Clinical impact of panel gene sequencing on therapy of advanced cancers of the digestive system: a retrospective, single center study.

BACKGROUND: Panel gene sequencing is an established diagnostic tool for precision oncology of solid tumors, but its utility for the treatment of cancers of the digestive system in clinical routine is less well documented. METHODS: We retrospectively identified patients with advanced or metastatic gastrointestinal, pancreaticobiliary or hepatic cancers who received panel gene sequencing at a tertiary university hospital from 2015 to 2022. For these cases, we determined the spectrum of genetic alterations, clinicopathological parameters and treatment courses. Assessment of actionability of genetic alterations was based on the OncoKB database, cancer-specific ESMO treatment guidelines, and recommendations of the local molecular tumor board. RESULTS: In total, 155 patients received panel gene sequencing using either the Oncomine Focus (62 cases), Comprehensive (91 cases) or Childhood Cancer Research Assay (2 cases). The mean age of patients was 61 years (range 24-90) and 37% were female. Most patients suffered from either colorectal cancer (53%) or cholangiocellular carcinoma (19%). 327 genetic alterations were discovered in 123 tumor samples, with an average number of 2.1 alterations per tumor. The most frequently altered genes were TP53, KRAS and PIK3CA. Actionable gene alterations were detected in 13.5-56.8% of tumors, according to ESMO guidelines or the OncoKB database, respectively. Thirteen patients were treated with targeted therapies based on identified molecular alterations, with a median progression-free survival of 8.8 months. CONCLUSIONS: Actionable genetic alterations are frequently detected by panel gene sequencing in patients with advanced cancers of the digestive tract, providing clinical benefit in selected cases. However, for the majority of identified actionable alterations, sufficient clinical evidence for targeted treatments is still lacking.

The role of SWI/SNF complexes in digestive system neoplasms.

Chromatin remodeling is a critical step in the DNA damage response, and the ATP-dependent chromatin remodelers are a group of epigenetic regulators that alter nucleosome assembly and regulate transcription factor accessibility to DNA, preventing genomic instability and tumorigenesis caused by DNA damage. The SWI/SNF chromatin remodeling complex is one of them, and mutations in the gene encoding the SWI/SNF subunit are frequently found in digestive tumors. We review the most recent literature on the role of SWI/SNF complexes in digestive tumorigenesis, with different SWI/SNF subunits playing different roles. They regulate the biological behavior of tumor cells, participate in multiple signaling pathways, interact with multiple genes, and have some correlation with the prognosis of patients. Their carcinogenic properties may help discover new therapeutic targets. Understanding the mutations and defects of SWI/SNF complexes, as well as the underlying functional mechanisms, may lead to new strategies for treating the digestive system by targeting relevant genes or modulating the tumor microenvironment.

Integrated Pleiotropic Gene Set Unveils Comorbidity Insights across Digestive Cancers and Other Diseases.

Comorbidities are prevalent in digestive cancers, intensifying patient discomfort and complicating prognosis. Identifying potential comorbidities and investigating their genetic connections in a systemic manner prove to be instrumental in averting additional health challenges during digestive cancer management. Here, we investigated 150 diseases across 18 categories by collecting and integrating various factors related to disease comorbidity, such as disease-associated SNPs or genes from sources like MalaCards, GWAS Catalog and UK Biobank. Through this extensive analysis, we have established an integrated pleiotropic gene set comprising 548 genes in total. Particularly, there enclosed the genes encoding major histocompatibility complex or related to antigen presentation. Additionally, we have unveiled patterns in protein-protein interactions and key hub genes/proteins including TP53, KRAS, CTNNB1 and PIK3CA, which may elucidate the co-occurrence of digestive cancers with certain diseases. These findings provide valuable insights into the molecular origins of comorbidity, offering potential avenues for patient stratification and the development of targeted therapies in clinical trials.

The effect of metabolism-related lifestyle and clinical risk factors on digestive system cancers in East Asian populations: a two-sample Mendelian randomization analysis.

Metabolic factors play a critical role in the development of digestive system cancers (DSCs), and East Asia has the highest incidence of malignant tumors in the digestive system. We performed a two-sample Mendelian randomization analysis to explore the associations between 19 metabolism-related lifestyle and clinical risk factors and DSCs, including esophageal, gastric, colorectal, hepatocellular, biliary tract, and pancreatic cancer. The causal association was explored for all combinations of each risk factor and each DSC. We gathered information on the instrumental variables (IVs) from various sources and retrieved outcome information from Biobank Japan (BBJ). The data were all from studies of east Asian populations. Finally, 17,572 DSCs cases and 195,745 controls were included. Our analysis found that genetically predicted alcohol drinking was a strong indicator of gastric cancer (odds ratio (OR) = 0.95; 95% confidence interval (CI): 0.93-0.98) and hepatocellular carcinoma (OR = 1.11; 95% CI: 1.05-1.18), whereas coffee consumption had a potential protective effect on hepatocellular carcinoma (OR = 0.69; 95% CI: 0.53-0.90). Triglyceride was potentially associated with a decreased risk of biliary tract cancer (OR = 0.53; 95% CI: 0.34-0.81), and uric acid was associated with pancreatic cancer risk (OR = 0.59; 95% CI: 0.37-0.96). Metabolic syndrome (MetS) was associated with esophageal and gastric cancer. Additionally, there was no evidence for a causal association between other risk factors, including body mass index, waist circumference, waist-to-hip ratio, educational levels, lipoprotein cholesterol, total cholesterol, glycine, creatinine, gout, and Graves' disease, and DSCs. The leave-one-out analysis revealed that the single nucleotide polymorphism (SNP) rs671 from the ALDH2 gene has a disproportionately high contribution to the causal association between alcohol drinking and gastric cancer and hepatocellular carcinoma, as well as the association between coffee consumption and hepatocellular carcinoma. The present study revealed multiple metabolism-related lifestyle and clinical risk factors and a valuable SNP rs671 for DSCs, highlighting the significance of metabolic factors in both the prevention and treatment of DSCs.

Dendritic cell-derived exosome (DEX) therapy for digestive system cancers: Recent advances and future prospect.

Tumor-mediated immunosuppression is a fundamental obstacle to the development of dendritic cell (DC)-based cancer vaccines, which despite their ability to stimulate host anti-tumor CD8 T cell immunity, have not been able to generate meaningful therapeutic responses. Exosomes are inactive membrane vesicles that are nanoscale in size and are produced by the endocytic pathway. They are essential for intercellular communication. Additionally, DC-derived exosomes (DEXs) contained MHC class I/II (MHCI/II), which is frequently complexed with antigens and co-stimulatory molecules and is therefore able to prime CD4 and CD8 T cells that are specific to particular antigens. Indeed, vaccines with DEXs have been shown to exhibit better anti-tumor efficacy in eradicating tumors compared to DC vaccines in pre-clinical models of digestive system tumors. Also, there is room for improvement in the tumor antigenic peptide (TAA) selection process. DCs release highly targeted exosomes when the right antigenic peptide is chosen, which could aid in the creation of DEX-based antitumor vaccines that elicit more targeted immune responses. Coupled with their resistance to tumor immunosuppression, DEXs-based cancer vaccines have been heralded as the superior alternative cell-free therapeutic vaccines over DC vaccines to treat digestive system tumors. In this review, current studies of DEXs cancer vaccines as well as potential future directions will be deliberated.

Identification roles of NFE2L3 in digestive system cancers.

BACKGROUND: Morbidity and mortality rates of Digestive System Cancers (DSC) continue to pose human lives and health. Nuclear factor erythroid 2-like protein 3 (NFE2L3) is aberrantly expressed in DSC. This study aimed to explore the clinical value and underlying mechanisms of NFE2L3 as a novel biomarker in DSC. METHODS: We utilized data from databases and clinical gastric cancer specimens to validate the aberrant expression level of NFE2L3 and further assessed the clinical value of NFE2L3. To investigate the potential molecular mechanism of NFE2L3, we analyzed the correlation of NFE2L3 with immune molecular mechanisms, constructed PPI network, performed GO analysis and KEGG analysis, and finally explored the biological function of NFE2L3 in gastric cancer cells. RESULTS: NFE2L3 expression is up-regulated in DSC and has both prognostic and diagnostic value. NFE2L3 correlates with various immune mechanisms, PPI network suggests proteins interacting with NFE2L3, GSEA analysis suggests potential molecular mechanisms for NFE2L3 to play a role in cancer promotion, and in vitro cellular experiments also confirmed the effect of NFE2L3 on the biological function of gastric cancer cells. CONCLUSION: Our study confirms the aberrant expression and molecular mechanisms of NFE2L3 in DSC, indicating that NFE2L3 could serve as a novel biomarker for diagnosis and prognosis of DSC.

Emerging function of main RNA methylation modifications in the immune microenvironment of digestive system tumors.

Digestive system tumors have been reported in more than 25% of all cancer cases worldwide, bringing a huge burden on the healthcare system. RNA methylation modification-an important post-transcriptional modification-has become an active research area in gene regulation. It is a dynamic and reversible process involving several enzymes, such as methyltransferases, demethylases, and methylation reader proteins. This review provides insights into the role of three major methylation modifications, namely m6A, m5C, and m1A, in the development of digestive system tumors, specifically in the development of tumor immune microenvironment (TIME) of these malignancies. Abnormal methylation modification affects immunosuppression and antitumor immune response by regulating the recruitment of immune cells and the release of immune factors. Understanding the mechanisms by which RNA methylation regulates digestive system tumors will be helpful in exploring new therapeutic targets.

Nationwide Audit of Postoperative Mortality and Complications After Digestive Cancer Surgery: Will New Legal Thresholds be Sufficient?

BACKGROUND: French policymakers recently chose to regulate high-risk digestive cancer surgery (DCS). A minimum of five cases per year should be performed for each of the following types of curative cancer surgery: esophagus/esogastric junction (ECS), stomach (GCS), liver (LCS, metastasis included), pancreas (PCS), and rectum (RCS). This study aimed to evaluate the hypothetical beneficial effects of the new legal minimal volume thresholds on the rates of 90-day postoperative mortality (90POM) for each high-risk DCS. METHODS: This nationwide observational population-based cohort study used data extracted from the French National Health Insurance Database from 1 January 2015-31 December 2017. Mixed-effects logistic regression models were performed to estimate the independent effect of hospital volume. RESULTS: During the study period, 61,169 patients (57.1 % male, age 69.7 ±12.2 years) underwent high-risk DCS including ECS (n = 4060), GCS (n = 5572), PCS (n = 8598), LCS (n = 10,988), and RCS (n = 31,951), with 90POM of 6.6 %, 6.9 %, 6.0 %, 5.2 %, and 2.9 %, respectively. For hospitals fulfilling the new criteria, 90POM was lower after adjustment only for LCS (odds ratio [OR],15.2; 95 % confidence interval [CI], 9.5-23.2) vs OR, 7.6; 95 % CI, 5.2-11.0; p < 0.0001) and PCS (OR, 3.6; 95 % CI, 1.7-7.6 vs OR, 2.1; 95 % CI, 1.0-4.4; p<0.0001). With higher thresholds, all DCSs showed a lower adjusted risk of 90POM (e.g., OR, 0.38; 95 % CI, 0.28-0.51) for PCS of 40 or higher. CONCLUSION: Based on retrospective data, thresholds higher than those promulgated would better improve the safety of high-risk DCS. New policies aiming to further centralize high-risk DCS should be considered, associated with a clear clinical pathway of care for patients to improve accessibility to complex health care in France.

Sialylated glycoproteins and sialyltransferases in digestive cancers: Mechanisms, diagnostic biomarkers, and therapeutic targets.

Sialic acid (SA), as the ultimate epitope of polysaccharides, can act as a cap at the end of polysaccharide chains to prevent their overextension. Sialylation is the enzymatic process of transferring SA residues onto polysaccharides and is catalyzed by a group of enzymes known as sialyltransferases (SiaTs). It is noteworthy that the sialylation level of glycoproteins is significantly altered when digestive cancer occurs. And this alteration exhibits a close correlation with the progression of these cancers. In this review, from the perspective of altered SiaTs expression levels and changed glycoprotein sialylation patterns, we summarize the pathogenesis of gastric cancer (GC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and hepatocellular carcinoma (HCC). Furthermore, we propose potential early diagnostic biomarkers and prognostic indicators for different digestive cancers. Finally, we summarize the therapeutic value of sialylation in digestive system cancers.

Intratumoral microorganisms in tumors of the digestive system.

Tumors of the digestive system pose a significant threat to human health and longevity. These tumors are associated with high morbidity and mortality rates, leading to a heavy economic burden on healthcare systems. Several intratumoral microorganisms are present in digestive system tumors, and their sources and abundance display significant heterogeneity depending on the specific tumor subtype. These microbes have a complex and precise function in the neoplasm. They can facilitate tumor growth through various mechanisms, such as inducing DNA damage, influencing the antitumor immune response, and promoting the degradation of chemotherapy drugs. Therefore, these microorganisms can be targeted to inhibit tumor progression for improving overall patient prognosis. This review focuses on the current research progress on microorganisms present in the digestive system tumors and how they influence the initiation, progression, and prognosis of tumors. Furthermore, the primary sources and constituents of tumor microbiome are delineated. Finally, we summarize the application potential of intratumoral microbes in the diagnosis, treatment, and prognosis prediction of digestive system tumors. Video Abstract.

Analysis of Correlation between Rab1A Expression and its Prognosis in Cancers: a Meta-Analysis.

BACKGROUND: Rab1A not only regulates eukaryotic secretion, autophagy and intracellular traffic, but also extensively participates in the development of cancer. Thus, we collected data to investigate the clinical value of Rab1A in cancers. METHODS: English web database was searched for appropriate studies. The role of Rab1A in cancer patients was evaluated by combining hazard ratios and odds ratios. RESULTS: There were 15 studies in 14 articles, including 1,791 cancer patients. The results showed that upregulated Rab1A led to poor prognosis in cancer patients (pooled HR = 2.545, 95% CI = 1.924 - 3.367, p < 0.001). Notably, a high level of Rab1A was associated with a poorer prognosis than patients with a low level of Rab1A in digestive system cancer (pooled HR = 2.484, 95% CI = 1.796 - 3.437, p < 0.001). In order to explore the possible carcinogenic mechanism, we further analyzed and confirmed that high expression of Rab1A was associated with worse histologic grade, deeper tumor invasion, higher TNM stage, positive LN metastasis, positive neural invasion, positive vascular invasion, and larger tumor size (p < 0.05). CONCLUSIONS: Rab1A overexpression was associated with poor prognosis and adverse clinicopathological parameters in cancer patients and had the potential to be a target for future cancer therapy.

State of the scientific evidence and recommendations for the management of older patients with gastric cancer.

Gastric cancer is one of the most frequent and deadly tumours worldwide. However, the evidence that currently exists for the treatment of older adults is limited and is derived mainly from clinical trials in which older patients are poorly represented. In this article, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Group for the Treatment of Digestive Tumours (TTD), and the Spanish Multidisciplinary Group on Digestive Cancer (GEMCAD) reviews the existing scientific evidence for older patients (≥65 years old) with gastric cancer and establishes a series of recommendations that allow optimization of management during all phases of the disease. Geriatric assessment (GA) and a multidisciplinary approach should be fundamental parts of the process. In early stages, endoscopic submucosal resection or laparoscopic gastrectomy is recommended depending on the stage. In locally advanced stage, the tolerability of triplet regimens has been established; however, as in the metastatic stage, platinum- and fluoropyrimidine-based regimens with the possibility of lower dose intensity are recommended resulting in similar efficacy. Likewise, the administration of trastuzumab, ramucirumab and immunotherapy for unresectable metastatic or locally advanced disease is safe. Supportive treatment acquires special importance in a population with different life expectancies than at a younger age. It is essential to consider the general state of the patient and the psychosocial dimension.

The Diagnostic Value of Circulating miR-29 Family for Digestive System Malignancies: A Meta-Analysis.

OBJECTIVE: To evaluate the diagnostic value of circulating microRNA-29 (miR-29) in digestive system malignant neoplasms by meta-analysis. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science to collect studies, published through September 2022, on the diagnostic value of miR-29 in digestive system tumors. RESULTS: We included 7 studies in this meta-analysis, including colorectal cancer, esophageal squamous cell carcinomas, and cholangiocarcinoma. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 0.64 (95% CI, 0.53-0.74), 0.83 (0.60-0.94), 3.75 (1.42-9.91), 0.44 (0.31-0.61), and 8.63 (2.54-29.26), respectively. The area under the summary receiver operating characteristic curve was 0.75. The sensitivity of miR-29 derived from serum was higher than that of miR-29 derived from plasma for malignant digestive system tumors (0.71 vs 0.54; P = .04). CONCLUSION: This meta-analysis suggests that the circulating miR-29 family has good diagnostic performance for digestive system malignant tumors, with moderate sensitivity and good specificity.

The Functional Mechanisms of Toll-Like Receptor 3 and Its Implications in Digestive System Tumors.

Toll-like receptor 3 (TLR3) is a prominent member of the Toll-like receptor (TLR) family and has the ability to recognize and bind intracellular double-stranded RNA (dsRNA). Once triggered by a viral infection or other pathological condition, TLR3 activates immune cells and induces the production of interferons and other immune response molecules. Additionally, TLR3 is considered an important immune modulator, as it can regulate cell apoptosis and promote anticancer immunity. The investigation and application of TLR3 agonists in digestive system tumors have attracted widespread attention and are regarded as a promising cancer treatment strategy with potential clinical applications. TLR3 expression levels are generally elevated in most digestive system tumors, and higher TLR3 expression is associated with a better prognosis. Therefore, TLR3 has emerged as a novel therapeutic target for digestive system tumors. It has been used in combination with chemotherapy, radiotherapy, and targeted therapy and demonstrated excellent efficacy and tolerability. This has provided new ideas and hopes for the treatment of digestive system tumors. This review discusses the mechanisms of TLR3 and its frontier research in digestive system tumors.

The Potential of Glycyrrhiza from "Medicine Food Homology" in the Fight against Digestive System Tumors.

Glycyrrhiza has a long history of applications and a wide range of pharmacological effects. It is known as the "king of all herbs". Glycyrrhiza is effective in clearing heat, detoxifying, relieving cough, and tonifying qi and has good bioactivity in multiple inflammatory, immune, and tumor diseases. This review aims to summarize the origin, distribution, and anti-digestive system tumor mechanism of glycyrrhiza and its homologous applications in medicine and food. The active compounds include triterpenoids, flavonoids, and coumarins, which are widely used in clinical treatments, disease prevention, and daily foods because of their "enhancement of efficacy" and "reduction of toxicity" against digestive system tumors. This paper reviews the use of glycyrrhiza in digestive system tumors and provides an outlook on future research and clinical applications.

The association of serum choline concentrations with the risk of cancers: a community-based nested case-control study.

Few studies have been designed to investigate the effect of serum choline on the risk of incident cancer. This study aims to explore the association between serum choline and the risk of new-onset cancer. We conducted a case-control study, including 199 patients with incident cancer and 199 matched controls during a median of 3.9 years of follow-up, nested within the China Stroke Primary Prevention Trial. Cubic spline regression (RCS) and conditional logistic regression analysis was used to assess the association of serum choline and incident cancer risk. We observed a positive dose-response association between serum choline levels and the risk of overall (p for overall = 0.046) and digestive system cancer (p for overall = 0.039). Compared with patients with the lowest choline levels (Q1 group), patients in the highest levels of choline (Q4) had a 3.69-fold and 6.01-fold increased risk of overall (OR = 3.69, 95% CI 1.17-11.63) and digestive system cancer (OR = 6.01, 95% CI 1.14-31.67). Elevated choline levels (per SD, 11.49 µg/mL) were associated with a higher risk of overall cancer among participants who were older, male, and smokers in the subgroup analyses. We found a positive association between elevated levels of serum choline with increased risk of incident cancer. Our findings have critical clinical implications for cancer prevention and diagnosis.Trial registration CSPPT, NCT00794885. Registered: November 20, 2008. https://www.clinicaltrials.gov/ct2/show/study/NCT00794885 https://www.clinicaltrials.gov/ct2/show/study/NCT00794885.

Prognostic value of tertiary lymphoid structures (TLS) in digestive system cancers: a systematic review and meta-analysis.

BACKGROUND: Existing literature suggests that tertiary lymphatic structure (TLS) is associated with the progression of cancer. However, the prognostic role of TLS in digestive system cancers remains controversial. This meta-analysis aims to synthesize currently available evidence in the association between TLS and the survival of digestive system cancers. METHODS: We systematically searched three digital databases (PubMed, Embase, Web of Science) for articles published from database inception to December 23, 2022. Study selection criteria are based on PECO framework: P (population: patients with digestive system cancers), E (exposure: presence of TLS), C (comparator: absence of TLS), O (outcome: overall survival, OS; recurrence-free survival, RFS; disease-free survival, DFS). The Quality in Prognostic Studies (QUIPS) tool was used to assess risk of bias for included studies. The study protocol was registered with PROSPERO (CRD42023416307). RESULTS: A total of 25 studies with 6910 patients were included into the final meta-analysis. Random-effects models revealed that the absence of TLS was associated with compromised OS, RFS, and DFS of digestive system cancers, with pooled hazard ratios (HRs) of 1.74 (95% CI: 1.50-2.03), 1.96 (95% CI: 1.58-2.44), and 1.81 (95% CI: 1.49-2.19), respectively. Subgroup analyses disclosed a stronger TLS-survival association for pancreatic cancer, compared with other digestive system cancers. CONCLUSION: TLS may be of prognostic significance for digestive system cancers. More original studies are needed to further corroborate this finding.