Digestive Tract Cancer Research Articles

Deep Learning Radiomics Model of Contrast-Enhanced CT for Differentiating the Primary Source of Liver Metastases

Rationale and ObjectivesTo develop and validate a deep learning radiomics (DLR) model based on contrast-enhanced computed tomography (CT) to identify the primary source of liver metastases. Materials and MethodsIn total, 657 liver metastatic lesions, including breast cancer (BC), lung cancer (LC), colorectal cancer (CRC), gastric cancer (GC), and pancreatic cancer (PC), from 428 patients were collected at three clinical centers from January 2018 to October 2023 series. The lesions were randomly assigned to the training and validation sets in a 7:3 ratio. An additional 112 lesions from 61 patients at another clinical center served as an external test set. A DLR model based on contrast-enhanced CT of the liver was developed to distinguish the five pathological types of liver metastases. Stepwise classification was performed to improve the classification efficiency of the model. Lesions were first classified as digestive tract cancer (DTC) and non-digestive tract cancer (non-DTC). DTCs were divided into CRC, GC, and PC and non-DTCs were divided into LC and BC. To verify the feasibility of the DLR model, we trained classical machine learning (ML) models as comparison models. Model performance was evaluated using accuracy (ACC) and area under the receiver operating characteristic curve (AUC). ResultsThe classification model constructed by the DLR algorithm showed excellent performance in the classification task compared with ML models. Among the five categories task, highest ACC and average AUC were achieved at 0.563 and 0.796 in the validation set, respectively. In the DTC and non-DTC and the LC and BC classification tasks, AUC was achieved at 0.907 and 0.809 and ACC was achieved at 0.843 and 0.772, respectively. In the CRC, GC, and PC classification task, ACC and average AUC were the highest, at 0.714 and 0.811, respectively. ConclusionThe DLR model is an effective method for identifying the primary source of liver metastases.

Abstract PO3-09-03: Dysbiosis of gut microbiota in patients with breast cancer

Abstract [Background] The effects of gut microbiome on various diseases have become widely known, and many studies reported that there was a correlation between the change of gut microbiota, that is dysbiosis, and the progression of digestive tract cancer. In addition, it is well-known that gut microbiota was correlated to the efficacy of immune checkpoint inhibitors for multiple types of cancer. However, the significance of gut microbiota in patients with breast cancer still remains unclear. The aim of this study is to analyze the gut microbiota in patients with breast cancer, compared with healthy women. [Subjects and Methods] We used the pre-treatment feces of 79 patients with primary breast cancer who received treatment at our facility and performed metagenome analysis of the V3-4 region of 16S rDNA. We also analyzed the breast cancer patients' microbiota with QIIME2 analysis method, compared to randomly selected 100 women aged 30-77 years from NIBIOHN's public data . We also assessed the characteristics of the gut microbiota of breast cancer patients by subtypes and its relationship with clinical and pathological factors. [Results] In Japanese gut microbiota, the Firmicutes and Bacteroidetes phyla make up the majority, but Firmicutes was the most common bacterial phylum in 52% of the public cohort, whereas 96.2% (76/79) of the breast cancer patients’ group (BC) showed a significantly higher proportion (p< 0.0001). In addition, ANCOM analysis revealed that the relative bacterial amounts of the Firmicutes, Bacteroidetes, and Proteobacteria phyla were significantly decreased in BC compared to the public cohort (PC), and at the bacterial genus level, the Feacalibacterium genus was significantly decreased in BC. Furthermore, the percentage of Fusobacteria phylum, which is a well-known oral bacteria that exacerbates digestive tract cancer, was 49.3% in BC, compared to 35% in PC (p=0.04). Among BC, the relative frequency of Fusobacteria phylum was significantly higher in the HER2-negative group than in the HER2-positive group (p< 0.0001). In BC, both alpha diversity (p< 0.0001) and beta diversity (p=0.001) were significantly lower than in PC. [Conclusion] An increase in the Firmicutes phylum is known to be associated with obesity, and also likely to affect the incidence risk of breast cancer. The results suggest that the Fusobacteria phylum and Feacalibacterium genus may be risk or preventive factors for breast cancer. Dysbiosis of gut microbiota is suggested to be associated with various diseases, and in this study the decrease in bacterial amount and diversity was observed in BC compared to PC, which may affect the onset and progression of breast cancer. Citation Format: Mai Yamada, Takafumi Morisaki, Yo Sato, Kimihisa Mizoguchi, Yuka Takao, Yurina Ochiai, Yoshiki Ootubo, Saori Hayashi, Masafumi Nakamura, Makoto Kubo. Dysbiosis of gut microbiota in patients with breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-09-03.

The Role of Delirium on Short- and Long-Term Postoperative Outcomes Following Major Gastrointestinal Surgery for Cancer.

The growing burden of an aging population has raised concerns about demands on healthcare systems and resources, particularly in the context of surgical and cancer care. Delirium can affect treatment outcomes and patient recovery. We sought to determine the prevalence of postoperative delirium among patients undergoing digestive tract surgery for malignant indications and to analyze the role of delirium on surgical outcomes. Medicare claims data were queried to identify patients diagnosed with esophageal, gastric, hepatobiliary, pancreatic, and colorectal cancers between 2018 and 2021. Postoperative delirium, occurring within 30 days of operation, was identified via International Classification of Diseases, 10th edition codes. Clinical outcomes of interested included "ideal" textbook outcome (TO), characterized as the absence of complications, an extended hospital stay, readmission within 90 days, or mortality within 90 days. Discharge disposition, intensive care unit (ICU) utilization, and expenditures also were examined. Among 115,654 cancer patients (esophageal: n = 1854, 1.6%; gastric: n = 4690, 4.1%; hepatobiliary: n = 6873, 5.9%; pancreatic: n = 8912, 7.7%; colorectal: n = 93,325, 90.7%), 2831 (2.4%) were diagnosed with delirium within 30 days after surgery. On multivariable analysis, patients with delirium were less likely to achieve TO (OR 0.27 [95% CI 0.25-0.30]). In particular, patients who experienced delirium had higher odds of complications (OR 3.00 [2.76-3.25]), prolonged length of stay (OR 3.46 [3.18-3.76]), 90-day readmission (OR 1.96 [1.81-2.12]), and 90-day mortality (OR 2.78 [2.51-3.08]). Furthermore, patients with delirium had higher ICU utilization (OR 2.85 [2.62-3.11]). Upon discharge, patients with delirium had a decreased likelihood of being sent home (OR 0.40 [0.36-0.46]) and instead were more likely to be transferred to a skilled nursing facility (OR 2.17 [1.94-2.44]). Due to increased utilization of hospital resources, patients with delirium incurred in-hospital expenditures that were 55.4% higher (no delirium: $16,284 vs. delirium: $28,742) and 90-day expenditures that were 100.7% higher (no delirium: $2564 vs. delirium: $8226) (both p < 0.001). Notably, 3-year postoperative survival was adversely affected by delirium (no delirium: 55.5% vs. delirium: 37.3%), even after adjusting risk for confounding factors (HR 1.79 [1.70-1.90]; p < 0.001). Postoperative delirium occurred in one in 50 patients undergoing surgical resection of a digestive tract cancer. Delirium was linked to a reduced likelihood of achieving an optimal postoperative outcome, increased ICU utilization, higher expenditures, and a worse long-term prognosis. Initiatives to prevent delirium are vital to improve postoperative outcomes among cancer surgery patients.

S100 protein family: Emerging role and mechanism in digestive tract cancer (Review).

Digestive tract cancer is one of the most common types of cancers globally, with ~4.8 million new cases and 3.4 million cancer‑associated deaths in 2018, accounting for 26% of cancer incidence and 35% of cancer‑related deaths worldwide. S100 protein family is involved in regulating cancer cell proliferation, angiogenesis, epithelial‑mesenchymal transition (EMT), metastasis, metabolism and immune microenvironment homeostasis. The critical role of S100 protein family in digestive tract cancer involves complicated mechanisms, such as cancer stemness remodeling, anaerobic glycolysis regulation, tumor‑associated macrophage differentiation and EMT. The present study systematically reviewed published studies on the compositions, function and the underlying molecular mechanisms of the S100 family, as well as guidance for diagnosis, treatment and prognosis of digestive tract cancer. Systematic review of the roles and underlying molecular mechanisms of S100 protein family may provide new insight into exploring potential cancer biomarkers and the optimized therapeutic strategies for digestive tract cancer.

Development of an efficient liposomal DOX delivery formulation for HCC therapy by targeting CK2α.

Hepatocellular carcinoma (HCC) is a digestive tract cancer with high mortality and poor prognosis, especially in China. Current chemotherapeutic drugs lead to poor prognosis, low efficacy, and high side effects due to weak targeting specificity and rapidly formed multidrug resistance (MDR). Based on the previous studies on the doxorubicin (DOX) formulation for cancer targeting therapy, we developed a novel DOX delivery formulation for the targeting chemotherapy of HCC and DOX resistant HCC. HCSP4 was previously screened and casein kinase 2α (CK2α) was predicted as its specific target on HCC cells in our lab. In the study, miR125a-5p was firstly predicted as an MDR inhibiting miRNA, and then CK2α was validated as the target of HCSP4 and miR125a-5p using CK2α-/-HepG2 cells. Based on the above, an HCC targeting and MDR inhibiting DOX delivery liposomal formulation, HCSP4/Lipo-DOX/miR125a-5p was synthesized and tested for its HCC therapeutic efficacy in vitro. The results showed that the liposomal DOX delivery formulation targeted to HCC cells specifically and sensitively, and presented the satisfied therapeutic efficacy for HCC, particularly for DOX resistant HCC. The potential therapeutic mechanism of the DOX delivery formulation was explored, and the formulation inhibited the expression of MDR-relevant genes including ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein), ATP-binding cassette subfamily C member 5 (ABCC5), enhancer of zeste homolog 2 (EZH2), and ATPase Na+/K+ transporting subunit beta 1 (ATP1B1). Our study presents a novel targeting chemotherapeutic drug formulation for the therapy of HCC, especially for drug resistant HCC, although it is primarily and needs further study in vivo, but provided a new strategy for the development of novel anticancer drugs.

Interaction of Vitamin D Supplements and Marine n-3 Fatty Acids on Digestive Tract Cancer Prognosis.

A meta-analysis suggested that marine n-3 polyunsaturated fatty acids (PUFAs), e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), might reduce cancer mortality. However, a randomized clinical trial of marine n-3 PUFA and vitamin D supplementation failed to verify this benefit. This study aimed to investigate the potential interaction between vitamin D supplementation and serum EPA and DHA levels. This post hoc analysis of the AMATERASU trial (UMIN000001977), a randomized controlled trial (RCT), included 302 patients with digestive tract cancers divided into two subgroups stratified by median serum levels of EPA + DHA into higher and lower halves. The 5-year relapse-free survival (RFS) rate was significantly higher in the higher half (80.9%) than the lower half (67.8%; hazard ratio (HR), 2.15; 95% CI, 1.29-3.59). In the patients in the lower EPA + DHA group, the 5-year RFS was significantly higher in the vitamin D (74.9%) than the placebo group (49.9%; HR, 0.43; 95% CI, 0.24-0.78). Conversely, vitamin D had no effect in the higher half, suggesting that vitamin D supplementation only had a significant interactive effect on RFS in the lower half (p for interaction = 0.03). These results suggest that vitamin D supplementation may reduce the risk of relapse or death by interacting with marine n-3 PUFAs.

Digestive Tract Cancers: Epidemiological, Anatomical and Clinical Aspects and Management at Conakry Hospital

Introduction: Digestive cancers represent between 10 and 50% of all cancers and therefore occupy a preponderant place in digestive surgery departments. Our general objective was to study the epidemiological, anatomo-clinical and therapeutic aspects of cancers of the digestive tract at the Conakry University Hospital. Methodology: This was a retrospective descriptive study covering a period of 6 years, from January 1, 2014 to December 31, 2019. Result: the hospital prevalence of cancers of the digestive tract was 6.34% with a male predominance of 54% and a sex ratio of 1.17. The average age was 52.7 years with the extremes of 13 and 84 years and 57% resided in Conakry. Alcohol and tobacco are the most popular stimulants. The most frequent reasons for consultations were epigastralgia 64.31%, vomiting / nausea 44.11%, Stomach and colon cancers were the most represented, i.e. 40.07% and 30.30% respectively. The treatment was curative (surgery) in 85.19% of cases and the outcome was favorable in almost three quarters of cases, or 71.04% of cases. We have 71 registered death cases. Conclusion: Cancers of the digestive tract remain non-negligible in our country and that of the stomach is the most common. The hope lies in equipping structures with proximity and adequate infrastructure for diagnosis and with consequent therapeutic means (radiotherapy), as well as raising awareness of early diagnosis within the community.

Post-Pandemic Burden of COVID-19-Related Restrictions in the Management of Digestive Tract Cancers: A Single Center Study.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has required a complete change in the management of patients with gastrointestinal disease who needed to undergo endoscopic procedures. In the second year of the COVID-19 pandemic, due to restrictions for elective endoscopic procedures, a large number of cancer patients were prevented from early diagnosis of several digestive cancers, which has led to a serious burden in the health system that now needs to be dealt with. We designed a prospective study that included patients in whom access to elective endoscopic examinations during the COVID-19 pandemic had been delayed. Our aim was to investigate the impact of the COVID-19 pandemic on the diagnosis rate of digestive tract malignancies in the context of health crisis management that generates an ethical dilemma regarding the balance of utilitarianism versus deontology. Our study shows that the decrease in the number of newly diagnosed gastrointestinal cancers by endoscopy and biopsy during the pandemic restrictions and the delay in diagnosis have had a clear impact on stage migration due to disease progression.

Reduction in the Number of Diagnoses of Upper Digestive Tract Cancer during the Covid-19 Pandemic: An Integrative Literature Review

Introduction: In 2019, the World Health Organization was alerted about cases of infection with COVID-19. Due to the measures taken to prevent contamination, many pre-scheduled consultations, treatments and exams were suspended or cancelled. Objectives: This study aims to identify literature data on upper digestive tract cancer diagnosis numbers in patients that had performed endoscopy during the COVID-19 pandemic, along with a pre-pandemic control group. Methods: A literature review was performed through searches on the SciELO, Science Direct, PubMed, and BVS Regional Portal platforms. After applying the inclusion and exclusion criteria, 8 articles were selected for the study. Results: All articles reported a decrease in diagnoses of upper digestive tract cancer (reduction ranged from 76.3% to 19.28%) and in endoscopies performed (reduction ranged from 87.5% to 43.1%) during the pandemic. Conclusion: The COVID-19 pandemic reduced the accessibility of resources and; consequently, increased the number of underdiagnoses of pathologies with no direct relationship with the coronavirus. Thus, a significant reduction in the number of diagnoses of upper digestive tract cancer was observed due to the decline in the number of endoscopies performed.

Global analysis of T-cell groups reveals immunological features and common antigen targets of digestive tract tumors

BackgroundT cells are key players in the tumor immune microenvironment (TIME), as they can recognize and eliminate cancer cells that express neoantigens derived from somatic mutations. However, the diversity and specificity of T-cell receptors (TCRs) that recognize neoantigens are largely unknown, due to the high variability of TCR sequences among individuals.MethodsTo address this challenge, we applied GLIPH2, a novel algorithm that groups TCRs based on their predicted antigen specificity and HLA restriction, to cluster the TCR repertoire of 1,702 patients with digestive tract cancer. The patients were divided into five groups based on whether they carried tumor-infiltrating or clonal-expanded TCRs and calculated their TCR diversity. The prognosis, tumor subtype, gene mutation, gene expression, and immune microenvironment of these groups were compared. Viral specificity inference and immunotherapy relevance analysis performed for the TCR groups.ResultsThis approach reduced the complexity of TCR sequences to 249 clonally expanded and 150 tumor-infiltrating TCR groups, which revealed distinct patterns of TRBV usage, HLA association, and TCR diversity. In gastric adenocarcinoma (STAD), patients with tumor-infiltrating TCRs (Patients-TI) had significantly worse prognosis than other patients (Patients-nonTI). Patients-TI had richer CD8+ T cells in the immune microenvironment, and their gene expression features were positively correlated with immunotherapy response. We also found that tumor-infiltrating TCR groups were associated with four distinct tumor subtypes, 26 common gene mutations, and 39 gene expression signatures. We discovered that tumor-infiltrating TCRs had cross-reactivity with viral antigens, indicating a possible link between viral infections and tumor immunity.ConclusionBy applying GLIPH2 to TCR sequences from digestive tract tumors, we uncovered novel insights into the tumor immune landscape and identified potential candidates for shared TCRs and neoantigens.

Cancer-associated non-bacterial thrombotic endocarditis-Clinical series from a single institution.

Premortem clinical presentation of cancer-associated non-bacterial thrombotic endocarditis (Ca-NBTE), therapy, and the clinal course is limited to case reports and small clinical series. An electronic search of Mayo Clinic records (03/31/2002-06/30/2022) with a subsequent manual review was performed to identify adult patients with echocardiographically detected NBTE and active malignancy, excluding those with infectious endocarditis or lupus anticoagulant/antiphospholipid antibodies. In this retrospective cohort study, we analyzed 115 Ca-NBTE patients (mean age 63.2 ± 9.7 years, 66.1% female) involving 71 (61.7%) mitral, 58 (50.4%) aortic, 8 (6.9%) tricuspid, and 1 (0.9%) pulmonary valve. The most common cancer was lung (n = 45 cases (39.1%), followed by pancreatic (n = 19, 16.5%), gynecological (17, 14.8%), gastrointestinal (n = 10, 8.7%), and 10 (8.7%) with hematologic malignancy; 6 patients had two active cancers. Embolic complications at presentation were frequent: 94 (81.7%) brain, 11 splenic, 10 renal, 6 coronary, and 4 to the extremities. Of 104 anticoagulated patients, 60 received low molecular weight heparin, 17 unfractionated heparin, 16 apixaban, 8 warfarin, and 3 rivaroxaban. There were 18 arterial thromboembolisms; the Kaplan-Meier estimates of the incidence at 2 years were consistent with a rate of 15.9% [95% Confidence Interval (CI) 9.9-23.3], including 14 strokes (12.4%, 95%CI, 7.1-19.2), and 8 other arterial emboli (10.5%, 95%CI, 4.7-18.9); there were 10 venous thromboembolisms (8.9%, 95%CI, 4.5-15.0). Fourteen major bleedings occurred (12.8%, 95%CI, 7.3-19.9) and 94 patients died during follow-up (77.9%, 95%CI, 71.1-85.8). Ca-NBTE predominantly affected women with lung adenocarcinoma or digestive tract cancers and manifested by stroke with high mortality and frequent embolic and bleeding complications during anticoagulation therapy.

Cloud platform to improve efficiency and coverage of asynchronous multidisciplinary team meetings for patients with digestive tract cancer.

Multidisciplinary team (MDT) meetings are the gold standard of cancer treatment. However, the limited participation of multiple medical experts and the low frequency of MDT meetings reduce the efficiency and coverage rate of MDTs. Herein, we retrospectively report the results of an asynchronous MDT based on a cloud platform (cMDT) to improve the efficiency and coverage rate of MDT meetings for digestive tract cancer. The participants and cMDT processes associated with digestive tract cancer were discussed using a cloud platform. Software programming and cMDT test runs were subsequently conducted to further improve the software and processing. cMDT for digestive tract cancer was officially launched in June 2019. The doctor response duration, cMDT time, MDT coverage rate, National Comprehensive Cancer Network guidelines compliance rate for patients with stage III rectal cancer, and uniformity rate of medical experts' opinions were collected. The final cMDT software and processes used were determined. Among the 7462 digestive tract cancer patients, 3143 (control group) were diagnosed between March 2016 and February 2019, and 4319 (cMDT group) were diagnosed between June 2019 and May 2022. The average number of doctors participating in each cMDT was 3.26 ± 0.88. The average doctor response time was 27.21 ± 20.40 hours, and the average duration of cMDT was 7.68 ± 1.47 min. The coverage rates were 47.85% (1504/3143) and 79.99% (3455/4319) in the control and cMDT groups, respectively. The National Comprehensive Cancer Network guidelines compliance rates for stage III rectal cancer patients were 68.42% and 90.55% in the control and cMDT groups, respectively. The uniformity rate of medical experts' opinions was 89.75% (3101/3455), and 8.97% (310/3455) of patients needed online discussion through WeChat; only 1.28% (44/3455) of patients needed face-to-face discussion with the cMDT group members. A cMDT can increase the coverage rate of MDTs and the compliance rate with National Comprehensive Cancer Network guidelines for stage III rectal cancer. The uniformity rate of the medical experts' opinions was high in the cMDT group, and it reduced contact between medical experts during the COVID-19 pandemic.

Causal Relationships of Chronic Constipation and Irritable Bowel Syndrome with Digestive Tract Cancers: A Mendelian Randomization Study.

Chronic constipation and irritable bowel syndrome (IBS) manifest as prevalent gastrointestinal disorders, while digestive tract cancers (DTCs) present formidable challenges to global well-being. However, extant observational studies proffer uncertain insights into potential causal relationships of constipation and IBS with susceptibility to DTCs. We executed Mendelian randomization (MR) analysis to establish causal connections between these conditions and seven distinct categories of DTCs, including colorectal carcinoma (CRC), hepatocellular cancer (HCC), esophageal malignancy (ESCA), pancreatic adenocarcinoma (PAAD), biliary tract carcinoma (BTCs), gastric carcinoma (GC), and small intestine neoplasm (SIC). Leveraging instrumental variables (IVs) obtained from GWAS data of the FinnGen database, we employed a range of analytical methodologies, including inverse-variance weighting multiplicative random effects (IVW_MRE), inverse-variance weighting fixed effects (IVW_FE), maximum likelihood (ML), weighted median (WM), MR‒Egger regression, and the MR-PRESSO test. We observed a substantial linkage between genetically predicted constipation and increased vulnerability to PAAD (OR = 2.29, 95% CI: 1.422-3.69, P = 0.001) via the IVW method. Following the removal of outlier SNPs through MR-PRESSO, genetically predicted IBS was affiliated with an increased risk of CRC (OR = 1.17, 95% CI: 1-1.37, P = 0.05). Nonetheless, decisive causal correlations of constipation or IBS with other DTCs remain elusive. In summary, genetically predicted constipation was associated with an augmented PAAD risk, and IBS was associated with an increased CRC susceptibility within European cohorts, in agreement with some observational studies. Nevertheless, the causal associations of constipation and IBS with other DTCs remain inconclusive.

Dysregulation of lysine acetylation in the pathogenesis of digestive tract cancers and its clinical applications.

Recent advances in high-resolution mass spectrometry-based proteomics have improved our understanding of lysine acetylation in proteins, including histones and non-histone proteins. Lysine acetylation, a reversible post-translational modification, is catalyzed by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Proteins comprising evolutionarily conserved bromodomains (BRDs) recognize these acetylated lysine residues and consequently activate transcription. Lysine acetylation regulates almost all cellular processes, including transcription, cell cycle progression, and metabolic functions. Studies have reported the aberrant expression, translocation, and mutation of genes encoding lysine acetylation regulators in various cancers, including digestive tract cancers. These dysregulated lysine acetylation regulators contribute to the pathogenesis of digestive system cancers by modulating the expression and activity of cancer-related genes or pathways. Several inhibitors targeting KATs, KDACs, and BRDs are currently in preclinical trials and have demonstrated anti-cancer effects. Digestive tract cancers, including encompass esophageal, gastric, colorectal, liver, and pancreatic cancers, represent a group of heterogeneous malignancies. However, these cancers are typically diagnosed at an advanced stage owing to the lack of early symptoms and are consequently associated with poor 5-year survival rates. Thus, there is an urgent need to identify novel biomarkers for early detection, as well as to accurately predict the clinical outcomes and identify effective therapeutic targets for these malignancies. Although the role of lysine acetylation in digestive tract cancers remains unclear, further analysis could improve our understanding of its role in the pathogenesis of digestive tract cancers. This review aims to summarize the implications and pathogenic mechanisms of lysine acetylation dysregulation in digestive tract cancers, as well as its potential clinical applications.

EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin-angiotensin system.

Green tea polyphenol (-)-Epigallocatechin-3-gallate (EGCG) has been well studied for its biological activities in the prevention of chronic diseases. However, the biological activities of EGCG oxidation-derived polymers remain unclear. Previously, we found that these polymers accumulated in intraperitoneal tissues after intraperitoneal injection and gained an advantage over native EGCG in increasing insulin sensitivity via regulating the renin-angiotensin system (RAS) in type 2 diabetic mice. The present study determined the pro-apoptosis activities and anticancer mechanisms of the EGCG oxidation-derived polymer preparation (the >10 kDa EGCG polymers) in digestive tract cancer cells. Upon incubation of the >10 kDa EGCG polymers with CaCo2 colon cancer cells, these polymers coated the cell surface and regulated multiple components of the RAS in favor of cancer inhibition, including the downregulation of angiotensin-converting enzyme (ACE), angiotensin-II (AngII) and AngII receptor type 1 (AT1R) in the pro-tumor axis, as well as the upregulation of angiotensin-converting enzyme 2 (ACE2) and angiotensin1-7 (Ang(1-7)) in the anti-tumor axis. The treatment also markedly increased angiotensinogen (AGT), which is the precursor of the angiotensin peptides. The regulation of these RAS components occurred prior to apoptosis. Similar pro-apoptotic mechanisms of the >10 kDa EGCG polymers, were also observed in TCA8113 oral cancer cells. The >10 kDa EGCG polymers exhibited compromised activities in scavenging or initiating reactive oxygen species compared to EGCG, but gained a higher reactivity toward sulfhydryl groups, including protein cysteine thiols. We propose that the polymers bind onto the cell surface and regulate multiple RAS components by reacting with the sulfhydryl groups on the ectodomains of transmembrane proteins.

Tripartite Motif-containing Protein 11 Silencing Inhibits Proliferation and Glycolysis and Promotes Apoptosis of Esophageal Squamous Cell Carcinoma Cells by Inactivating Signal Transduction and Activation of Transcription Factor 3/c-Myc Signaling.

Esophageal squamous cell carcinoma (ESCC) is a common type of human digestive tract cancer with poor survival. Tripartite motif-containing protein 11 (TRIM11) is an oncogene in certain cancers that can regulate glycolysis and signal transduction and activation of transcription factor 3 (STAT3) signaling. This study was designed to investigate the role and the mechanism of TRIM11 in ESCC. First, TRIM11 expression in ESCC tissues and the correlation between TRIM11 expression and prognosis were analyzed using bioinformatics tools. After TRIM11 expression was detected by Western blot in ESCC cells, TRIM11 was silenced to evaluate its effect on the malignant phenotypes of ESCC cells. Cell proliferation and apoptosis were assessed by cell counting kit-8 assay, ethynyl-2'- deoxyuridine staining, and flow cytometry, respectively. The glucose uptake and lactate secretion were detected to examine glycolysis. In addition, Western blot was employed to detect the expression of proteins related to apoptosis, glycolysis, and STAT3/c-Myc signaling. Then, ESCC cells were treated with STAT3 activator further to clarify the regulatory effect of TRIM11 on STAT3/c-Myc signaling. TRIM11 was upregulated in ESCC tissues and cells, and high expression of TRIM11 was associated with a poor prognosis. TRIM11 knockdown inhibited the proliferation and glycolysis while facilitating apoptosis of ESCC cells. Besides, the expression of p-STAT3 and c-Myc was significantly downregulated by TRIM11 silencing. Of note, the STAT3 activator partially reversed the effects of TRIM11 depletion on the proliferation, apoptosis, and glycolysis in ESCC cells. Collectively, TRIM11 loss-of-function affects the proliferation, apoptosis, and glycolysis in ESCC cells by inactivating STAT3/c-Myc signaling.

Mechanical properties and tissue damage caused by staples in gastrointestinal anastomosis.

Gastrointestinal surgery using a stapler is usually associated with tissue damage, anastomosis leakage, bleeding, and other complications, which is one of the effective methods for treating digestive tract cancer. The cutting properties of staples and the tissue damage occurring in the process of stapling porcine esophageal and gastric tissues have been evaluated and a new type of stapler has been designed. Since different structural and mechanical properties esophageal and gastric tissues layers, the puncturing force exhibits a fluctuating trend. Compressive stress caused by the bending of the staple legs can lead to the destruction of the vascular network inside the tissue, tissue deforms and tears. Finally, a staple with an internal incision arc (IIA) tip is designed, which meeting the performance requirements.

Periodontitis and risk of cancer: Mechanistic evidence

AbstractThis review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low‐grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro‐aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non‐indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor‐associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor‐infiltrating T cells) and the increased expression of pro‐inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors.

Prebiotics and the Risk of Upper Digestive Tract and Stomach Cancers: The PrebiotiCa Study.

Fiber intake may lower digestive tract cancer risk, possibly by modulating the composition of gut microbiota. However, no data are available about the role of specific fiber fractions with prebiotic activity (e.g., inulin-type fructans (ITFs), fructo-oligosaccharides (FOSs) and galactooligosaccharides (GOSs)) on the risk lower digestive tract cancers. The objective was to assess the association between prebiotic intake and the risk of cancers of the upper digestive tract and stomach. Within the PrebiotiCa study, data were derived from a network of Italian case-control studies conducted between 1992 and 2009. Participants' usual diet was assessed using a food frequency questionnaire. ITFs, and selected FOSs (nystose, kestose, and 1F-β-fructofuranosylnystose) and GOSs (raffinose and stachyose) were quantified in several food products via laboratory analyses. Participants' prebiotic intake was calculated by multiplying food frequency questionnaire intake by the prebiotic content of each food item. Cases were patients admitted to major hospitals with incident histologically confirmed cancers; there were 946 cases of cancer of the oral cavity/pharynx, 198 of the nasopharynx, 304 of the esophagus, 230 of the stomach. More than 4,000 patients admitted to the same hospitals for acute nonneoplastic and not diet-related conditions were selected as control subjects. The outcomes were oral and pharyngeal, nasopharyngeal, esophageal, and stomach cancers. The odds ratios and corresponding 95% CIs of the various cancers were derived using logistic regression models adjusted for major confounders and energy intake. No association was observed between intake of prebiotics and risk of cancers of the oral cavity and pharynx, nasopharynx, and esophagus. High raffinose intake reduced stomach cancer risk (odds ratio for the third vs the first tertile 0.6, 95% CI 0.3 to 0.9); no other prebiotic was associated with stomach cancer. The current study does not support a major role of prebiotic fibers on selected upper digestive tract cancers. The association between high raffinose intake and reduced stomach cancer risk needs further investigation.

Genetically Predicted Causal Effects of Gut Microbiota and Gut Metabolites on Digestive Tract Cancer: A Two-Sample Mendelian Randomization Analysis.

Evidence from numerous observational studies and clinical trials has linked gut microbiota and metabolites to digestive tract cancer. However, the causal effect between these factors remains uncertain. Data for this study were obtained from the MiBioGen, TwinsUK Registry, and FinnGen (version R8). Two-sample Mendelian randomization analysis with inverse variance weighting method was primarily used, and the results were validated by heterogeneity analysis, pleiotropy test, and sensitivity analysis. At P < 5 × 10-8, our analysis identified four gut microbiotas as risk factors for digestive tract cancer and six as risk factors for colorectal cancer. Conversely, one gut microbiota exhibited protection against bile duct cancer, and two showed protective effects against stomach cancer. At P < 1 × 10-5, our investigation revealed five, six, three, eight, eight, and eight gut microbiotas as risk factors for esophageal, stomach, bile duct, liver, pancreatic, and colorectal cancers, respectively. In contrast, four, two, eight, two, two, and five gut microbiotas exhibited protective effects against these cancers. Additionally, GABA, a metabolite of gut microbiota, displayed a significant protective effect against colorectal cancer. In conclusion, specific gut microbiota and metabolites play roles as risk factors or protective factors for digestive tract cancer, and a causal relationship between them has been established, offering novel insights into gut microbiota-mediated cancer development.