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Resección Endoscópica de la Mucosa , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Várices Esofágicas y Gástricas , Humanos , Carcinoma de Células Escamosas de Esófago/complicaciones , Carcinoma de Células Escamosas de Esófago/cirugía , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/cirugía , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/cirugía , Neoplasias Esofágicas/patología , Cicatriz/patología , Resultado del TratamientoRESUMEN
Chimeric antigen receptor (CAR)-T cell therapy is a promising form of immunotherapy that has seen significant advancements in the past few decades. It involves genetically modifying T cells to target cancer cells expressing specific antigens, providing a novel approach to treating various types of cancer. However, the initial success of first-generation CAR-T cells was limited due to inadequate proliferation and undesirable outcomes. Nonetheless, significant progress has been made in CAR-T cell engineering, leading to the development of the latest fifth-generation CAR-T cells that can target multiple antigens and overcome individual limitations. Despite these advancements, some shortcomings prevent the widespread use of CAR-T therapy, including life-threatening toxicities, T-cell exhaustion, and inadequate infiltration for solid tumors. Researchers have made considerable efforts to address these issues by developing new strategies for improving CAR-T cell function and reducing toxicities. This review provides an overview of the path of CAR-T cell development and highlights some of the prominent advances in its structure and manufacturing process, which include the strategies to improve antigen recognition, enhance T-cell activation and persistence, and overcome immune escape. Finally, the review briefly covers other immune cells for cancer therapy and ends with the discussion on the broad prospects of CAR-T in the treatment of various diseases, not just hematological tumors, and the challenges that need to be addressed for the widespread clinical application of CAR-T cell therapies.
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BACKGROUND: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease that results in the tissue destruction of multiple organs. IgG4-RD is often underdiagnosed or misdiagnosed as malignant, infectious, or other inflammatory disorder. CASE PRESENTATION: We describe a 56-year-old woman presented with jaundice and weight loss. Radiological imaging showed common hepatic duct wall thickening and nodular lesions in the pancreas, which was highly suspicious of malignancy. However, she was contraindicated for biopsy; hence, the diagnosis of IgG4-RD was made based on her high serum IgG4 level, multiorgan involvement, and steroid response. The effect of steroid therapy was significant, although the disease relapsed during the maintenance treatment. The dosage of steroid was re-increased, and the patient was under close follow-up. CONCLUSIONS: The diagnosis of IgG4-RD is challenging due to its diverse manifestations. Therefore, a careful systematic assessment is necessary to improve the accuracy of IgG4-RD diagnosis, and a close follow-up is important to monitor the disease development as well as adjust the treatment strategy accordingly.
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Autoimmune metaplastic atrophic gastritis (AMAG) is associated with an increased risk of gastric neoplasms. This study aimed to systematically analyze the incidence rate of gastric cancer (GC), low-grade dysplasia (LGD) and type-1 gastric neuroendocrine tumor (gNETs) development in AMAG adults. Studies on AMAG patients reporting the incidence of gastric neoplasms was identified through a systematic search in PUBMED and EMBASE. Study quality was assessed using the Joanna Briggs Institute quality assessment tool. Incidence rates of GC, LGD and type-1 gNETs were examined by meta-analysis. Thirteen studies met eligibility criteria. Incidence rate of gastric cancer calculated from the pooled data was 0.14% per person-year in both single-center studies and national registration studies. Meta-analysis showed a relative risk of 11.05 (95% CI: 6.39-19.11) for gastric cancer development in AMAG patients. The calculated pooled gastric LGD and type-1 gNETs incidence rates were 0.52% and 0.83% per person-year, respectively. As for experience from our center, we presented three distinctive cases of gastric neoplasm arising from the background of AMAG. This study underscores the potential for malignant transformation of precancerous lesions and reiterates the importance of careful esophagogastroduodenoscopy screening.
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The USDA-FSIS has zero tolerance for E. coli O157:H7 in raw ground beef. Currently, FSIS collects samples from beef processing facilities and ships them overnight to regional testing laboratories. Pathogen detection requires robust methods that employ an initial 15-24 h culture enrichment. This study assessed the potential of using the ΦV10nluc phage-based luminescence detection assay during enrichment while the sample is in transit. Parameters including phage concentrations, temperature, and media-to-sample ratios were evaluated. Results in liquid media showed that 1.73× 103 pfu/mL of ΦV10nluc was able to detect 2 CFU in 10 h. The detection of E. coli O157:H7 was further evaluated in kinetic studies using ratios of 1:3, 1:2, and 1:1 ground beef sample to enrichment media, yielding positive results for as little as 2-3 CFU in 325 g ground beef in about 15 h at 37 °C. These results suggest that this approach is feasible, allowing the detection of a presumptive positive upon arrival of the sample to the testing lab. As the current cargo hold controlled temperature is required to be 15-25 °C, the need for elevated temperature should be easily addressed. If successful, this approach could be expanded to other pathogens and foods.
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ß-Thalassemia (ß-thal) is one of the most common monogenic recessive inherited diseases worldwide. The mutation spectrum of ß-thal has been increasingly broadened by various genetic testing methods. The discovery and identification of novel and rare pathogenic thalassemia variants enable better disease prevention, especially in high prevalence regions. In this study, a Chinese thalassemia family with an unclear etiology was recruited to the Thalassemia Screening Program. Blood samples collected from them were primarily screened by hematology analysis and clinical routine genetic screening. Subsequently, targeted next-generation sequencing (NGS) and Sanger sequencing were performed to find and identify a novel deletion variant. The deletion, discovered by targeted NGS, was validated through real-time quantitative polymerase chain reaction (qPCR). First, a large novel ß-thal deletion (3488 bp) related to a high Hb F level, NC_000011.9: g.5245533_5249020del (Chongqing deletion) (GRCh37/hg19), was found and identified in the proband and her mother. The deletion removed the entire ß-globin gene and led to absent ß-globin (ß0). We then validated this large novel deletion in the proband and her mother by qPCR. We first discovered and identified a large novel ß-thal deletion related to elevated Hb F level, it helps broaden the spectrum of pathogenic mutants that may cause ß-thal intermedia (ß-TI) or ß-thal major (ß-TM), paving the way for effective thalassemia screening. Next-generation sequencing has the potential of finding rare and novel thalassemia mutants.
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Talasemia beta , Femenino , Humanos , Talasemia beta/diagnóstico , Talasemia beta/genética , Mutación , Globinas beta/genética , Alelos , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
The initiation of flowering in cereals is a critical process influenced by environmental and endogenous signals. Flowering Locus T-like (FT-like) genes encode the main signals for flowering. Of the 13 FT-like genes in the rice genome, Hd3a/OsFTL2 and RFT1/OsFTL3 have been extensively studied and revealed to be critical for flowering. In this study, a rice FT-like gene, OsFTL4, was functionally characterized. Specifically, osftl4 mutants were generated using a CRISPR/Cas9 system. Compared with the wild-type control (Guangluai 4), the osftl4-1 and osftl4-2 mutants flowered 9.6 and 5.8 days earlier under natural long-day and short-day conditions, respectively. Additionally, OsFTL4 was mainly expressed in the vascular tissue, with the resulting OsFTL4 protein localized in both the nucleus and cytoplasm. Furthermore, OsFTL4 was observed to compete with Hd3a for the interaction with multiple 14-3-3 proteins. An analysis of the effects of simulated drought stress suggested that silencing OsFTL4 enhances drought tolerance by decreasing stomatal conductance and water loss. These results indicate that OsFTL4 helps integrate the flowering process and the drought response in rice.
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Grain weight is a key trait that determines rice quality and yield, and it is primarily controlled by quantitative trait loci (QTL). Recently, attention has been paid to minor QTLs. A minor effect QTL qTGW7 that controls grain weight was previously identified in a set of chromosomal fragment substitution lines (CSSLs) derived from Nipponbare (NPB)/93-11. Compared to NPB, the single segment substitution line (SSSL) N83 carrying the qTGW7 introgression exhibited an increase in grain length and width and a 4.5% increase in grain weight. Meanwhile, N83 was backcrossed to NPB to create a separating population, qTGW7b, a QTL distinct from qTGW7, which was detected between markers G31 and G32. Twelve near-isogenic lines (NILs) from the BC9F3 population and progeny of five NILs from the BC9F3:4 population were genotyped and phenotyped, resulting in the fine mapping of the minor effect QTL qTGW7b to the approximately 86.2-kb region between markers G72 and G32. Further sequence comparisons and expression analysis confirmed that five genes, including Os07g39370, Os07g39430, Os07g39440, Os07g39450, and Os07g39480, were considered as the candidate genes underlying qTGW7b. These results provide a crucial foundation for further cloning of qTGW7b and molecular breeding design in rice.
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Oryza , Sitios de Carácter Cuantitativo , Mapeo Cromosómico , Cromosomas de las Plantas/genética , Grano Comestible/genética , Oryza/genéticaRESUMEN
BACKGROUND: Esophageal neuroendocrine carcinoma (ENEC) is an extremely rare type of malignancy. Clinical data of ENEC are limited to case reports and case series. More information is needed on its clinical feature, management, and prognosis. METHODS: This study collected information of ENEC patients diagnosed pathologically from 2010 to 2018. Data including demographic information, clinical features, and survival trends were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Statistical analyses were performed with STATA/SE 15.1, SPSS 25.0, and GraphPad Prism 8. RESULTS: A total of 283 ENEC patients were included in this study. The small-cell and large-cell subtypes of ENEC possess similar clinical features. The lower third of the esophagus (58%) was the most common location of ENEC. At the time of diagnosis, most ENEC patients were AJCC 7th stage IV (48.1%). Metastasis occurred in more than half of the ENEC patients (53.4%), and the most common metastatic site was the liver (37.1%). Compared with poorly differentiated esophageal squamous cell carcinoma (ESCC), another aggressive malignancy of the esophagus sometimes confused with ENEC because of similar histological features, our study showed differences in tumor location and metastatic rate, but similar poor survival rates. Multivariate survival analysis showed that ENEC located at the middle third of esophagus (p = 0.013), "Brain metastasis" (p = 0.019), and "Liver metastasis" (p < 0.001) were independent predictors of worse outcomes. "Surgery" (p = 0.003), and "Chemotherapy" (p < 0.001) were associated with better survival. CONCLUSION: A significant proportion of patients with newly diagnosed ENEC presented with metastatic disease. Predictors of poor survival included tumor location, brain metastasis, and liver metastasis. ENEC and poorly differentiated ESCC share certain histological features, but differ in tumor location and metastatic rate. Yet, no standard treatment strategy has been established, but surgery and chemotherapy were related to better outcomes.
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Carcinoma Neuroendocrino , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas de Esófago/patología , Pronóstico , Estadificación de Neoplasias , Carcinoma Neuroendocrino/epidemiología , Carcinoma Neuroendocrino/terapia , Tasa de SupervivenciaRESUMEN
Cancer stem cells (CSCs) are a subpopulation of cancer cells that drive tumour progression and metastasis. Anti-CSC strategies represent new targets for cancer therapies. However, CSCs are highly plastic and heterogeneous, making validation and targeting difficult without bona fide markers that define their identity, especially in a clinical setting. Here, we report that a leucine-rich repeat containing G protein-coupled receptor 4 (LGR4) cooperates with CD44 and PrPc; the latter contributes significantly to metastatic capacity and defines the stemness characteristics of colorectal CSCs. CD44+PrPc+LGR4+ cells effectively developed into organoids and, when transplanted, generated orthotopic and metastatic tumours. Importantly, targeting LGR4 and PrPc with lentiviral shRNAs inhibited organoid development and the growth of orthotopic tumours by inhibiting Wnt/ß-catenin signalling. Thus, our study offers a novel therapeutic strategy that simultaneously targets CSC stemness and metastatic properties.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Células Madre Neoplásicas/patología , Receptores Acoplados a Proteínas G/genética , Vía de Señalización WntRESUMEN
Colorectal cancer (CRC) has a high prevalence and mortality rate globally. To date, the progression mechanisms of CRC are still elusive. Exosomes (~100 nm in diameter) correspond to a subset of extracellular vesicles formed by an array of cancerous cells and stromal cells. These particular nanovesicles carry and transmit bioactive molecules, like proteins, lipids, and genetic materials, which mediate the crosstalk between cancer cells and the microenvironment. Accumulating evidence has shown the decisive functions of exosomes in the development, metastasis, and therapy resistance of CRC. Furthermore, some recent studies have also revealed the abilities of exosomes to function as either biomarkers or therapeutic targets for CRC. This review focuses on the specific mechanisms of exosomes in regulating CRC progression and summarizes the potential clinical applications of exosomes in the diagnosis and therapy of CRC.
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Neoplasias Colorrectales , Exosomas , Vesículas Extracelulares , Biomarcadores/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Exosomas/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Microambiente TumoralRESUMEN
BACKGROUND: Dysbacteriosis may be a crucial environmental factor for ulcerative colitis (UC). Further study is required on microbiota alterations in the gastrointestinal tract of patients with UC for better clinical management and treatment. AIM: To analyze the relationship between different clinical features and the intestinal microbiota, including bacteria and fungi, in Chinese patients with UC. METHODS: Eligible inpatients were enrolled from January 1, 2018 to June 30, 2019, and stool and mucosa samples were collected. UC was diagnosed by endoscopy, pathology, Mayo Score, and Montreal classification. Gene amplicon sequencing of 16S rRNA gene and fungal internal transcribed spacer gene was used to detect the intestinal microbiota composition. Alpha diversity, principal component analysis, similarity analysis, and Metastats analysis were employed to evaluate differences among groups. RESULTS: A total of 89 patients with UC and 33 non-inflammatory bowel disease (IBD) controls were enrolled. For bacterial analysis, 72 stool and 48 mucosa samples were obtained from patients with UC and 21 stool and 12 mucosa samples were obtained from the controls. For fungal analysis, stool samples were obtained from 43 patients with UC and 15 controls. A significant difference existed between the fecal and mucosal bacteria of patients with UC. The α-diversity of intestinal bacteria and the relative abundance of some families, such as Lachnospiraceae and Ruminococcaceae, decreased with the increasing severity of bowel inflammation, while Escherichia-Shigella showed the opposite trend. More intermicrobial correlations in UC in remission than in active patients were observed. The bacteria-fungi correlations became single and uneven in patients with UC. CONCLUSION: The intestinal bacteria flora of patients with UC differs significantly in terms of various sample types and disease activities. The intermicrobial correlations change in patients with UC compared with non-IBD controls.
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Colitis Ulcerosa , Microbioma Gastrointestinal , China/epidemiología , Colitis Ulcerosa/diagnóstico , Disbiosis , Heces , Humanos , Mucosa Intestinal , ARN Ribosómico 16S/genéticaRESUMEN
α-Thalassemia (α-thal) is one of the most common genetic diseases in Southern China. Although more than 300 α-thal mutations have been reported in the world, the mutation spectrum is still not comprehensive. In this study, a novel mutation (HBA1: c.349G>T) in a newborn (proband) was first found by next-generation sequencing (NGS). Subsequently, hematological analysis and thalassemia genetic testing were performed for the family members. The results showed that both the proband and her mother were heterozygotes for this novel mutation and presented abnormal hematological indices. Based on the features observed in clinical practice, this novel mutation was considered as a type of α-thal variation.
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Talasemia alfa , Talasemia beta , Femenino , Hemoglobina Glucada , Heterocigoto , Humanos , Recién Nacido , Mutación , Talasemia alfa/genéticaRESUMEN
BACKGROUND AND OBJECTIVE: Small bowel adenocarcinoma (SBA) is a rare malignant tumor with a poor prognosis. Most patients with SBA are diagnosed with advanced-stage disease. Due to the lack of randomized controlled trials and prospective studies, it is difficult to predict the prognosis of patients with SBA. Thus, this study aimed to establish a prognostic nomogram for evaluating the prognosis of SBA patients. METHODS: The clinical features and follow-up data of all patients diagnosed with SBA during 2004-2016 were summarized from the Surveillance, Epidemiology, and End Results (SEER) database. We separated these patients into training and validation groups. Multivariate Cox regression analyses were performed to identify independent prognostic variables for predicting cancer-specific survival (CSS) and overall survival (OS). According to the independent risk factors, we established nomograms and used the calibration curves to evaluate the accuracy. RESULTS: The data of 3301 patients with SBA were collected from the SEER database. The multivariate analysis showed that age, marital status, tumor site, grade, TNM stage and surgical history were associated with CSS and OS (P < 0.05). Based on these results, we established nomograms of CSS and OS that can predict the 3- and 5-year survival rates of SBA patients (C-index > 0.7). The calibration curves showed that the predicted survival was very close to the actual survival. CONCLUSION: We analyzed the independent risk factors for prognosis of SBA patients, and established nomograms to predict the 3- and 5-year survival rates of OS and CSS. These new prognostic tools can help clinicians to predict the survival of patients with SBA, further to guide treatment strategy.
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Adenocarcinoma , Neoplasias Intestinales , Intestino Delgado , Nomogramas , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Humanos , Neoplasias Intestinales/mortalidad , Neoplasias Intestinales/patología , Intestino Delgado/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Programa de VERF , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Thyroid Hurthle cell carcinoma (HCC) is a rare disease with high risk of invasion and metastasis and poor prognosis. The clinical characteristics, prognosis and treatment of HCC are still controversial, and clinical data are still limited to some case reports. Therefore, understanding the characteristics and survival factors of HCC is clinically necessary. METHODS: This study collected data from HCC patients diagnosed pathologically from 2004 to 2015, including basic population characteristics, tumor characteristics, and epidemiological and survival data. The data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database to conduct a population cohort study. RESULTS: A total of 2101 HCC patients with an average age of 55.42 ± 15.27 years were enrolled in this study. Of them, 1740 (82.82%) patients had local disease, 245 (11.66%) had regional disease, and 89 (4.24%) had distant disease. Total thyroidectomy was performed in 1669 (79.44%) patients, partial thyroidectomy was performed in 382 (18.18%) patients, and radioactive iodine (RAI) was used in 1155 (54.97%) patients. The 5-year and 10-year cancer-specific survival rate was 95.4 and 92.6%, respectively. The distant disease group had significantly more male patients, multifocal tumors, and extensive tumors compared to the local disease group. Multivariate survival analysis showed that age (P < 0.05), SEER stage (P < 0.001), and T-stage (P = 0.001) had significant effects on survival. There was no significant difference in survival between total and partial thyroidectomy (P = 0.078), or between RAI and non-RAI (P = 0.733). CONCLUSION: Male gender, multifocal tumors, and extended tumors are associated with increased risk of late stage HCC. Age over 45 years, distant SEER stage, and late T-stage are independent risk factors for mortality in HCC.
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Adenocarcinoma Folicular/patología , Adenoma Oxifílico/patología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Neoplasias de la Tiroides/patología , Tiroidectomía/métodos , Adenocarcinoma Folicular/cirugía , Adenoma Oxifílico/cirugía , Carcinoma Hepatocelular/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Programa de VERF , Tasa de Supervivencia , Neoplasias de la Tiroides/cirugíaRESUMEN
BACKGROUND: To examine the tumor characteristics, treatments and survival outcomes of prostate cancer (PCa) patients with a prostate-specific antigen (PSA) level < 4 ng/ml. METHODS: Of 205,913 men with primary prostate adenocarcinoma in the Surveillance, Epidemiology and End Results (SEER) database (2010 to 2015), 24,054 (11.68%) patients were diagnosed with a PSA level < 4 ng/ml. Comparisons of categorical variables among different groups were performed by using the Chi square test. Multivariate Cox regression analysis was adjusted for age, ethnicity, marital status, insurance status, TNM stage, Gleason grade, treatment and survival. Kaplan-Meier survival curves were constructed for overall mortality and tested by the log-rank test. RESULTS: PCa patients with a PSA level < 4 ng/ml generally had more favorable tumor characteristics: younger, lower T stage, lower Gleason grade and lower lymph node metastasis rate. However, there were more patients in stage M1 in the group of PSA level < 4 ng/ml than that in the groups of PSA level of 4-10 ng/ml, 10-20 ng/ml and > 20 ng/ml. The multivariate Cox regression model revealed that overall mortality was associated with age, marital status, race, Gleason grade, M stage and treatment approach. CONCLUSIONS: In conclusion, PCa patients with a PSA level < 4 ng/ml have more favorable tumor characteristics at diagnosis and receive more benefit from active treatment. However, those patients with advanced TNM stage and high Gleason grade should be paid more attention in clinical application.
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Adenocarcinoma/mortalidad , Biomarcadores de Tumor/sangre , Antígeno Prostático Específico/sangre , Prostatectomía/mortalidad , Neoplasias de la Próstata/mortalidad , Adenocarcinoma/sangre , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Estudios de Seguimiento , Humanos , Masculino , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Programa de VERF , Tasa de SupervivenciaRESUMEN
In this study, two chlorophyll A/B binding protein (CAB) genes (CsCP1 and CsCP2) in tea plant were cloned. The proteins encoded by these genes belong to the external or internal antenna proteins of PS II, respectively. They may be the targets of physiological regulation for tea leaf cell PS II because they all contain multiple functional domains and modifiable sites. The CAB gene family in the tea genome consists of 25 homologous genes. We measured the expression patterns of ten genes in the CsCP1 and CsCP2 subfamily under six different stresses. CsCP1 expression was inhibited in response to 6 kinds of stress; CsCP2 expression was slightly upregulated only after cold stress and ABA treatment. However, the expression levels of CSA016997 and CSA030476 were upregulated significantly in the six stresses. The results suggested that the 10 CAB genes may have different functions in tea leaves. Moreover, changes in the expression of the 10 genes under stress appear to be related to ABA- and MeJA-dependent signalling pathways, and their responses to MeJA treatment is faster than those to ABA. In addition, we introduced our experiences for cloning the genes in the context of complex genomes.
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Camellia sinensis/genética , Proteínas de Unión a Clorofila/genética , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Familia de Multigenes , Camellia sinensis/metabolismo , Proteínas de Unión a Clorofila/química , Proteínas de Unión a Clorofila/metabolismo , Clonación Molecular , Perfilación de la Expresión Génica , Modelos Moleculares , Fotosíntesis/genética , Filogenia , Conformación Proteica , Relación Estructura-Actividad , TranscriptomaRESUMEN
BACKGROUND: Neuroendocrine neoplasm is a rare solid tumor. Metastatic pattern of the gastrointestinal neuroendocrine neoplasm (GI-NEN) has not been fully explored. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (SEER-9 registry) from 1973 to 2015. Incidence was estimated by Joinpoint regression analyses. Data with additional treatment fields of GI-NEN were extracted from the SEER-18 registry from 1 January 2010 to 31 December 2015. A total of 14 685 GI-NEN patients were included in this study. Statistical analyses were performed with SPSS 25.0, the Intercooled Stata SE 15.0, and GraphPad Prism 7. RESULTS: Incidence of GI-NENs increased from 0.51 per 100 000 patients in 1973 to 6.20 per 100 000 patients in 2015. Of them, 2003 patients were stage IV GI-NEN at the time of diagnosis, including 1459 (72.84%) patients with liver metastasis, 144 (7.19%) lung metastasis, 115 (5.74%) bone metastasis, and 27 (1.35%) brain metastasis. Esophageal NEN had the highest risk of metastasis (52.68%). The median survival for patients with liver, lung, bone, and brain metastasis was 38, 6, 9, and 2 months, respectively. The presence of lung or liver metastasis indicated higher risk of concurrent existence of bone and brain metastasis than those without. CONCLUSION: Bone and brain metastasis should be screened in the GI-NEN patients if they had lung or liver metastasis. Findings of the current study could help clinicians to identify distant metastasis of GI-NENs as early as possible, and by which, to improve survival rate of GI-NENs.