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BACKGROUND: The use of artificial intelligence (AI) can revolutionize health care, but this raises risk concerns. It is therefore crucial to understand how clinicians trust and accept AI technology. Gastroenterology, by its nature of being an image-based and intervention-heavy specialty, is an area where AI-assisted diagnosis and management can be applied extensively. OBJECTIVE: This study aimed to study how gastroenterologists or gastrointestinal surgeons accept and trust the use of AI in computer-aided detection (CADe), computer-aided characterization (CADx), and computer-aided intervention (CADi) of colorectal polyps in colonoscopy. METHODS: We conducted a web-based questionnaire from November 2022 to January 2023, involving 5 countries or areas in the Asia-Pacific region. The questionnaire included variables such as background and demography of users; intention to use AI, perceived risk; acceptance; and trust in AI-assisted detection, characterization, and intervention. We presented participants with 3 AI scenarios related to colonoscopy and the management of colorectal polyps. These scenarios reflect existing AI applications in colonoscopy, namely the detection of polyps (CADe), characterization of polyps (CADx), and AI-assisted polypectomy (CADi). RESULTS: In total, 165 gastroenterologists and gastrointestinal surgeons responded to a web-based survey using the structured questionnaire designed by experts in medical communications. Participants had a mean age of 44 (SD 9.65) years, were mostly male (n=116, 70.3%), and mostly worked in publicly funded hospitals (n=110, 66.67%). Participants reported relatively high exposure to AI, with 111 (67.27%) reporting having used AI for clinical diagnosis or treatment of digestive diseases. Gastroenterologists are highly interested to use AI in diagnosis but show different levels of reservations in risk prediction and acceptance of AI. Most participants (n=112, 72.72%) also expressed interest to use AI in their future practice. CADe was accepted by 83.03% (n=137) of respondents, CADx was accepted by 78.79% (n=130), and CADi was accepted by 72.12% (n=119). CADe and CADx were trusted by 85.45% (n=141) of respondents and CADi was trusted by 72.12% (n=119). There were no application-specific differences in risk perceptions, but more experienced clinicians gave lesser risk ratings. CONCLUSIONS: Gastroenterologists reported overall high acceptance and trust levels of using AI-assisted colonoscopy in the management of colorectal polyps. However, this level of trust depends on the application scenario. Moreover, the relationship among risk perception, acceptance, and trust in using AI in gastroenterology practice is not straightforward.
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The role of appendectomy in the pathogenesis of colorectal cancer (CRC) is a recent topic of contention. Given that appendectomy remains one of the most commonly performed operations and a first-line management strategy of acute appendicitis, it is inherently crucial to elucidate the association between prior appendectomy and subsequent development of CRC, as there may be long-term health repercussions. In this review, we summarize the data behind the relationship of CRC in post-appendectomy patients, discuss the role of the microbiome in relation to appendectomy and CRC pathogenesis, and provide an appraisal of our current understanding of the function of the appendix. We seek to piece together the current landscape surrounding the microbiome and immunological changes in the colon post-appendectomy and suggest a direction for future research involving molecular, transcriptomic, and immunologic analysis to complement our current understanding of the alterations in gut microbiome.
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Apendicectomía , Apéndice , Neoplasias Colorrectales , Microbioma Gastrointestinal , Humanos , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/etiología , Apéndice/microbiología , Apendicectomía/efectos adversos , Apendicitis/microbiología , Apendicitis/cirugía , Colon/microbiología , Complicaciones Posoperatorias/microbiología , Complicaciones Posoperatorias/etiologíaRESUMEN
OBJECTIVE: Gut microbiota is a key player in dictating immunotherapy response. We aimed to explore the immunomodulatory effect of probiotic Lactobacillus gallinarum and its role in improving anti-programmed cell death protein 1 (PD1) efficacy against colorectal cancer (CRC). DESIGN: The effects of L. gallinarum in anti-PD1 response were assessed in syngeneic mouse models and azoxymethane/dextran sulfate sodium-induced CRC model. The change of immune landscape was identified by multicolour flow cytometry and validated by immunohistochemistry staining and in vitro functional assays. Liquid chromatography-mass spectrometry was performed to identify the functional metabolites. RESULTS: L. gallinarum significantly improved anti-PD1 efficacy in two syngeneic mouse models with different microsatellite instability (MSI) statuses (MSI-high for MC38, MSI-low for CT26). Such effect was confirmed in CRC tumourigenesis model. L. gallinarum synergised with anti-PD1 therapy by reducing Foxp3+ CD25+ regulatory T cell (Treg) intratumoural infiltration, and enhancing effector function of CD8+ T cells. L. gallinarum-derived indole-3-carboxylic acid (ICA) was identified as the functional metabolite. Mechanistically, ICA inhibited indoleamine 2,3-dioxygenase (IDO1) expression, therefore suppressing kynurenine (Kyn) production in tumours. ICA also competed with Kyn for binding site on aryl hydrocarbon receptor (AHR) and antagonised Kyn binding on CD4+ T cells, thereby inhibiting Treg differentiation in vitro. ICA phenocopied L. gallinarum effect and significantly improved anti-PD1 efficacy in vivo, which could be reversed by Kyn supplementation. CONCLUSION: L. gallinarum-derived ICA improved anti-PD1 efficacy in CRC through suppressing CD4+Treg differentiation and enhancing CD8+T cell function by modulating the IDO1/Kyn/AHR axis. L. gallinarum is a potential adjuvant to augment anti-PD1 efficacy against CRC.
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Neoplasias Colorrectales , Inhibidores de Puntos de Control Inmunológico , Quinurenina , Lactobacillus , Animales , Ratones , Linfocitos T CD8-positivos , Neoplasias Colorrectales/tratamiento farmacológico , Quinurenina/metabolismo , Receptores de Hidrocarburo de Aril/efectos de los fármacos , Receptores de Hidrocarburo de Aril/metabolismo , Linfocitos T Reguladores , Lactobacillus/química , Receptor de Muerte Celular Programada 1/efectos de los fármacos , Receptor de Muerte Celular Programada 1/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Lisados Bacterianos/farmacología , Lisados Bacterianos/uso terapéuticoRESUMEN
Using prostate-specific antigen (PSA) for prostate cancer (PCa) screening led to overinvestigation and overdiagnosis of indolent PCa. We aimed to investigate the value of prostate health index (PHI) and magnetic resonance imaging (MRI) prostate in an Asian PCa screening program. Men aged 50-75 years were prospectively recruited from a community-based PSA screening program. Men with PSA 4.0-10.0 ng ml -1 had PHI result analyzed. MRI prostate was offered to men with PSA 4.0-50.0 ng ml -1 . A systematic prostate biopsy was offered to men with PSA 4.0-9.9 ng ml -1 and PHI ≥35, or PSA 10.0-50.0 ng ml -1 . Additional targeted prostate biopsy was offered if they had PI-RADS score ≥3. Clinically significant PCa (csPCa) was defined as the International Society of Urological Pathology (ISUP) grade group (GG) ≥2 or ISUP GG 1 with involvement of ≥30% of total systematic cores. In total, 12.8% (196/1536) men had PSA ≥4.0 ng ml -1 . Among 194 men with PSA 4.0-50.0 ng ml -1 , 187 (96.4%) received MRI prostate. Among them, 28.3% (53/187) had PI-RADS ≥3 lesions. Moreover, 7.0% (107/1536) men were indicated for biopsy and 94.4% (101/107) men received biopsy. Among the men received biopsy, PCa, ISUP GG ≥2 PCa, and csPCa was diagnosed in 42 (41.6%), 24 (23.8%), and 34 (33.7%) men, respectively. Compared with PSA/PHI pathway in men with PSA 4.0-50.0 ng ml -1 , additional MRI increased diagnoses of PCa, ISUP GG ≥2 PCa, and csPCa by 21.2% (from 33 to 40), 22.2% (from 18 to 22), and 18.5% (from 27 to 32), respectively. The benefit of additional MRI was only observed in PSA 4.0-10.0 ng ml -1 , and the number of MRI needed to diagnose one additional ISUP GG ≥2 PCa was 20 in PHI ≥35 and 94 in PHI <35. Among them, 45.4% (89/196) men with PSA ≥4.0 ng ml -1 avoided unnecessary biopsy with the use of PHI and MRI. A screening algorithm with PSA, PHI, and MRI could effectively diagnose csPCa while reducing unnecessary biopsies. The benefit of MRI prostate was mainly observed in PSA 4.0-9.9 ng ml -1 and PHI ≥35 group. PHI was an important risk stratification step for PCa screening.
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Neoplasias de la Próstata , Humanos , Masculino , Detección Precoz del Cáncer/métodos , Pueblos del Este de Asia , Biopsia Guiada por Imagen/métodos , Imagen por Resonancia Magnética/métodos , Próstata/patología , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Estudios Retrospectivos , Persona de Mediana Edad , AncianoRESUMEN
OBJECTIVE: Roseburia intestinalis is a probiotic species that can suppress intestinal inflammation by producing metabolites. We aimed to study the role of R. intestinalis in colorectal tumourigenesis and immunotherapy. DESIGN: R. intestinalis abundance was evaluated in stools of patients with colorectal cancer (CRC) (n=444) and healthy controls (n=575). The effects of R. intestinalis were studied in ApcMin/+ or azoxymethane (AOM)-induced CRC mouse models, and in syngeneic mouse xenograft models of CT26 (microsatellite instability (MSI)-low) or MC38 (MSI-high). The change of immune landscape was evaluated by multicolour flow cytometry and immunohistochemistry staining. Metabolites were profiled by metabolomic profiling. RESULTS: R. intestinalis was significantly depleted in stools of patients with CRC compared with healthy controls. R. intestinalis administration significantly inhibited tumour formation in ApcMin/+ mice, which was confirmed in mice with AOM-induced CRC. R. intestinalis restored gut barrier function as indicated by improved intestinal permeability and enhanced expression of tight junction proteins. Butyrate was identified as the functional metabolite generated by R. intestinalis. R. intestinalis or butyrate suppressed tumour growth by inducing cytotoxic granzyme B+, interferon (IFN)-γ+ and tumour necrosis factor (TNF)-α+ CD8+ T cells in orthotopic mouse models of MC38 or CT26. R. intestinalis or butyrate also significantly improved antiprogrammed cell death protein 1 (anti-PD-1) efficacy in mice bearing MSI-low CT26 tumours. Mechanistically, butyrate directly bound to toll-like receptor 5 (TLR5) receptor on CD8+ T cells to induce its activity through activating nuclear factor kappa B (NF-κB) signalling. CONCLUSION: R. intestinalis protects against colorectal tumourigenesis by producing butyrate, which could also improve anti-PD-1 efficacy by inducing functional CD8+ T cells. R. intestinalis is a potential adjuvant to augment anti-PD-1 efficacy against CRC.
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Linfocitos T CD8-positivos , Neoplasias Colorrectales , Humanos , Ratones , Animales , Butiratos/farmacología , Carcinogénesis , Transformación Celular Neoplásica , Neoplasias Colorrectales/metabolismoRESUMEN
BACKGROUND AND AIM: Serrated polyps have been recognized as a premalignant lesion accounting for a significant proportion of colorectal cancer. Limited data are available regarding the risk factors for colorectal sessile serrated lesions (SSLs). We aimed to investigate clinical risk factors of SSLs and compared them with colorectal adenomas in a study population of Chinese individuals. METHODS: A retrospective case-control study was performed in an academic tertiary-referral center in Hong Kong. Subjects with SSLs and adenomas were identified from the hospital pathology database from January 2010 to December 2020, and additional clinical data were retrieved from the electronic patient record system. We compared clinical features and risk factors of SSL patients with those without these lesions. RESULTS: A total of 2295 subjects were included in the study, including 459 subjects with SSLs, 918 subjects with adenomas, and 918 subjects with normal colonoscopy. By multivariable logistic regression, compared with normal subjects, patients with SSLs only were significantly more likely to have dyslipidemia (adjusted OR: 1.431, 95% CI 1.008-2.030) and diabetes mellitus (adjusted OR: 2.119, 95% CI 1.439-3.122). CONCLUSIONS: Dyslipidemia and diabetes were independent risk factors for SSLs. Our findings suggest these metabolic factors may be important for the risk of SSLs. The findings may improve our understanding of SSLs and shed light on patient selection for screening and risk stratification.
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Adenoma , Pólipos del Colon , Neoplasias Colorrectales , Humanos , Pólipos del Colon/diagnóstico , Pólipos del Colon/epidemiología , Pólipos del Colon/patología , Estudios Retrospectivos , Estudios de Casos y Controles , Pueblos del Este de Asia , Colonoscopía , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/patología , Factores de Riesgo , Adenoma/diagnóstico , Adenoma/epidemiología , Adenoma/patologíaRESUMEN
OBJECTIVE: Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC). Squalene epoxidase (SQLE), a rate-limiting enzyme in cholesterol biosynthesis, is upregulated in CRC. Here, we aim to determine oncogenic function of SQLE and its interplay with gut microbiota in promoting colorectal tumourigenesis. DESIGN: Paired adjacent normal tissues and CRC from two cohorts were analysed (n=202). Colon-specific Sqle transgenic (Sqle tg) mice were generated by crossing Rosa26-lsl-Sqle mice to Cdx2-Cre mice. Stools were collected for metagenomic and metabolomic analyses. RESULTS: SQLE messenger RNA and protein expression was upregulated in CRC (p<0.01) and predict poor survival of patients with CRC. SQLE promoted CRC cell proliferation by inducing cell cycle progression and suppressing apoptosis. In azoxymethane-induced CRC model, Sqle tg mice showed increased tumourigenesis compared with wild-type mice (p<0.01). Integrative metagenomic and metabolomic analyses unveiled gut dysbiosis in Sqle tg mice with enriched pathogenic bacteria, which was correlated to increased secondary bile acids. Consistent with detrimental effect of secondary bile acids, gut barrier function was impaired in Sqle tg mice, with reduced tight junction proteins Jam-c and occludin. Transplantation of Sqle tg mice stool to germ-free mice impaired gut barrier function and stimulated cell proliferation compared with control mice stool. Finally, we demonstrated that terbinafine, a SQLE inhibitor, could be repurposed for CRC by synergising with oxaliplatin and 5-fluorouracil to inhibit CRC growth. CONCLUSION: This study demonstrates that SQLE mediates oncogenesis via cell intrinsic effects and modulation of gut microbiota-metabolite axis. SQLE represents a therapeutic target and prognostic marker in CRC.
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Neoplasias Colorrectales , Escualeno-Monooxigenasa , Animales , Azoximetano , Ácidos y Sales Biliares , Carcinogénesis/genética , Proliferación Celular/genética , Colesterol , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología , Disbiosis , Fluorouracilo , Ratones , Ocludina , Oxaliplatino , ARN Mensajero , Escualeno-Monooxigenasa/genética , Escualeno-Monooxigenasa/metabolismo , TerbinafinaRESUMEN
Hepatocellular carcinoma (HCC) is a major cancer burden worldwide with increasing incidence in many developed countries. Super-enhancers (SEs) drive gene expressions required for cell type-specificity and tumor cell identity. However, their roles in HCC remain unclear because of data scarcity from primary tumors. Herein, chromatin profiling of non-alcoholic fatty liver disease (NAFLD)-associated HCCs and matched liver tissues uncovered an average of â¼500 somatically-acquired SEs per patient. The identified SE-target genes were functionally enriched for aberrant metabolism and cancer phenotypes, especially chromatin regulators including deacetylases and Polycomb repressive complexes. Notably, all examined tumors exhibited SE activation of Sirtuin 7 (SIRT7), genome-wide promoter H3K18 deacetylation and concurrent H3K27me3, as well as tumor-suppressor gene silencing. Depletion of SIRT7 SE in hepatoma cells induced global H3K18 acetylation and reactivated key metabolic and immune regulators, leading to marked suppression of tumorigenicity in vitro and in vivo. In concordance, SIRT7 physically interacted with the methyltransferase EZH2, and they were co-expressed in primary HCCs. In summary, our integrative analysis establishes a compendium of SEs in NAFLD-associated HCCs and uncovers SIRT7-driven chromatin regulatory network as potential druggable vulnerability of this increasingly prevalent cancer.
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Carcinoma Hepatocelular/genética , Elementos de Facilitación Genéticos/genética , Neoplasias Hepáticas/genética , Sirtuinas/genética , Carcinogénesis/genética , Carcinoma Hepatocelular/patología , Reprogramación Celular/genética , Epigenómica , Femenino , Silenciador del Gen , Humanos , Neoplasias Hepáticas/patología , Masculino , Sirtuinas/antagonistas & inhibidoresRESUMEN
BACKGROUND & AIMS: Processed meat and high sodium intake are common in Western diet. The objective was to examine their independent effects on the risk of colorectal cancer (CRC). METHODS: We performed both observational analysis with UK Biobank and genetic analysis with Mendelian randomization (MR). The 24-h urinary sodium (UNa) and reported intake of processed meat were fitted on incident CRC by multivariable Cox proportional hazard model, adjusted for covariates, such as age, gender, family history, etc. Different sodium measures were used for sensitivity analyses. Two-sample MR analyses were performed using summary data from genome-wide association studies of UNa and CRC. Multivariable MR was adjusted for body mass index. RESULTS: We included 415 524 eligible participants from UK Biobank. During a median follow-up of 11.1 years, 2663 participants were diagnosed with CRC. High intake of processed meat independently increased risk of CRC by 23% (HR 1.23; 95% CI: 1.03 to 1.46), but 24-h UNa was not significantly associated with CRC (HR 0.96; 95% CI: 0.87 to 1.06). Furthermore, MR also showed little evidence for the effect of UNa on CRC (OR 1.02; 95% CI: 0.11 to 9.42). Sensitivity analyses showed consistent results across different measurements of sodium intake. CONCLUSIONS: Intake of processed meat had an independent effect on the risk of CRC, but the risk was not associated with sodium level. Reduction of processed meat intake may be an effective strategy for CRC prevention, while sodium reduction should still be recommended to achieve other health benefits.
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Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Dieta/efectos adversos , Carne/efectos adversos , Sodio en la Dieta/efectos adversos , Bancos de Muestras Biológicas , Dieta/estadística & datos numéricos , Femenino , Manipulación de Alimentos , Estudio de Asociación del Genoma Completo , Humanos , Incidencia , Masculino , Carne/estadística & datos numéricos , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sodio/orina , Reino Unido/epidemiologíaRESUMEN
BACKGROUND AND AIM: We have previously shown that fecal microbial markers might be useful for non-invasive diagnosis of colorectal cancer (CRC) and adenoma. Here, we assessed the application of microbial DNA markers, as compared with and in combination with fecal immunochemical test (FIT), in detecting CRC and adenoma in symptomatic patients and asymptomatic subjects. METHODS: We recruited 676 subjects [210 CRC, 115 advanced adenoma (AA), 86 non-advanced adenoma, and 265 non-neoplastic controls], including 241 symptomatic and 435 asymptomatic subjects. Fecal abundances of Fusobacterium nucleatum, a Lachnoclostridium sp. m3, Bacteroides clarus, and Clostridium hathewayi were quantified by quantitative PCR. Combining score of the four microbial markers (4Bac) and diagnostic prediction were determined using our previously established scoring model and cutoff values and FIT with a cutoff of 100 ng Hb/mL. RESULTS: 4Bac detected similar percentages of CRC [85.3% (95%CI: 79.2-90.2%) vs 84.9% (68.1-94.9%)] and AA [35.7% (12.8-64.9%) vs 38.6% (29.1-48.8%)], while FIT detected more CRC [72.1% (63.7-79.4%) vs 66.7% (48.2-82.0%)] and AA [28.6% (8.4-58.1%) vs 16.8% (10.1-25.6%)], in symptomatic vs asymptomatic subjects, respectively. Focusing on the asymptomatic cohort, 4Bac was more sensitive for diagnosing CRC and AA than FIT (P < 0.001), with lower specificity [83.3% (77.6-88.0%) vs 98.6% (96.0-99.7%)]. FIT failed to detect any non-advanced adenoma [0% (0.0-4.2%)] compared with 4Bac [41.9% (31.3-53.0%), P < 0.0001]. Combining 4Bac with FIT improved sensitivities for CRC [90.9% (75.7-98.1%)] and AA [48.5% (38.4-58.7%)] detection. CONCLUSION: Quantitation of fecal microbial DNA markers may serve as a new test, stand alone, or in combination with FIT for screening colorectal neoplasm in asymptomatic subjects.
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Adenoma/diagnóstico , Enfermedades Asintomáticas , Neoplasias Colorrectales/diagnóstico , ADN Bacteriano/análisis , Heces/microbiología , Microbioma Gastrointestinal/genética , Anciano , Biomarcadores/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
Colorectal cancer (CRC) is a heterogeneous disease with different gene expression patterns. There are two major colorectal carcinogenesis pathways: conventional adenoma-carcinoma pathway and alternative serrated neoplasia pathway. Apart from the conventional pathway that is typically initiated by characteristic APC mutation and chromosomal instability, the serrated neoplasia pathway is mainly characterized by mutations of BRAF or KRAS, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Despite the malignant potential of serrated lesions, they can be easily overlooked during endoscopy screening and even in pathological assessment due to its anatomical location, morphology, and histological features. It has been shown that environmental factors especially the gut microbial composition play a key role in CRC pathogenesis. Thus, the preferential localization of serrated lesions in specific intestine areas suggest that niche-specific microbiota composition might intertwined with host genetic perturbations during the development of serrated lesions. Although serrated lesions and conventional adenomas are biologically different, most studies have focused on conventional adenomas, while the pathophysiology and role of microorganisms in the development of serrated lesions remain elusive. In this review, we discuss on the role of gut microbiota in the serrated neoplasia pathway of colorectal carcinogenesis and its specific clinical and molecular features, and summarize the potential mechanisms involved.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología , Microbioma Gastrointestinal , Lesiones Precancerosas/genética , Lesiones Precancerosas/microbiología , Adenoma/genética , Adenoma/microbiología , Adenoma/patología , Carcinogénesis , Neoplasias Colorrectales/patología , Disbiosis , Humanos , Mutación , Lesiones Precancerosas/patologíaRESUMEN
OBJECTIVE: A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of Helicobacter pylori for prevention of gastric cancer (GC). METHODS: 28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed. RESULTS: Consensus was reached in 26 statements. At an individual level, eradication of H. pylori reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. H. pylori eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of 'the point of no return'. At the general population level, the strategy of screen-and-treat for H. pylori infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of H. pylori. CONCLUSION: Evidence supports the proposal that eradication therapy should be offered to all individuals infected with H. pylori. Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of H. pylori should be considered in populations at higher risk of GC.
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Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/prevención & control , Antibacterianos/administración & dosificación , Programas de Optimización del Uso de los Antimicrobianos , Toma de Decisiones Clínicas , Análisis Costo-Beneficio , Técnica Delphi , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Farmacorresistencia Bacteriana , Detección Precoz del Cáncer , Endoscopía Gastrointestinal , Gastritis Atrófica/microbiología , Gastritis Atrófica/prevención & control , Reflujo Gastroesofágico , Microbioma Gastrointestinal , Marcadores Genéticos , Salud Global , Infecciones por Helicobacter/epidemiología , Helicobacter pylori , Humanos , Síndrome Metabólico , Metaplasia/microbiología , Metaplasia/prevención & control , Inhibidores de la Bomba de Protones/administración & dosificación , Reinfección , Neoplasias Gástricas/epidemiologíaRESUMEN
BACKGROUND: While the chemoprevention effect of aspirin is well-established, the effects of metformin in cancer prevention is still controversial. This study is to investigate the use of aspirin, metformin, or the combination of both is associated with delayed cancer incidence. METHOD: This dataset is based on the electronic medical record of public hospitals in Hong Kong. Patients were classified into 1. aspirin user, 2. metformin user, 3. both aspirin and metformin user and 4. control group with neither aspirin nor metformin used. Aspirin and/or metformin must have been taken for over 6 months in the treatment group and cancer incidences was counted at least 6 months after exposure to such medications. The primary outcome of this study was overall incidence of cancer during the follow-up period. The secondary outcomes were cancer incidences of specific sites, including colon/rectum, liver, oesophagus, pancreas, stomach, lung, breast, kidney, bladder and prostate. Cox proportional hazards regression models were fitted to estimate hazard ratios of cancer risks. Inverse probability of treatment weighting was used to control for the medication effects. RESULTS: A total of 120,971 aspirin users, 11,365 metformin users, and 6630 aspirin plus metformin users, were identified. Compare to the control groups, those who used aspirin alone demonstrated a significant reduction in overall cancer risk (HR 0.80, 95% CI 0.73-0.87). Similarly, those who used metformin alone also showed an overall reduction in cancer risk (HR 0.79, 95% CI 0.71-0.88). Patients who received both aspirin and metformin showed the most significant reduction in overall cancer risk (HR 0.53, 95% CI 0.45-0.63). Metformin showed a significant reduction in cancer risk of lung, oesophagus and bladder. CONCLUSION: There is a similar decrease in overall cancer rate with the use of aspirin or metformin alone. A more significant reduction in overall cancer risk was found with the use of both agents.
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Aspirina/uso terapéutico , Metformina/uso terapéutico , Anciano , Anciano de 80 o más Años , Aspirina/farmacología , Diagnóstico Tardío , Femenino , Humanos , Incidencia , Masculino , Metformina/farmacología , Persona de Mediana Edad , Neoplasias/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND & AIMS: Mutant KRAS promotes glutaminolysis, a process that uses steps from the tricarboxylic cycle to convert glutamine to α-ketoglutarate and other molecules via glutaminase and SLC25A22. This results in inhibition of demethylases and epigenetic alterations in cells that increase proliferation and stem cell features. We investigated whether mutant KRAS-mediated glutaminolysis affects the epigenomes and activities of colorectal cancer (CRC) cells. METHODS: We created ApcminKrasG12D mice with intestine-specific knockout of SLC25A22 (ApcminKrasG12DSLC25A22fl/fl mice). Intestine tissues were collected and analyzed by histology, immunohistochemistry, and DNA methylation assays; organoids were derived and studied for stem cell features, along with organoids derived from 2 human colorectal tumor specimens. Colon epithelial cells (1CT) and CRC cells (DLD1, DKS8, HKE3, and HCT116) that expressed mutant KRAS, with or without knockdown of SLC25A22 or other proteins, were deprived of glutamine or glucose and assayed for proliferation, colony formation, glucose or glutamine consumption, and apoptosis; gene expression patterns were analyzed by RNA sequencing, proteins by immunoblots, and metabolites by liquid chromatography-mass spectrometry, with [U-13C5]-glutamine as a tracer. Cells and organoids with knocked down, knocked out, or overexpressed proteins were analyzed for DNA methylation at CpG sites using arrays. We performed immunohistochemical analyses of colorectal tumor samples from 130 patients in Hong Kong (57 with KRAS mutations) and Kaplan-Meier analyses of survival. We analyzed gene expression levels of colorectal tumor samples in The Cancer Genome Atlas. RESULTS: CRC cells that express activated KRAS required glutamine for survival, and rapidly incorporated it into the tricarboxylic cycle (glutaminolysis); this process required SLC25A22. Cells incubated with succinate and non-essential amino acids could proliferate under glutamine-free conditions. Mutant KRAS cells maintained a low ratio of α-ketoglutarate to succinate, resulting in reduced 5-hydroxymethylcytosine-a marker of DNA demethylation, and hypermethylation at CpG sites. Many of the hypermethylated genes were in the WNT signaling pathway and at the protocadherin gene cluster on chromosome 5q31. CRC cells without mutant KRAS, or with mutant KRAS and knockout of SLC25A22, expressed protocadherin genes (PCDHAC2, PCDHB7, PCDHB15, PCDHGA1, and PCDHGA6)-DNA was not methylated at these loci. Expression of the protocadherin genes reduced WNT signaling to ß-catenin and expression of the stem cell marker LGR5. ApcminKrasG12DSLC25A22fl/fl mice developed fewer colon tumors than ApcminKrasG12D mice (P < .01). Organoids from ApcminKrasG12DSLC25A22fl/fl mice had reduced expression of LGR5 and other markers of stemness compared with organoids derived from ApcminKrasG12D mice. Knockdown of SLC25A22 in human colorectal tumor organoids reduced clonogenicity. Knockdown of lysine demethylases, or succinate supplementation, restored expression of LGR5 to SLC25A22-knockout CRC cells. Knockout of SLC25A22 in CRC cells that express mutant KRAS increased their sensitivity to 5-fluorouacil. Level of SLC25A22 correlated with levels of LGR5, nuclear ß-catenin, and a stem cell-associated gene expression pattern in human colorectal tumors with mutations in KRAS and reduced survival times of patients. CONCLUSIONS: In CRC cells that express activated KRAS, SLC25A22 promotes accumulation of succinate, resulting in increased DNA methylation, activation of WNT signaling to ß-catenin, increased expression of LGR5, proliferation, stem cell features, and resistance to 5-fluorouacil. Strategies to disrupt this pathway might be developed for treatment of CRC.
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Colon/patología , Neoplasias Colorrectales/genética , Mucosa Intestinal/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Desmetilación del ADN , Resistencia a Antineoplásicos , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Glutamina/metabolismo , Hong Kong/epidemiología , Humanos , Estimación de Kaplan-Meier , Ácidos Cetoglutáricos/metabolismo , Masculino , Ratones Noqueados , Proteínas de Transporte de Membrana Mitocondrial/genética , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Vía de Señalización Wnt/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Artificial intelligence (AI) is coming to medicine in a big wave. From making diagnosis in various medical conditions, following the latest advancements in scientific literature, suggesting appropriate therapies, to predicting prognosis and outcome of diseases and conditions, AI is offering unprecedented possibilities to improve care for patients. Gastroenterology is a field that AI can make a significant impact. This is partly because the diagnosis of gastrointestinal conditions relies a lot on image-based investigations and procedures (endoscopy and radiology). AI-assisted image analysis can make accurate assessment and provide more information than conventional analysis. AI integration of genomic, epigenetic, and metagenomic data may offer new classifications of gastrointestinal cancers and suggest optimal personalized treatments. In managing relapsing and remitting diseases such as inflammatory bowel disease, irritable bowel syndrome, and peptic ulcer bleeding, convoluted neural network may formulate models to predict disease outcome, enhancing treatment efficacy. AI and surgical robots can also assist surgeons in conducting gastrointestinal operations. While the advancement and new opportunities are exciting, the responsibility and liability issues of AI-assisted diagnosis and management need much deliberations.