAS40 phosphorylation in GBC cell survival and aggressiveness. This study also elucidates phospho-PRAS40 as a clinical marker in GBC and the role of PIM1 as a therapeutic target in GBC.
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    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.
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    Sex disparities in gallstone disease: insights from the MAUCO prospective population-based cohort study
    (2024) Gatta, Danae Rodriguez; Huidobro, Laura; Petermann-Rocha, Fanny; Van de Wyngard, Vanessa; Godoy, Franco; Cid, Vicente; Garrido, Macarena; Cook, Paz; Roa, Juan Carlos; Vargas, Claudio; Araya, Juan Carlos; Cortes, Sandra; Cruz, Francisco; Koshiol, Jill; Arrese, Marco; Ferreccio, Catterina
    Objective To investigate factors associated with the prevalence and incidence of gallstone disease (GSD) in women and men of the MAUCO population-based prospective cohort. Design 8948 MAUCO participants (aged 38-74 years) underwent abdominal ultrasound at baseline (2015-2019); 4385 received follow-up ultrasound at years 2 or 4. Factors associated with prevalent GSD were assessed using Poisson multiple regression and with incident GSD using Cox regression models. Results GSD prevalence was 40.4% in women (13.1% gallstones, 27.3% cholecystectomies) and 17.1% in men (8.9% gallstones, 8.2% cholecystectomies). In men, GSD prevalence rate ratio (PRR) by age in >64 years was 3.85 (95% CI 3.00 to 4.94), doubling that of women's PRR 1.78 (95% CI 1.57 to 2.01). In women, waist circumference and diabetes were stronger GSD factors; a higher number of children and worse metabolic and socioeconomic conditions were also highlighted. GSD men had higher cardiovascular disease and a family history of GSD and gallbladder cancer. 198 GSD cases developed during follow-up, with incidence increasing by 2% (95% CI 1.005% to 1.03%) per each centimetre above the ideal waist circumference, statistically significant only in women. In men, age was the strongest factor for incidence, followed by a family history of GSD and low high-density lipoprotein increased incidence risk. Conclusions GSD burden was high in this population; a third of women had their gallbladder removed, which may pose them at risk of other health problems. Abdominal obesity was the only preventable GSD risk factor, highlighting the need for effective public health policies promoting obesity reduction.
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    T2 gallbladder cancer shows substantial survival variation between continents and this is not due to histopathologic criteria or pathologic sampling differences
    (2021) DeSimone, Mia S.; Goodman, Michael; Pehlivanoglu, Burcin; Memis, Bahar; Balci, Serdar; Roa, Juan Carlos; Jang, Kee-Taek; Jang, Jin-Young; Hong, Seung-Mo; Lee, Kyoungbun; Kim, Haeryoung; Choi, Hye-Jeong; Muraki, Takashi; Araya, Juan Carlos; Bellolio, Enrique; Sarmiento, Juan M.; Maithel, Shishir K.; Losada, Hector F.; Basturk, Olca; Reid, Michelle D.; Koshiol, Jill; Adsay, Volkan
    Published data on survival of T2 gallbladder carcinoma (GBC) from different countries show a wide range of 5-year survival rates from 30-> 70%. Recently, studies have demonstrated substantial variation between countries in terms of their approach to sampling gallbladders, and furthermore, that pathologists from different continents apply highly variable criteria in determining stage of invasion in this organ. These findings raised the question of whether these variations in pathologic evaluation could account for the vastly different survival rates of T2 GBC reported in the literature. In this study, survival of 316 GBCs from three countries (Chile n = 137, South Korea n = 105, USA n = 74), all adequately sampled (with a minimum of five tumor sections examined) and histopathologically verified as pT2 (after consensus examination by expert pathologists from three continents), was analyzed. Chilean patients had a significantly worse prognosis based on 5-year all-cause mortality (HR: 1.89, 95% CI: 1.27-2.83, p = 0.002) and disease-specific mortality (HR: 2.41, 95% CI: 1.51-3.84, p < 0.001), compared to their South Korean counterparts, even when controlled for age and sex. Comparing the USA to South Korea, the survival differences in all-cause mortality (HR: 1.75, 95% CI: 1.12-2.75, p = 0.015) and disease-specific mortality (HR: 1.94, 95% CI: 1.14-3.31, p = 0.015) were also pronounced. The 3-year disease-specific survival rates in South Korea, the USA, and Chile were 75%, 65%, and 55%, respectively, the 5-year disease-specific survival rates were 60%, 50%, and 50%, respectively, and the overall 5-year survival rates were 55%, 45%, and 35%, respectively. In conclusion, the survival of true T2 GBC in properly classified cases is neither as good nor as bad as previously documented in the literature and shows notable geographic differences even in well-sampled cases with consensus histopathologic criteria. Future studies should focus on other potential reasons including biologic, etiopathogenetic, management-related, populational, or healthcare practice-related factors that may influence the survival differences of T2 GBC in different regions.
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    Targeting hypoxia-inducible factor-1 alpha suppresses Helicobacter pylori-induced gastric injury via attenuation of both cag-mediated microbial virulence and proinflammatory host responses
    (2023) Noto, Jennifer M.; Piazuelo, M. Blanca; Romero-Gallo, Judith; Delgado, Alberto G.; Suarez, Giovanni; Akritidou, Konstantina; Hoffman, Miguel Girod; Roa, Juan Carlos; Taylor, Cormac T.; Peek, Richard M., Jr.
    Helicobacter pylori-induced inflammation is the strongest known risk factor for gastric adenocarcinoma. Hypoxia-inducible factor-1 (HIF-1 alpha) is a key transcriptional regulator of immunity and carcinogenesis. To examine the role of this mediator within the context of H. pylori-induced injury, we first demonstrated that HIF-1 alpha levels were significantly increased in parallel with the severity of gastric lesions in humans. In interventional studies targeting HIF-1 alpha, H. pylori-infected mice were treated +/- dimethyloxalylglycine (DMOG), a prolyl hydroxylase inhibitor that stabilizes HIF-1 alpha. H. pylori significantly increased proinflammatory chemokines/cytokines and inflammation in vehicle-treated mice; however, this was significantly attenuated in DMOG-treated mice. DMOG treatment also significantly decreased function of the H. pylori type IV secretion system (T4SS) in vivo and significantly reduced T4SS-mediated NF-kappa B activation and IL-8 induction in vitro. These results suggest that prolyl hydroxylase inhibition protects against H. pylori-mediated pathologic responses, and is mediated, in part, via attenuation of H. pylori cag-mediated virulence and suppression of host proinflammatory responses.
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    TPPP-BRD9 fusion-related gallbladder carcinomas are frequently associated with intracholecystic neoplasia, neuroendocrine carcinoma, and a distinctive small tubular-type adenocarcinoma commonly accompanied with a syringomatous pattern
    (2024) Pehlivanoglu, Burcin; Araya, Juan Carlos; Lawrence, Scott; Roa, Juan Carlos; Balci, Serdar; Andersen, Jesper B.; Rashid, Asif; Hsing, Ann W.; Zhu, Bin; Gao, Yu-Tang; Koshiol, Jill; Adsay, Volkan
    A fusion between tubulin polymerization-promoting protein (TPPP), a regulatory cytoskeletal gene, and the chromatin remodeling factor, bromodomain-containing protein 9 (BRD9), TPPP-BRD9 fusion has been found in rare cancer cases, including lung and gallbladder cancers (GBC). In this study, we investigated the histopathological features of 16 GBCs previously shown by RNA sequencing to harbor the TPPP-BRD9 fusion. Findings in the fusion-positive GBCs were compared with 645 GBC cases from the authors' database. Among the 16 TPPPBRD9 fusion-positive GBC cases, most were females (F:M = 7:1) of Chinese ethnicity (12/16), whereas the remaining cases were from Chile. The histopathological examination showed the following findings: 1) Intracholecystic neoplasm (ICN) in 7/15 (47% vs. 7% 645 reference GBCs, p < 0.001), all with gastropancreatobiliary phenotype, often with clear cell change, and in the background of pyloric gland metaplasia and extensive high-grade dysplasia. 2) Neuroendocrine carcinoma (NEC) morphology: 3 cases (27% vs. 4.6% in the reference database, p = 0.001) showed a sheet-like and nested/trabecular growth pattern of monotonous cells with salt-and-pepper chromatin characteristic of NECs. Two were large cell type, one had prominent clear cell features, a rare finding in GBNECs; the other one had relatively bland, well-differentiated morphology, and the remaining case was small cell type. 3) Adenocarcinoma identified in 8 cases had a distinctive pattern characterized by widely separated small, round tubular units with relatively uniform nuclei in a fashion seen in mesonephric adenocarcinomas, including hobnail-like arrangement and apical snouts, reminiscent of tubular carcinomas of the breast in many areas. In some foci, the epithelium was attenuated, and glands were elongated, some with comma shapes, which along with the mucinous/necrotic intraluminal debris created a "syringoid" appearance. 4) Other occasional patterns included the cribriform, glomeruloid patterns, and metaplastic tubularspindle cell pattern accompanied by hemorrhage. In conclusion, TPPP-BRD9 fusion-positive GBCs often develop through intracholecystic neoplasms (adenoma-carcinoma sequence) of gastro-pancreatobiliary lineage, appear more prone to form NEC morphology and have a propensity to display clear cell change. Invasive adenocarcinomas arising in this setting often seem to display a distinctive appearance that we tentatively propose as the TPPP-BRD9 fusion-positive pattern of GBC.