RESUMO
A plethora of experimental and epidemiological evidence supports a critical role for inflammation and adaptive immunity in the onset of cancer and in shaping its response to therapy. These data are particularly robust for gastrointestinal (GI) cancers, such as those affecting the GI tract, liver, and pancreas, on which this review is focused. We propose a unifying hypothesis according to which intestinal barrier disruption is the origin of tumor-promoting inflammation that acts in conjunction with tissue-specific cancer-initiating mutations. The gut microbiota and its products impact tissue-resident and recruited myeloid cells that promote tumorigenesis through secretion of growth- and survival-promoting cytokines that act on epithelial cells, as well as fibrogenic and immunosuppressive cytokines that interfere with the proper function of adaptive antitumor immunity. Understanding these relationships should improve our ability to prevent cancer development and stimulate the immune system to eliminate existing malignancies.
Assuntos
Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Microbioma Gastrointestinal , Neoplasias Gastrointestinais/etiologia , Neoplasias Gastrointestinais/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Imunidade Adaptativa , Animais , Mucosa Gástrica/patologia , Microbioma Gastrointestinal/imunologia , Neoplasias Gastrointestinais/patologia , Humanos , Imunidade Inata , Mucosa Intestinal/patologia , Fígado/imunologia , Fígado/metabolismo , Fígado/patologiaRESUMO
Cancer is one of the foremost health problems worldwide and is among the leading causes of death in the United States. Gastrointestinal tract cancers account for almost one third of the cancer-related mortality globally, making it one of the deadliest groups of cancers. Early diagnosis and prompt management are key to preventing cancer-related morbidity and mortality. With advancements in technology and endoscopic techniques, endoscopy has become the core in diagnosis and management of gastrointestinal tract cancers. In this extensive review, the authors discuss the role endoscopy plays in early detection, diagnosis, and management of esophageal, gastric, colorectal, pancreatic, ampullary, biliary tract, and small intestinal cancers.
Assuntos
Gastroenterologia , Neoplasias Gastrointestinais , Humanos , Estados Unidos/epidemiologia , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Endoscopia/métodos , PâncreasRESUMO
Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-ß-signaling-dependent conversion of NK cells (CD49a-CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b-Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-ß-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.
Assuntos
Reprogramação Celular/imunologia , Fibrossarcoma/imunologia , Neoplasias Gastrointestinais/imunologia , Tumores do Estroma Gastrointestinal/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Experimentais/imunologia , Evasão Tumoral/imunologia , Animais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Células Matadoras Naturais/citologia , Linfócitos/citologia , Linfócitos/imunologia , Camundongos , Análise de Sequência de RNA , Transdução de Sinais , Fator de Crescimento Transformador beta/imunologiaRESUMO
Gastrointestinal (GI) cancers, including colorectal, gastric, esophageal, pancreatic, and liver, are associated with high mortality and morbidity rates worldwide. One of the underlying reasons for the poor survival outcomes in patients with these malignancies is late disease detection, typically when the tumor has already advanced and potentially spread to distant organs. Increasing evidence indicates that earlier detection of these cancers is associated with improved survival outcomes and, in some cases, allows curative treatments. Consequently, there is a growing interest in the development of molecular biomarkers that offer promise for screening, diagnosis, treatment selection, response assessment, and predicting the prognosis of these cancers. Extracellular vesicles (EVs) are membranous vesicles released from cells containing a repertoire of biological molecules, including nucleic acids, proteins, lipids, and carbohydrates. MicroRNAs (miRNAs) are the most extensively studied non-coding RNAs, and the deregulation of miRNA levels is a feature of cancer cells. EVs miRNAs can serve as messengers for facilitating interactions between tumor cells and the cellular milieu, including immune cells, endothelial cells, and other tumor cells. Furthermore, recent years have witnessed considerable technological advances that have permitted in-depth sequence profiling of these small non-coding RNAs within EVs for their development as promising cancer biomarkers -particularly non-invasive, liquid biopsy markers in various cancers, including GI cancers. Herein, we summarize and discuss the roles of EV-associated miRNAs as they play a seminal role in GI cancer progression, as well as their promising translational and clinical potential as cancer biomarkers as we usher into the area of precision oncology.
Assuntos
Vesículas Extracelulares , Neoplasias Gastrointestinais , MicroRNAs , Humanos , MicroRNAs/genética , Relevância Clínica , Células Endoteliais/metabolismo , Medicina de Precisão , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Vesículas Extracelulares/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biologia , Biomarcadores/metabolismoRESUMO
BACKGROUND & AIMS: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to characterize the proteomic features of GIST to understand biological processes and treatment vulnerabilities. METHODS: Quantitative proteomics and phosphoproteomics analyses were performed on 193 patients with GIST to reveal the biological characteristics of GIST. Data-driven hypotheses were tested by performing functional experiments using both GIST cell lines and xenograft mouse models. RESULTS: Proteomic analysis revealed differences in the molecular features of GISTs from different locations or with different histological grades. MAPK7 was identified and functionally proved to be associated with tumor cell proliferation in GIST. Integrative analysis revealed that increased SQSTM1 expression inhibited the patient response to imatinib mesylate. Proteomics subtyping identified 4 clusters of tumors with different clinical and molecular attributes. Functional experiments confirmed the role of SRSF3 in promoting tumor cell proliferation and leading to poor prognosis. CONCLUSIONS: Our study provides a valuable data resource and highlights potential therapeutic approaches for GIST.
Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Humanos , Animais , Camundongos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteômica , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Fatores de Processamento de Serina-ArgininaRESUMO
BACKGROUND: Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy. METHODS: In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011. FINDINGS: Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit. INTERPRETATION: If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings. FUNDING: National Cancer Institute.
Assuntos
Inteligência Artificial , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Humanos , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Antineoplásicos/uso terapêutico , Quimioterapia Adjuvante , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Gastrointestinais/cirurgia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Adulto , Estudos de Coortes , Resultado do TratamentoRESUMO
Previous metabolomics studies have highlighted the predictive value of metabolites on upper gastrointestinal (UGI) cancer, while most of them ignored the potential effects of lifestyle and genetic risk on plasma metabolites. This study aimed to evaluate the role of lifestyle and genetic risk in the metabolic mechanism of UGI cancer. Differential metabolites of UGI cancer were identified using partial least-squares discriminant analysis and the Wilcoxon test. Then, we calculated the healthy lifestyle index (HLI) score and polygenic risk score (PRS) and divided them into three groups, respectively. A total of 15 metabolites were identified as UGI-cancer-related differential metabolites. The metabolite model (AUC = 0.699) exhibited superior discrimination ability compared to those of the HLI model (AUC = 0.615) and the PRS model (AUC = 0.593). Moreover, subgroup analysis revealed that the metabolite model showed higher discrimination ability for individuals with unhealthy lifestyles compared to that with healthy individuals (AUC = 0.783 vs 0.684). Furthermore, in the genetic risk subgroup analysis, individuals with a genetic predisposition to UGI cancer exhibited the best discriminative performance in the metabolite model (AUC = 0.770). These findings demonstrated the clinical significance of metabolic biomarkers in UGI cancer discrimination, especially in individuals with unhealthy lifestyles and a high genetic risk.
Assuntos
Neoplasias Gastrointestinais , Estilo de Vida Saudável , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bancos de Espécimes Biológicos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/sangue , Estratificação de Risco Genético , Metabolômica/métodos , Biobanco do Reino Unido , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: Gastrointestinal cancer is one of the most common malignant tumors in the world, and its incidence rate is always high. In recent years, research has shown that microorganisms may play a broad role in the diagnosis, pathogenesis, and treatment of cancer. METHODS: In this study, samples were first classified according to the microbial expression data of Gastrointestinal cancer, followed by functional enrichment and Immunoassay. In order to better understand the role of intratumor microorganisms in the prognosis, we screened gene signatures and constructed risk model through univariate cox and lasso regression and multivariable cox, then screened microbial signatures using zero-inflated model regression model and constructed risk index (RI), and finally predicted the immunotherapeutic effect of the risk model. RESULTS: The results indicate that the composition of tumor microorganisms in the C3 subtype is closely related to tumor angiogenesis, and there is a significant difference in the proportion of innate and acquired immune cells between the C2 and C1 subtypes, as well as differences in the physiological functions of immune cells. There are significant differences in the expression of microbial signatures between high and low risk subtypes, with 9 microbial signatures upregulated in high risk subtypes and 15 microbial signatures upregulated in low risk subtypes. These microbial signatures were significantly correlated with the prognosis of patients. The results of immunotherapy indicate that immunotherapy for high-risk subtypes is more effective. CONCLUSION: Overall, we analyze from the perspective of microorganisms within tumors, pointing out new directions for the diagnosis and treatment of cancer.
Assuntos
Neoplasias Gastrointestinais , Multiômica , Humanos , Neoplasias Gastrointestinais/genética , Imunoterapia , Microambiente Tumoral , PrognósticoRESUMO
Immune checkpoint inhibitors (ICIs) have become prominent therapies for gastrointestinal cancer (GC). However, it is urgent to screen patients who can benefit from ICIs. Protein patched homolog 1 (PTCH1) is a frequently altered gene in GC. We attempt to explore the association between PTCH1 mutation and immunotherapy efficacy. The Memorial Sloan Kettering Cancer Center (MSKCC) cohort (nâ =â 236) with GC (esophageal, gastric and colorectal cancers) patients receiving ICIs was used for discovery and the Peking University Cancer Hospital (PUCH) GC cohort (nâ =â 92) was used for validation. Overall survival (OS) and tumor mutational burden (TMB) of the PTCH1 mutant-type (PTCH1-MUT) and PTCH1 wild-type (PTCH1-WT) groups were compared. Furthermore, GC data were collected from The Cancer Genome Atlas to assess the potential mechanisms. In the MSKCC cohort, PTCH1-MUT group showed significantly better OS (Pâ =â 0.017) and higher TMB. Multivariate analysis showed that PTCH1 mutation was associated with better OS. In the PUCH cohort, PTCH1-MUT group showed significantly longer OS (Pâ =â 0.036) and progression-free survival, and higher durable clinical benefit and TMB. Immune cell infiltration analysis revealed that PTCH1-MUT group had significantly higher distributions of CD8 T cells, CD4 T cells, NK cells, mast cells and M1 cells. The PTCH1-MUT group showed significantly higher expression of most immune-related genes. Gene set enrichment analysis showed that the PTCH1-MUT group had enriched INF-γ response, INF-α response, glycolysis and reactive oxygen species pathway gene sets. PTCH1 mutation may represent a potential biomarker for predicting ICIs response in GC. Nevertheless, prospective cohort studies should be performed to further validate our results.
Assuntos
Biomarcadores Tumorais , Neoplasias Gastrointestinais , Inibidores de Checkpoint Imunológico , Mutação , Receptor Patched-1 , Humanos , Receptor Patched-1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Biomarcadores Tumorais/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Masculino , Pessoa de Meia-Idade , Idoso , Prognóstico , AdultoRESUMO
Gastrointestinal cancer (GIC) is the most prevalent and highly metastatic malignant tumor and has a significant impact on mortality rates. Nevertheless, the swift advancement of contemporary technology has not seamlessly aligned with the evolution of detection methodologies, resulting in a deficit of innovative and efficient clinical assays for GIC. Given that exosomes are preferentially released by a myriad of cellular entities, predominantly originating from neoplastic cells, this confers exosomes with a composition enriched in cancer-specific constituents. Furthermore, exosomes exhibit ubiquitous presence across diverse biological fluids, endowing them with the inherent advantages of non-invasiveness, real-time monitoring, and tumor specificity. The unparalleled advantages inherent in exosomes render them as an ideal liquid biopsy biomarker for early diagnosis, prognosticating the potential development of GIC metastasis.In this review, we summarized the latest research progress and possible potential targets on cancer-derived exosomes (CDEs) in GIC with an emphasis on the mechanisms of exosome promoting cancer metastasis, highlighting the potential roles of CDEs as the biomarker and treatment in metastatic GIC.
Assuntos
Exossomos , Neoplasias Gastrointestinais , Humanos , Exossomos/patologia , Biomarcadores Tumorais , Biomarcadores , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/patologia , Biópsia Líquida/métodosRESUMO
Immune checkpoint inhibitors are becoming an increasingly common treatment for advanced gastrointestinal cancer, but the possibility of immune-related adverse events has raised concerns. This study aimed to evaluate the risks of immune-related adverse events between patients who received immune checkpoint inhibitors and those who received chemotherapy among different types of gastrointestinal cancer. The study utilized data from the multicenter TriNetX database in the United States covering the period between 2015 and 2022. Hazard ratios and 95% confidence intervals were used to describe the relative hazard of immune-related adverse events based on comparing time-to-event rates. Our study revealed that the incidence of immune-related adverse events was significantly higher in patients who received immune checkpoint inhibitors and chemotherapy compared to those who received chemotherapy only in treating gastrointestinal cancer. CTLA-4 inhibitors tended to have a higher rate of immune-related adverse events compared to PD-1/PD-L1 inhibitors. Our study found a lower mortality rate among patients who developed immune-related adverse events compared to those who did not after propensity score matching (HR, 0.661; 95% CI 0.620-0.704; p < .01). We provide important real-world data on the incidence and impact of immune-related adverse events in patients with advanced gastrointestinal cancer treated with immune checkpoint inhibitors. Our study's results support clinicians in making informed decisions about the potential benefits and risks of immune checkpoint inhibitor therapy for patients with gastrointestinal cancer.
Assuntos
Neoplasias Gastrointestinais , Inibidores de Checkpoint Imunológico , Humanos , Neoplasias Gastrointestinais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Estados Unidos , Estudos Multicêntricos como Assunto , Bases de Dados como AssuntoRESUMO
The burden of digestive cancers is increasing worldwide. The Global Cancer Observatory (GLOBOCAN) 2020 and the Global Burden of Disease (GBD) 2019 are two primary cancer databases, which have a significant impact on policy formulation and resource allocation. We aim to compare the incidence and mortality of digestive cancers between them. Digestive cancer (esophageal, stomach, colorectal, liver, gallbladder and pancreatic cancer) incidence was obtained from the Cancer Today and GBD 2019 result tool. The top five countries with the most or minor difference between GLOBOCAN 2020 and GBD 2019 in age-standardized incidence rates (ASIRs) of digestive cancers were identified. A systematic search on the incidence of specific digestive cancer in selected countries from PubMed and Embase was conducted, and 20 of 281 publications were included. The most significant differences in digestive cancers incidence were commonly found in Asian countries (70%), particularly Indonesia, Vietnam and Myanmar, located in Southeast Asia. The ASIRs for most digestive cancers, except liver cancer, in GLOBOCAN 2020 were higher than those in GBD 2019. Gallbladder cancer had the highest average ratio, followed by liver cancer. The most commonly used standard population was Segi's standard population, followed by the World Health Organization standard population. The data sources nor the processing methods of GLOBOCAN 2020 and GBD 2019 were not similar. Low- and middle-income countries without population-based cancer registries were more likely to have selection bias in data collection and amplify regional variations of etiological factors. Better judgments on the quality of cancer data can be made.
Assuntos
Neoplasias da Vesícula Biliar , Neoplasias Gastrointestinais , Neoplasias Hepáticas , Humanos , Carga Global da Doença , Incidência , Neoplasias Hepáticas/epidemiologia , Saúde GlobalRESUMO
The relationship between Helicobacter pylori (H. pylori) infection and upper gastrointestinal (UGI) cancers is complex. This multicenter, population-based cohort study conducted in seven areas in China aimed to assess the correlation between current H. pylori infection and the severity of UGI lesions, as well as its association with the risk of gastric cancer (GC) and esophageal cancer (EC). From 2015 to 2017, 27,085 participants (aged 40-69) completed a standardized questionnaire, and underwent a 13C-urea breath test. Then a subset underwent UGI endoscopy to assess the UGI lesion detection rates. All individuals were followed up until December 2021 to calculate the hazard ratios (HRs) for UGI cancers. H. pylori infection prevalence was 45.9%, and among endoscopy participants, 22.2% had gastric lesions, 19.2% had esophageal lesions. Higher detection rates of gastric lesions were noted in the H. pylori-positive population across all lesion severity levels. Over a median follow-up of 6.3 years, 104 EC and 179 GC cases were observed, including 103 non-cardia gastric cancer (NCGC) cases and 76 cardia gastric cancer (CGC) cases. H. pylori-infected individuals exhibited a 1.78-fold increased risk of GC (HR 1.78, 95% confidence interval [CI] 1.32-2.40) but no significant increase in EC risk (HR 1.07, 95% CI 0.73-1.57). Notably, there was a higher risk for both NCGC and CGC in H. pylori-infected individuals. This population-based cohort study provides valuable evidence supporting the association between current H. pylori infection and the risk of both NCGC and CGC. These findings contribute to the empirical basis for risk stratification and recommendations for UGI cancer screening.
Assuntos
Neoplasias Esofágicas , Infecções por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Pessoa de Meia-Idade , Masculino , Feminino , Helicobacter pylori/isolamento & purificação , Adulto , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Idoso , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/microbiologia , Neoplasias Esofágicas/etiologia , China/epidemiologia , Estudos de Coortes , Fatores de Risco , Prevalência , Neoplasias Gastrointestinais/microbiologia , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/etiologia , Trato Gastrointestinal Superior/patologia , Trato Gastrointestinal Superior/microbiologiaRESUMO
Infection by certain pathogens is associated with cancer development. We conducted a case-cohort study of ~2500 incident cases of esophageal, gastric and duodenal cancer, and gastric and duodenal ulcer and a randomly selected subcohort of ~2000 individuals within the China Kadoorie Biobank study of >0.5 million adults. We used a bead-based multiplex serology assay to measure antibodies against 19 pathogens (total 43 antigens) in baseline plasma samples. Associations between pathogens and antigen-specific antibodies with risks of site-specific cancers and ulcers were assessed using Cox regression fitted using the Prentice pseudo-partial likelihood. Seroprevalence varied for different pathogens, from 0.7% for Hepatitis C virus (HCV) to 99.8% for Epstein-Barr virus (EBV) in the subcohort. Compared to participants seronegative for the corresponding pathogen, Helicobacter pylori seropositivity was associated with a higher risk of non-cardia (adjusted hazard ratio [HR] 2.73 [95% CI: 2.09-3.58]) and cardia (1.67 [1.18-2.38]) gastric cancer and duodenal ulcer (2.71 [1.79-4.08]). HCV was associated with a higher risk of duodenal cancer (6.23 [1.52-25.62]) and Hepatitis B virus was associated with higher risk of duodenal ulcer (1.46 [1.04-2.05]). There were some associations of antibodies again some herpesviruses and human papillomaviruses with risks of gastrointestinal cancers and ulcers but these should be interpreted with caution. This first study of multiple pathogens with risk of gastrointestinal cancers and ulcers demonstrated that several pathogens are associated with risks of gastrointestinal cancers and ulcers. This will inform future investigations into the role of infection in the etiology of these diseases.
Assuntos
Neoplasias Duodenais , Úlcera Duodenal , Infecções por Vírus Epstein-Barr , Neoplasias Gastrointestinais , Infecções por Helicobacter , Helicobacter pylori , Hepatite C , Adulto , Humanos , Estudos de Coortes , Úlcera Duodenal/epidemiologia , Úlcera Duodenal/complicações , Úlcera/complicações , Estudos Soroepidemiológicos , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Cárdia , Hepatite C/complicações , Hepatite C/epidemiologia , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologiaRESUMO
Pre-clinical evidence suggests that 5-alpha reductase inhibitors (5ARi's), prescribed in the treatment of benign prostatic hyperplasia, reduce colorectal and gastro-oesophageal cancer incidence via action on the male hormonal pathway. However, few studies to date have investigated this association at the population level. Our study aimed to investigate the risk of colorectal and gastro-oesophageal cancers with the use of 5ARi's. We conducted a retrospective cohort study of new users of 5ARi's and alpha-blockers among patients with benign prostatic hyperplasia in the UK Clinical Practice Research Datalink. Patients were followed until a first ever diagnosis of colorectal or gastro-oesophageal cancer, death from any cause or end of registration with the general practice or 31st of December 2017. Cox proportional hazards models with inverse probability of treatment weights were used to calculate weighted hazard ratios (HR) and 95% confidence intervals (CIs) of incident colorectal cancer or gastro-oesophageal cancer associated with the use of 5ARi's compared to alpha-blockers. During a mean follow-up of 6.6 years, we found no association between the use of 5ARi's and colorectal (HR: 1.13, 95% CI 0.91-1.41) or gastro-oesophageal (HR 1.14, 95% CI 0.76-1.63) cancer risk compared to alpha-blockers. Sensitivity analysis showed largely consistent results when varying lag periods, using multiple imputations, and accounting for competing risk of death. Our study found no association between the use of 5ARi's and risk of colorectal or gastro-oesophageal cancer in men with benign prostatic hyperplasia.
Assuntos
Inibidores de 5-alfa Redutase , Hiperplasia Prostática , Humanos , Masculino , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/epidemiologia , Inibidores de 5-alfa Redutase/uso terapêutico , Inibidores de 5-alfa Redutase/efeitos adversos , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Incidência , Neoplasias Gastrointestinais/epidemiologia , Reino Unido/epidemiologia , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas Adrenérgicos alfa/efeitos adversos , Idoso de 80 Anos ou mais , Neoplasias Colorretais/epidemiologia , Modelos de Riscos Proporcionais , Fatores de Risco , Neoplasias Esofágicas/epidemiologiaRESUMO
The long interspersed nuclear element-1 (LINE-1) retrotransposons are a major family of mobile genetic elements, comprising approximately 17% of the human genome. The methylation state of LINE-1 is often used as an indicator of global DNA methylation levels and it regulates the retrotransposition and somatic insertion of the genetic element. We have previously reported the significant relationship between LINE-1 hypomethylation and poor prognosis in upper gastrointestinal (GI) cancers. However, the causal relationships between LINE-1 hypomethylation, retrotransposition, and tumor-specific insertion in upper GI cancers remain unknown. We used bisulfite-pyrosequencing and quantitative real-time PCR to verify LINE-1 methylation and copy number in tissue samples of 101 patients with esophageal and 103 patients with gastric cancer. Furthermore, we analyzed the LINE-1 retrotransposition profile with an originally developed L1Hs-seq. In tumor samples, LINE-1 methylation levels were significantly lower than non-tumor controls, while LINE-1 copy numbers were markedly increased. As such, there was a significant inverse correlation between the LINE-1 methylation level and copy number in tumor tissues, with lower LINE-1 methylation levels corresponding to higher LINE-1 copy numbers. Of particular importance is that somatic LINE-1 insertions were more numerous in tumor than normal tissues. Furthermore, we observed that LINE-1 was inserted evenly across all chromosomes, and most often within genomic regions associated with tumor-suppressive genes. LINE-1 hypomethylation in upper GI cancers is related to increased LINE-1 retrotransposition and tumor-specific insertion events, which may collectively contribute to the acquisition of aggressive tumor features through the inactivation of tumor-suppressive genes.
Assuntos
Neoplasias Gastrointestinais , Neoplasias Gástricas , Humanos , Metilação de DNA/genética , Neoplasias Gastrointestinais/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Neoplasias Gástricas/genética , EsôfagoRESUMO
BACKGROUND: Food access is associated with higher gastrointestinal (GI) cancer mortality; however, its association with frailty, which is a predictor of premature mortality among older adults with cancer, is less understood. METHODS: The authors included 880 adults aged 60 years and older who were recently diagnosed with GI cancers and were undergoing self-reported geriatric assessment at their first prechemotherapy visit to the University of Alabama at Birmingham oncology clinic. Food access was measured using the 2019 US Department of Agriculture Economic Research Service designation low-income, low-access (LILA), classifying census tracts based on income and/or access to food stores at various distances. The primary outcome was frailty on the CARE (Cancer and Aging Resilience Evaluation) Frailty Index, a composite of the proportion of impaired geriatric assessment measures. The authors examined the LILA-frailty association with modified Poisson regression accounting for census-tract clustering. RESULTS: The median patient age was 69 years, 58.1% were men, 22.5% were non-Hispanic Black, 29.2% had colorectal cancer, 28.0% had pancreatic cancer, 70.1% presented with stage III/IV disease, and 34.9% were frail. A higher proportion in LILA areas were non-Hispanic Black (44.1% vs. 10.8%; p < .001) and had less education (high school or less: 48.1% vs. 37.9%; p = .020). Adjusting for age, race and ethnicity, sex, cancer type and stage, and education, an LILA designation was associated with 58% greater odds of worsening frailty status (95% confidence interval, 1.18-2.12). An analysis of LILA subcategories revealed that associations were maintained across all LILA measures. CONCLUSIONS: Poor food access was associated with a greater risk of frailty among newly diagnosed older adults with GI cancers before they received systemic treatment. Intervening on local food access, particularly in LILA areas, may be a target for improving rates of frailty and promoting health equity in this population.
Assuntos
Fragilidade , Neoplasias Gastrointestinais , Idoso , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Fragilidade/epidemiologia , Fragilidade/diagnóstico , Idoso Fragilizado , Avaliação Geriátrica , Neoplasias Gastrointestinais/epidemiologia , Sistema de RegistrosRESUMO
BACKGROUND: Impaired fasting glucose (IFG) is associated with the risk of various cancers, but the cumulative effect of IFG on gastrointestinal cancer risk remains unclear. This study evaluated the association between the cumulative exposure to IFG and gastrointestinal cancer risk. METHODS: The authors extracted data from the Korean National Health Insurance Service and health examination data sets. Among individuals ≥40 years old who were free of diabetes or cancer, 1,430,054 who underwent national health examinations over 4 consecutive years from 2009 to 2012 were selected and followed up until gastrointestinal cancer diagnosis, death, or December 31, 2019. The IFG exposure score (range, 0-4) was based on the number of IFG diagnoses over 4 years. RESULTS: The median follow-up duration was 6.4 years. Consistent normoglycemia for 4 years was found in 44.3% of the population, whereas 5.0% had persistent IFG and 50.7% had intermittent IFG. Compared to the group with an IFG exposure score of 0, groups with IFG exposure scores of 1, 2, 3, and 4 had a 5%, 8%, 9%, and 12% increased risk of gastrointestinal cancer, respectively (score 1: adjusted hazard ratio [aHR], 1.05; 95% confidence interval [CI], 1.01-1.08; score 2: aHR, 1.08; 95% CI, 1.04-1.12; score 3: aHR, 1.09; 95% CI, 1.05-1.14; score 4: aHR, 1.12; 95% CI, 1.06-1.19). Persistent IFG exposure was also associated with higher risks of individual cancer types (colorectum, stomach, pancreas, biliary tract, and esophagus). CONCLUSIONS: Cumulative exposure to IFG is associated with an increased risk of developing gastrointestinal cancer, in a dose-dependent manner. PLAIN LANGUAGE SUMMARY: Hyperglycemia, including both diabetes and prediabetes, has been associated with an increased risk of various cancers. However, the cumulative effect of impaired fasting glucose on the risk of developing gastrointestinal cancer remains unclear. A frequent diagnosis of impaired fasting glucose was dose-dependently associated with a higher risk of developing overall gastrointestinal cancer. Furthermore, risks of individual cancer types increased with persistent impaired fasting glucose. Early detection of hyperglycemia and strict glycemic control can lower the risk of gastrointestinal cancer by reducing hyperglycemic burden. Additionally, for some individuals, lifestyle changes such as managing metabolic syndrome or abstaining from alcohol may also be helpful.
Assuntos
Glicemia , Jejum , Neoplasias Gastrointestinais , Humanos , Masculino , Feminino , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/etiologia , Pessoa de Meia-Idade , Jejum/sangue , Glicemia/metabolismo , Glicemia/análise , República da Coreia/epidemiologia , Fatores de Risco , Adulto , Idoso , Estudos de CoortesRESUMO
BACKGROUND: It appears that tumour-infiltrating neoantigen-reactive CD8 + T (Neo T) cells are the primary driver of immune responses to gastrointestinal cancer in patients. However, the conventional method is very time-consuming and complex for identifying Neo T cells and their corresponding T cell receptors (TCRs). METHODS: By mapping neoantigen-reactive T cells from the single-cell transcriptomes of thousands of tumour-infiltrating lymphocytes, we developed a 26-gene machine learning model for the identification of neoantigen-reactive T cells. RESULTS: In both training and validation sets, the model performed admirably. We discovered that the majority of Neo T cells exhibited notable differences in the biological processes of amide-related signal pathways. The analysis of potential cell-to-cell interactions, in conjunction with spatial transcriptomic and multiplex immunohistochemistry data, has revealed that Neo T cells possess potent signalling molecules, including LTA, which can potentially engage with tumour cells within the tumour microenvironment, thereby exerting anti-tumour effects. By sequencing CD8 + T cells in tumour samples of patients undergoing neoadjuvant immunotherapy, we determined that the fraction of Neo T cells was significantly and positively linked with the clinical benefit and overall survival rate of patients. CONCLUSION: This method expedites the identification of neoantigen-reactive TCRs and the engineering of neoantigen-reactive T cells for therapy.
Assuntos
Antígenos de Neoplasias , Linfócitos T CD8-Positivos , Neoplasias Gastrointestinais , Linfócitos do Interstício Tumoral , Aprendizado de Máquina , Análise de Célula Única , Humanos , Linfócitos T CD8-Positivos/imunologia , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Análise de Célula Única/métodos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , TranscriptomaRESUMO
BACKGROUND: Patients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival. METHODS: We explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria. RESULTS: Most ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%). CONCLUSIONS: About one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture. CLINICAL TRIAL REGISTRATION: NCT00116935.