Homeobox A10 in gastrointestinal malignancies: unraveling metastatic mechanisms and novel therapeutic opportunities.

Gastrointestinal (GI) cancers have long been considered as highly heterogeneous and intractable, with high rates of morbidity and mortality globally [1] . Despite the important breakthroughs and clinical success of cancer immunotherapies such as immune checkpoint blockade (ICB) therapy in some cancer types like melanoma [2] , the overall response rate (ORR) of ICB therapy in the non-selective GI patients is still not satisfactory [3] . About 70-80% of GI patients displayed primary resistance to ICB therapy, while some patients subsequently developed immunotherapy resistance during the treatment process [3] . Both tumor-intrinsic factors, such as driver gene mutations or oncogenic pathway activation, and tumor-extrinsic factors, such as the suppressive tumor immune microenvironment (TIME), contribute to the complex drug resistance mechanisms in GI cancers. Thus, current studies aim to develop efficient overcoming strategies to improve treatment responses of immunotherapies [4] .In this research topic, with the efforts of five guest editors, 15 articles consisting of 6 reviews, 7 original researches and 2 case reports were collected, providing a deep understanding and new comprehensive insight of immunotherapy resistance mechanisms and potential overcoming strategies in GI cancers, including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC) and hepatocellular carcinoma (HCC).EC is among the deadliest malignancies due to its late-stage diagnosis and escalating worldwide incidence [5] . Besides conventional therapies, immunotherapy, represented by ICB, has gained promise in treating patients with EC. To offer an objective and integrated view of research navigations to promote future advances in ICB, Yang et al. systemically combed the publication trends and research highlights of PD-1/PD-L1 blockade therapy in EC treatment for the past ten years via visualized bibliometric methods. As publication characteristics were displayed varying from countries and time points in the article, the authors pointed out that current research hotspots are focused on neoadjuvant immunotherapy and biomarkers development for esophageal cancer, emphasizing the significance of developing effective biomarkers. GC is another common GI cancer worldwide with high incidence and mortality rates and poor prognosis. Despite immunotherapy (anti-PD-1/PD-L1, programmed cell death protein 1/ programmed cell death protein ligand 1) has been approved in advanced GC, the medium overall survival time is still fewer than 24 months [6] . CRC is another major type of GI cancers with a high morbidity rate and poor prognosis [7] . Although ICB therapy has achieved important progress in deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal CRC, the majority of CRC patients (approximately 85%) with proficient mismatch repair (pMMR)/microsatellite stability status still respond poorly to immunotherapies [8] . In HCC is the most prevalent pathological type of primary liver cancer with dismal prognoses. With the approval of ICB-based therapies as standards of care [9] , it is necessary to have an in-depth understanding of the complex TIME which impacts the efficacies of immunotherapy. The establishment of next-generation sequencing methods endows the possibility of analyzing cellular components in the TME and heterogeneous molecular features of HCC [10] . In summary, the 15 articles in this research topic explore or discuss the potential drug resistance mechanisms of immunotherapies for GI cancers from different aspects, and provide possible strategies targeting both tumor cells and TIME to improve the treatment efficacies. Unfortunately, the progress of immunotherapy in pancreatic cancer, the recognized immunotherapy-resistant tumor, is not covered in this research topic, which is worth further exploring in the future. More research and efforts are required to achieve successful applications of immunotherapy on GI cancers in the future.

Gastrointestinal (GI) cancers remain a leading cause of cancer-related death worldwide, and many patients with advanced disease still respond poorly to standard treatments such as surgery, chemotherapy, and radiotherapy. Immune checkpoint inhibitors have changed the management of several solid tumors, but their benefit in most GI malignancies is limited by low tumor mutational burden, microsatellite stability, and "cold" tumor immune microenvironments. This has created interest in safe adjuvant agents that can boost antitumor immunity and improve responses to immunotherapy. Ginseng, a traditional medicinal herb, contains ginsenosides and polysaccharides with documented antitumor and immunomodulatory activities. Experimental studies in liver, colorectal, gastric, and esophageal cancer models show that selected ginsenosides can promote apoptosis, modulate DNA damage responses, inhibit angiogenesis, reshape inflammatory signaling, and downregulate PD-L1 or other resistance pathways. Ginseng-derived nanoparticles and liposomal formulations further suggest a role in drug delivery and microenvironment remodeling. At the same time, clinical experience from traditional Chinese medicine indicates that ginseng-based preparations may alleviate cancer-related fatigue, support host immunity, and enhance tolerance to chemoradiotherapy. However, the pharmacological targets, optimal combinations, and predictive biomarkers for ginsenoside-based adjuvant therapy remain poorly defined. Integration of systems pharmacology, single-cell technologies, and modern clinical trial design will be essential to clarify the role of ginsenosides as partners in immunotherapy for GI cancers.

e15652 Background: Patients diagnosed with gastrointestinal (GI) cancers have long-term risks of cardiovascular disease and mortality. However, research comparing patients with colorectal cancer (CRC) to other GI cancers to assess their risk of acute cardiac complications is lacking. We evaluated the risk of hospitalization with acute cardiac complications (acute myocardial infarction [MI], arrhythmias and heart failure [HF]) among patients with CRC versus other GI cancers. Methods: A ten-year retrospective study using the Nationwide Inpatient Sample (NIS) database (2010-2019) was conducted. Using ICD-9 and ICD-10 codes, patients with diagnoses of GI cancers were identified. Multivariate logistic regression analysis was used to evaluate the odds of admission with an acute cardiac complication among patients with a diagnosis of CRC when compared to other GI cancers (esophageal, gastric, intestinal, hepatobiliary, and pancreatic cancers). Results: Among 4,408,321 GI cancer hospitalizations, 82,592 (0.18%) were for acute cardiac complications. Of these, 43.1% were in CRC patients and 56.9% were in those with other GI malignancies (P < 0.001). Multivariate analyses revealed that patients with CRC had more than two-fold higher odds of acute MI compared to other GI cancer patients (Adjusted Odds Ratio (AOR): 2.47; 95% Confidence interval ( CI): 2.30-2.65), 1.8 times higher risk of arrhythmia (AOR: 1.78; 95% CI: 1.69-1.87) and 2.2 times higher risk of HF (AOR: 2.23; 95% CI:2.11-2.36). Overall, in comparison to other GI cancers, CRC patients were twice as likely to be admitted for acute cardiac complications (AOR: 2.09; 95% CI:2.02-2.16). Conclusions: Colorectal cancer patients have significantly higher odds of hospitalizations with acute cardiac complications relative to other GI malignancies. Older age and pre-existing comorbidities of CRC patients are unlikely to sufficiently explain these findings. CRC patients would benefit from active surveillance for cardiac diseases as well as further research on the long-term survival impact of acute cardiac complications on CRC patients. [Table: see text]

The gastrointestinal (GI) tract is an anatomic term used to denote the tubular digestive system and its accessory organs. It is often divided into the upper GI tract, lower GI tract, and accessory organs for purposes of discussing its diseases. The upper GI tract consists of the esophagus, stomach, and duodenum, whereas the lower GI tract comprises the remainder of the small intestine, the colon, and the anus. The accessory organs include the liver, gallbladder, pancreas, and the hepatobiliary and pancreatic ducts. Although any portion of the GI tract may develop malignancy, the esophagus, stomach, and colon (including rectum) are the most common. In fact, esophagogastric and colorectal carcinomas are among the most frequently occurring deadly diseases in humans worldwide. Other commonly encountered GI primary tumors include lymphoproliferative disorders, hepatocellular carcinoma, and neuroendocrine and mesenchymal tumors (including GI stromal tumors). The pathogenesis and etiology of GI tumors is typically multi-factorial, varies with the specific tumor type, and may involve environmental factors (dietary, low socioeconomic status, cigarette smoking, alcohol use, nutritional deficiencies), host factors (certain precancerous conditions), infection (human papillomavirus, helicobacter pylori), and underlying genetic susceptibility. In the emerging era of personalized medicine, the pathologist’s role in the management of patients with GI malignancies has been greatly expanded from that of simply a traditional histomorphologist, to an active clinical consultant for gastroenterologists, surgeons, oncologists and medical geneticists, as well as patients. Today, the pathologist not only needs to provide an accurate histopathologic diagnosis, but is also responsible for accurately defining pathologic stage, evaluating surgical margins, assessing the efficacy of various neoadjuvant therapeutic modalities, and identifying the presence or absence of various relevant prognostic parameters and therapeutic targets. Pathologists also play a key role in analyzing the histologic features of various tumors with potential genetic and/or molecular abnormalities, selecting appropriate tissue for testing for mutation and other genetic testing, and interpreting the results of these important therapeutic and prognostic tests. This issue is dedicated to the pathologic aspects of commonly encountered GI tumors. Experts in the field offer their perspectives about the histopathology, cytopathology, precursor lesions, and recent advances in molecular pathology, and also provide up-to-date guidance in the application of immunohistochemical and molecular/genetic testing of commonly encountered GI, liver, and pancreatic tumors, with emphasis on their clinical relevance. In the first article, authors from UCLA review the histopathology and current molecular pathology of colorectal carcinoma and its precursor lesions, with emphasis on their clinical relevance (1). Next, investigators from Harbor-UCLA Medical Center discuss the role played by cell cycle arrest, TLR signaling macrophages and stem cell transformation to form cancer stem cells, and the significance of ballooned hepatocytes that form Mallory-Denk bodies as progenitor pre-cancer cells in the pathogenesis of the transformation of alcohol liver disease to hepatocellular carcinoma (ALD/HCC) (2). Chen and colleagues, from UC Davis, bring us up to date on the current classification of pancreatic neuroendocrine tumors (PNTs), with insight into genetic and molecular changes related to PNT subtypes and their clinical relevance (3). Zhao (UC Irvine) and Yue (LabCorp) update us on gastrointestinal stromal tumors (GIST), including their epidemiology, pathogenesis and genetics, diagnosis, role of molecular analysis, prognostic factors, and management strategies (4). Next, groups from Loma Linda University and UC Davis provide us with an update on primary gastrointestinal lymphomas and related neoplasms with respect to their pathogenesis, morphology, immunophenotype, molecular and genetic features, and prognostic factors (5). Following are reviews by teams from Guangdong General Hospital, China, and Loma Linda University, USA, discussing the association between obesity and esophageal cancer (6), and providing an update on Barrett’s esophagus, including current diagnostic criteria, clinical surveillance and promising endoscopic techniques for identifying patients at risk for malignancy (7). The next two articles, by teams from UC Davis and Loma Linda University and AmeriPath General Florida and Memorial Hospital of Jacksonville, Florida, educate us on the current classification of gastric cancer, including histologic features and genetic and molecular phenotypes; they clarify the characteristics of each subtype and highlight the potential for improving early diagnosis, prevention, and treatment (8,9). Advances in current understanding of molecular tumorigenesis and related targeted neoadjuvant therapeutic markers are also discussed, along with the application of immunohistochemical and molecular studies. The final two articles apply to GI tumors generally. Authors from the City of Hope National Medical Center review the immunohistochemical profiles of various GI tumors and discuss the application of immunohistochemistry in primary and differential diagnoses (10). Investigators from Loma Linda University discuss the role of cytopathology in the diagnosis and management of common GI tumors, including differential diagnoses and pitfalls, along with the advantages and limitations of different collection techniques (11). In summary, tumors of the GI tract include a wide variety of tumor types and are among the most common malignancies in clinical practice. New classification systems for some GI malignancies based on a combination of histologic features, immunophenotypes, and molecular/genetic abnormalities help us to better understand the characteristics of each subtype and offer a promise for improving early diagnosis, prevention, and treatment of these tumors. Recent advances in the understanding of the molecular pathways of GI tumorigenesis, including abnormalities in cell growth, the cell cycle, apoptosis, angiogenesis, invasion, and metastasis, have increasingly compartmentalized cancer into individual diseases, each with its own phenotype, each with its own set of biomarkers, and each with its own portfolio of targets for therapy. These factors allow the physician to tailored therapeutic approaches rationally to individual patients, with the potential for improving long-term survival and lowering the mortality of these often lethal tumors.

3538 Background: An immunosuppressive TIME can result in reduced efficacy of immune checkpoint inhibitors (ICIs) in GI tumors. GUC is preferentially expressed in colorectal (CRC), gastroesophageal junction (GEJ) and gastric adenocarcinoma (GA). There is an ongoing trial of a GUC-directed bispecific T cell-engager in advanced GI cancers. We sought to better characterize the TIME in GUC -high GI cancers to understand the immunogenicity of this novel target. Methods: CRC (N = 15,285), GEJ (N = 3,276) and GA (N = 2,420) tumors were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (592 genes or whole exome) and RNA (whole transcriptome). PD-L1 expression was assessed by IHC (22C3: TPS 1% [CRC] or 28-8: 2+, 80% [GEJ, GA]). A combination of IHC and NGS was used to assess mismatch repair and microsatellite instability ([MSI] high/low) status. GUC -high (H) and -low (L) expression (transcripts per million, TPM) was defined for each molecularly defined subtype as top and bottom quartile, respectively. Cell infiltration was estimated by QuantiSEQ. Mann-Whitney U and /Fisher’s exact tests were applied as appropriate, and significance was determined as p adjusted for multiple comparisons (Q<0.05). Real-world overall survival (OS) was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly-defined patients. Results: GUC expression was highest in CRC (22.0 TPM) followed by GEJ (4.9) and GA (4.4). GUC expression was higher in metastatic v primary tumors for CRC (24.0 v 21.7 TPM); the opposite was observed for GEJ (2.5 v 5.9) and GA (2.7 v 5.1, Q<.001 all). GUC expression was increased in left- v right-sided CRC (24.5 vs 19.0, Q<.001). Consensus molecular subtype 1 (CMS1) CRC had lower GUC expression compared to other CMS subtypes (CMS1: 9.5, CMS2: 28.8, CMS3: 20.2, CMS4: 21.9). GUC -H had a lower prevalence of PD-L1+ as compared to GUC-L for CRC MSI-H (5.2 v 46.4%), CRC MSS (.8 v 7.1%) and GEJ (26.6 v 45.7%, Q<.001 all) but not for GA (36.7 v 21.9%, Q=0.15). Across all tumor types, there were decreased M1 macrophages (mac) and increased M2 mac, neutrophils (NEU) and natural killer cell (NK) infiltrate in GUC -H v -L (Table). GUC -H tumors were associated with increased OS v GUC -L in CRC MSS (26.9 v 23.8 months, Q=.003) and GEJ tumors (13.9 v 10.8 months, Q=.021). Conclusions: GUC is expressed across GI cancers and GUC -H tumors are characterized by an “immune cold” TIME but longer OS. These results should be taken into consideration while evaluating the clinical utility of GUC as a novel immunotherapy target in advanced GI cancers that historically have not responded to ICI. GA GEJ CRC MSI CRC MSS Immune Infiltrate Mac. M1 Mac. M2 NEU NK cells Mac. M1 Mac. M2 NEU NK cells Mac. M1 Mac. M2 NEU NK cells Mac. M1 Mac. M2 NEU NK cells GUCY2C -L(% infiltrate) 5.10 3.2 4 4.9 5.1 2.8 4.5 4.3 8.4 1.1 3.5 2.5 5 2.5 4.9 2.8 GUCY2C -H(% infiltrate) 3.4 4.4 6.7 6.1 3.6 3.5 7.2 5.4 6.3 2.8 6 3.8 3.8 3.1 7.1 3.9

Gastrointestinal (GI) cancer is one of the most common malignancies, and a leading cause of cancer-related death worldwide. However, molecular targeted therapies are still lacking, leading to poor treatment efficacies. As an important layer of epigenetic regulation, RNA N6-Methyladenosine (m6A) modification is recently linked to various biological hallmarks of cancer by orchestrating RNA metabolism, including RNA splicing, export, translation, and decay, which is partially involved in a novel biological process termed phase separation. Through these regulatory mechanisms, m6A dictates gene expression in a dynamic and reversible manner and may play oncogenic, tumor suppressive or context-dependent roles in GI tumorigenesis. Therefore, regulators and effectors of m6A, as well as their modified substrates, represent a novel class of molecular targets for cancer treatments. In this review, we comprehensively summarize recent advances in this field and highlight research findings that documented key roles of RNA m6A modification in governing hallmarks of GI cancers. From a historical perspective, milestone findings in m6A machinery are integrated with a timeline of developing m6A targeting compounds. These available chemical compounds, as well as other approaches that target core components of the RNA m6A pathway hold promises for clinical translational to treat human GI cancers. Further investigation on several outstanding issues, e.g. how oncogenic insults may disrupt m6A homeostasis, and how m6A modification impacts on the tumor microenvironment, may dissect novel mechanisms underlying human tumorigenesis and identifies next-generation anti-cancer therapeutics.In this review, we discuss advances in our understanding of m6A RNA modification since its discovery in the 1970s to the latest progress in defining its potential clinic relevance. We summarize the molecular basis and roles of m6A regulators in the hallmarks of GI cancer and discuss their context-dependent functions. Furthermore, the identification and characterization of inhibitors or activators of m6A regulators and their potential anti-cancer effects are discussed. With the rapid growth in this field there is significant potential for developing m6A targeted therapy in GI cancers.

e16101 Background: To date, although a number of biomarker-related investigations have focused on the intrinsic properties of tumor cells and immune microenvironment, how germline genetics influences efficacy of immune checkpoint inhibitors (ICIs) immunotherapy in gastrointestinal (GI) cancer is scarcely understood. Methods: Our investigation enrolled 94 metastatic GI cancer patients treated with ICIs recruited from Peking University Cancer Hospital (PUCH) between August 1, 2015, and May 24, 2019. A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was used for validation. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood mononuclear cell (PBMC) from all 94 patients. Tumor tissues from 86 patients were subjected to WES analysis and immune oncology-related RNA profiling. Results: We assessed the clinic relevance of germline HLA heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) to immunotherapy in patients with advanced GI cancers from the PUCH cohort. Our data showed that neither HLA heterozygosity nor mean HED correlated with the overall survival (OS) in the PUCH cohort. However, patients with high HLA-B HED showed a better OS and durable clinic benefit (DCB) rate compared with the lower subgroup (p < 0.05 for all comparison). The prognostic value of HLA-B HED was consistently validated in the MSK GI cohort (N = 84). Notably, a combinatorial biomarker based on HLA-B HED and tumor mutation burden (TMB) could better stratify potential responders (86 patients with tumor samples). Survival analysis performed on the PUCH and MSK GI cancer datasets further demonstrated the potential joint utility of HLA-B HED and TMB for prognosis stratification. Moreover, HLA-B HED high subgroup was characterized with a lower prevalence of TP53 mutation and enrichment of multiple immune related pathways, indicating an immune-inflamed phenotype of this subgroup. Conclusions: Taken together, our data create an intriguing argument for the germline HLA-B sequence divergence and TMB as complementary biomarkers in guiding patient selection for GI cancer immunotherapy. Further investigation revealed a potential HLA-B restricted mutational pattern of TP53, and can be indicative of tumor immune microenvironment in GI cancer.

In the Modern era, immune checkpoint inhibitors (ICIs) have been the cornerstone of success in the treatment of several malignancies. Despite remarkable therapeutic advances, complex matrix together with significant molecular and immunological differences have led to conflicting outcomes of ICI therapy in gastrointestinal (GI) cancers. As far we are aware, to date, there has been no study to confirm the robustness of existing data, and this study is the first umbrella review to provide a more comprehensive picture about ICIs’ efficacy and safety in GI malignancies. Systematic search on PubMed, Scopus, Web of Science, EMBASE, and Cochrane library identified 14 meta-analyses. The pooled analysis revealed that ICIs application, especially programmed death-1 (PD-1) inhibitors such as Camrelizumab and Sintilimab, could partially improve response rates in patients with GI cancers compared to conventional therapies. However, different GI cancer types did not experience the same efficacy; it seems that hepatocellular carcinoma (HCC) and esophageal cancer (EC) patients are likely better candidates for ICI therapy than GC and CRC patients. Furthermore, application of ICIs in a combined-modal strategy are perceived opportunity in GI cancers. We also assessed the correlation of PD-L1 expression as well as microsatellite status with the extent of the response to ICIs; overall, high expression of PD-L1 in GI cancers is associated with better response to ICIs, however, additional studies are required to precisely elaborate ICI responses with respect to microsatellite status in different GI tumors. Despite encouraging ICI efficacy in some GI cancers, a greater number of serious and fatal adverse events have been observed; further highlighting the fact that ICI therapy in GI cancers is not without cost, and further studies are required to utmost optimization of this approach in GI cancers.

The miR-200 Family: Central Player for Gain and Loss of the Epithelial Phenotype

The crosstalk between the tumour immune microenvironment (TIME) and tumour cells promote immune evasion and resistance to immunotherapy in gastrointestinal (GI) tumours. Post-transcriptional regulation of genes is pivotal to GI tumours progression, and RNA-binding proteins (RBPs) serve as key regulators via their RNA-binding domains. RBPs may exhibit either anti-tumour or pro-tumour functions by influencing the TIME through the modulation of mRNAs and non-coding RNAs expression, as well as post-transcriptional modifications, primarily N6-methyladenosine (m6A). Aberrant regulation of RBPs, such as HuR and YBX1, typically enhances tumour immune escape and impacts prognosis of GI tumour patients. Further, while targeting RBPs offers a promising strategy for improving immunotherapy in GI cancers, the mechanisms by which RBPs regulate the TIME in these tumours remain poorly understood, and the therapeutic application is still in its early stages. This review summarizes current advances in exploring the roles of RBPs in regulating genes expression and their effect on the TIME of GI tumours, then providing theoretical insights for RBP-targeted cancer therapies.

Simple SummaryA disintegrin and metalloproteinase (ADAM) proteins are proteolytic enzymes that are responsible for destroying the extracellular matrix, but they also have adhesive properties. Recent investigations have demonstrated that the expression of several ADAMs is upregulated in gastrointestinal (GI) tumour cells and have linked the secretion of these proteins to pathogenesis of GI malignancies. Therefore, the aim of this review is to establish the involvement of selected ADAMs in the progression of GI malignancies as well as their prognostic significance. It was found that selected ADAMs might stimulate the proliferation and invasion of malignant cells and may be associated with unfavourable survival of patients with GI tumours. In conclusion, this review confirms the significance of selected ADAMs in the pathogenesis of the most common GI cancers and indicates their promising significance as potential prognostic biomarkers as well as therapeutic targets for GI malignancies.The global burden of gastrointestinal (GI) cancers is expected to increase. Therefore, it is vital that novel biomarkers useful for the early diagnosis of these malignancies are established. A growing body of data has linked secretion of proteolytic enzymes, such as metalloproteinases (MMPs), which destroy the extracellular matrix, to pathogenesis of GI tumours. A disintegrin and metalloproteinase (ADAM) proteins belong to the MMP family but have been proven to be unique due to both proteolytic and adhesive properties. Recent investigations have demonstrated that the expression of several ADAMs is upregulated in GI cancer cells. Thus, the objective of this review is to present current findings concerning the role of ADAMs in the pathogenesis of GI cancers, particularly their involvement in the development and progression of colorectal, pancreatic and gastric cancer. Furthermore, the prognostic significance of selected ADAMs in patients with GI tumours is also presented. It has been proven that ADAM8, 9, 10, 12, 15, 17 and 28 might stimulate the proliferation and invasion of GI malignancies and may be associated with unfavourable survival. In conclusion, this review confirms the role of selected ADAMs in the pathogenesis of the most common GI cancers and indicates their promising significance as potential prognostic biomarkers as well as therapeutic targets for GI malignancies. However, due to their non-specific nature, future research on ADAM biology should be performed to elucidate new strategies for the diagnosis of these common and deadly malignancies and treatment of patients with these diseases.

Gastrointestinal (GI) cancers are common cancers that are responsible for a large portion of global cancer fatalities. Due to this, there is a pressing need for innovative strategies to identify and treat GI cancers. MicroRNAs (miRNAs) are short ncRNAs that can be considered either cancer-causing or tumor-inhibiting molecules. MicroRNA-155, also known as miR-155, is a vital regulator in various cancer types. This miRNA has a carcinogenic role in a variety of gastrointestinal cancers, including pancreatic, colon, and gastric cancers. Since the abnormal production of miR-155 has been detected in various malignancies and has a correlation with increased mortality, it is a promising target for future therapeutic approaches. Moreover, exosomal miR-155 associated with tumors have significant functions in communicating between cells and establishing the microenvironment for cancer in GI cancers. Various types of genetic material, such as specifically miR-155 as well as proteins found in cancer-related exosomes, have the ability to be transmitted to other cells and have a function in the advancement of tumor. Therefore, it is critical to conduct a review that outlines the diverse functions of miR-155 in gastrointestinal malignancies. As a result, we present a current overview of the role of miR-155 in gastrointestinal cancers. Our research highlighted the role of miR-155 in GI cancers and covered critical issues in GI cancer such as pharmacologic inhibitors of miRNA-155, miRNA-155-assosiated circular RNAs, immune-related cells contain miRNA-155. Importantly, we discussed miRNA-155 in GI cancer resistance to chemotherapy, diagnosis and clinical trials. Furthermore, the function of miR-155 enclosed in exosomes that are released by cancer cells or tumor-associated macrophages is also covered.Graphical Various mechanisms can be affected by miNA-155 and exosomal miR-155. Various molecular processes linked to angiogenesis and apoptosis in GI cancers.

Simple SummaryPancreatic cancer is one of the most lethal cancer types and its high refractoriness to therapies, including immunotherapy, has often been associated with the predominantly immune suppressive tumor microenvironment that characterizes pancreatic tumors. Regulatory T cells (Tregs) are generally considered as drivers of immune suppression in cancers. However, an increasing number of reports suggest a paradoxical association between tumor infiltration by Tregs and improved patient prognosis, in particular in gastrointestinal cancers. Here we show that Treg infiltration in pancreatic ductal adenocarcinomas (PDAC) is associated with better overall survival of patients.Pancreatic ductal adenocarcinoma (PDAC) is considered to be a poorly immunogenic cancer type that combines a low mutation burden with a strong immunosuppressive tumor microenvironment. Regulatory T cells (Tregs) are major drivers of immune suppression but their prognostic role, particularly in gastrointestinal malignancies, remains controversial. Lymphocytic infiltration in 122 PDAC samples was assessed by multispectral immunofluorescence with anti-Keratin, -CD3, -CD8, -FOXP3 and -CD163 antibodies. Differential infiltration by Tregs was analyzed in the context of transcriptomic profiles that were available for 65 tumors. High infiltration of CD3+CD8− (mainly CD4+) T cells and, especially, of the subset expressing FOXP3 (Tregs) was associated with improved patient survival, whilst cytotoxic CD3+CD8+ T cell infiltration did not have an impact on overall survival. Transcriptomic analysis revealed three signatures in PDAC tumors comprising of epithelial-mesenchymal transition (EMT)/stromal, metabolic, and secretory/pancreatic signature. However, none of these signatures explained differences in Treg infiltration. We show that Tregs associate with improved overall survival in PDAC patients. This effect was independent of cytotoxic T cell infiltration and the transcriptomic profiles of their respective tumors. These findings provide a new layer of complexity in the study of PDAC tumor microenvironment that must be considered when developing immunotherapeutic interventions for this disease.

e16324 Background: Cirrhosis is a leading cause of death in the United States, and it represents a significant cause of deterioration in the quality of life of patients worldwide. Patients with cirrhosis can be affected by malignant and non-malignant co-morbid conditions, which can impact their prognosis. Among these, gastrointestinal (GI) malignancies like colorectal, pancreatic, and hepatic represent some of the most prevalent tumors affecting the GI tract. As both cirrhosis and cancer rates rise, our study aims to explore the impact of cirrhosis on hospitalization outcomes in gastrointestinal (GI) Cancer. Methods: We used the National Inpatient sample from 2016-2020 and identified admission with a diagnosis of GI cancer using International Classification of Disease-10 codes. The cohort was further stratified into patients with a secondary diagnosis of Cirrhosis compared to those without cirrhosis. All analysis was performed using STATA V17, considering P < 0.05 statistically significant. Multivariate regression analysis was used, and confounding variables adjusted were age, gender, race, insurance, and baseline hospital characteristics. Results: A total of 1,391,165 admissions with GI malignancies were identified from 2016 to 2020. Among these, 272,729 (19.6%) had a secondary diagnosis of cirrhosis, while 1,118,435 (80.4%) did not. The cirrhotic cohort was more likely to be male (71.4%) compared to the non-cirrhotic cohort (55.5%). Cirrhosis was most commonly associated with hepatocellular carcinoma (81.7%), pancreatic cancer (8.1%), and colorectal cancer (5.7%). Patients with cirrhosis have higher mortality rates in various GI cancers. This includes esophageal cancer (17.0%) compared to those without cirrhosis (10.7%), with an adjusted odds ratio of 1.55 (95% confidence interval: 1.02-2.34, P < 0.05). Similarly, higher mortality rates were observed in gastric cancer (15.8%), colorectal cancer (12.6%), hepatocellular carcinoma (11.1%), biliary tract cancer (13.9%), and pancreatic cancer (11.5%) compared to those without cirrhosis, with adjusted odds ratios of 1.63, 2.06, 1.41, 1.78, and 1.41 respectively. Conclusions: In this study of 1.4 million gastrointestinal malignancy-related admissions from 2016 to 2020, 19.6% had a secondary diagnosis of cirrhosis. This cohort of patients had a higher mortality rate in various gastrointestinal cancers than those without cirrhosis. Cirrhosis was more commonly associated with hepatocellular carcinoma, followed by gastric cancer. These findings suggest that cirrhosis is a significant risk factor linked with higher mortality in gastrointestinal malignancy-related admissions. Further research is necessary to characterize this association better in order to improve outcomes for patients with cirrhosis and GI malignancies.

Malnutrition, particularly under-nutrition, is highly prevalent among adult patients with a diagnosis of gastrointestinal (GI) cancer and negatively affects patient outcomes. Malnutrition is associated with clinical and surgical complications for patients undergoing therapy for GI cancers and the costs associated with those complications is a high burden for the US health system. Our objective was to identify high-quality evidence for nutrition support interventions associated with cost savings for patient care, followed by a complex economic value analysis to project cost savings for the US health system. A narrative literature search was conducted in which combined keywords in the areas of therapeutic nutrition (nutrition, malnutrition), a specific therapeutic area [GI cancer (esophageal, gastric, gallbladder, pancreatic, liver/hepatic, small and large intestine, colorectal)], and clinical outcomes and healthcare cost, to look for nutrition interventions that could significantly improve clinical outcomes. Medicare claims data were then analyzed using the findings of these identified studies and this modeling exercise supported identifying the cost and healthcare resource utilization implications of specific populations to determine the impact of nutrition support on reducing these costs as reflected in the summary of the evidence. Eight studies were found that provided clinical outcomes and health cost savings data, 2 of those had the strongest level of evidence and were used for Value Analysis calculations. Nutrition interventions such as oral diet modifications, enteral nutrition (EN) supplementation, and parenteral nutrition (PN) have been studied especially in the peri-operative setting. Specifically, peri-operative immunonutrition administration and utilization of enhanced recovery pathways after surgery have been associated with significant improvement in postoperative complications and decreased length of hospital stay (LOS). Utilizing economic modeling of Medicare claims data from GI cancer patients, potential annual cost savings of $242 million were projected by the widespread adoption of these interventions. Clinical outcomes can be improved with the use of nutrition interventions in patients with GI cancers. Healthcare costs can be reduced as a result of fewer in-hospital complications and shorter lengths of hospital stay. The application of nutrition intervention provides a positive clinical and economic value proposition to the healthcare system for patients with GI cancers.