Types Of Gastrointestinal Cancers Research Articles

Differences in pretreatment frailty across gastrointestinal (GI) cancers in older adults: Results from the Cancer and Aging Resilience Evaluation (CARE) registry.

542 Background: Frailty is an independent predictor of mortality in older adults and has been used to predict surgical complications and chemotherapy toxicities in GI cancers. How frailty differs between GI cancer types is unknown and could explain disparities in cancer outcomes. Our goal was to examine differences in pre-treatment frailty and geriatric assessment (GA) domain impairments between pancreatic, hepatobiliary, and colorectal cancers (CRC). We hypothesized that patients with more aggressive cancers (such as pancreatic cancer) would have increased frailty and more GA impairments, even prior to initiation of treatment. Methods: Our study included older adults age ≥60 years with cancer enrolled in the CARE Registry at the University of Alabama at Birmingham (UAB) who underwent a patient-reported GA during their initial visit with a GI medical oncologist. The GA was performed prior to any cancer-directed therapy. Frailty was defined using the 44-item CARE frailty index constructed based on principles of deficit accumulation described by Rockwood et al. We evaluated differences in frailty and GA domains between patients with CRC, pancreatic, and hepatobiliary cancers. Lastly, using a multivariable model we examined the adjusted odds ratio (aOR) of frailty by GI cancer type (reference CRC), adjusted for age, sex, race, cancer stage, and comorbidities. Results: Our study included 505 patients; 211 (41.8%) with CRC, 178 (35.2%) with pancreatic, and 116 (23.0%) with hepatobiliary cancers. Mean age of 70 years (standard deviation of 7) and 59% male. Cancer types did not differ by age, race, or sex. Patients with pancreatic and hepatobiliary cancers had more advanced cancer stage at time of assessment (stage IV 36.2% for CRC, 44.9% for pancreatic, and 45.2 for hepatobiliary; p=0.007). Older adults with pancreatic cancer had the highest prevalence of frailty (23.3% for CRC, 40.6% for pancreatic, and 34.3% for hepatobiliary; p=0.001), instrumental activities of daily living limitations (50.2% for CRC, 64.3% for pancreatic, and 52.7% for hepatobiliary; p=0.018), and malnutrition (40.8% for CRC, 70.3% for pancreatic, and 45.4% for hepatobiliary; p< 0.001). In multivariable analyses, older patients with pancreatic cancer had a 2.0 times higher odds of frailty in comparison to patients with CRC (aOR 2.0 95% CI 1.2-3.3, p=0.007). Conclusions: Older adults with pancreatic cancer had a higher prevalence of pre-treatment frailty, malnutrition, and functional impairments compared to CRC and hepatobiliary cancers. A focus on early intervention in these patients with optimization of nutrition and targeted physical/occupational therapy prior to and during treatment may help mitigate these factors and potentially improve outcomes.

Utilization of next generation sequencing (NGS) in stage IV gastrointestinal (GI) cancer patients (pts) and efficacy of electronic reminder notification (ERN) in improving utilization of NGS in the private practice community-based setting.

73 Background: NGS testing allows for identification of genetic mutations/alterations that can be important in determining treatment options for advanced cancer pts. The National Comprehensive Cancer Network (NCCN) includes NGS testing as part of standard of care for many tumor types including stage IV pancreatic cancer, colon cancer, and rectal cancer and all other GI solid tumor types. Previous reports have described the utilization of NGS in clinical practice at academic centers. To our knowledge this is the first report in the private practice setting. Methods: For the historical portion, we established baseline data to quantify NGS testing frequency in stage IV GI tumor pts in our community based oncology practice by performing a retrospective chart review. In the prospective portion, the intervention of an ERN was used to alert treating physicians if NGS had not been done. Primary endpoint is the percent (%) of pts with NGS sent compared to historical control. Secondary endpoint is the % of pts with targeted therapy options made available to them. Results: In a private practice multi-office setting, 200 charts of pts with stage IV GI cancer using Flatiron’s OncoEMR software were reviewed for the retrospective cohort between July 1 to December 31, 2020. Of the 200, 44.5% (89 pts) had colon cancer, 17.5% (35 pts) had pancreatic cancer, 15% (30 pts) had rectal cancer, and 23% (46 pts) had other types of GI cancer. Of these, 87 (43.5%) pts had NGS testing; of which 41 of 89 (46.0%) are colon pts, 13 of 35 (37.1%) are pancreatic pts and 16 of 30 (53.3%) are rectal pts. For the prospective portion, between July 1 and August 15, 2021 each physician’s schedule was evaluated and an ERN was sent shortly before each Stage IV GI pt was to be seen. A total of 114 pts were reviewed, and 92 (79%) had NGS sent. Of these, 47 pts of 54 (87%) are colon pts, 12 of 15 (80%) are pancreatic pts, 16 of 21(76%) are rectal pts, and 17 of 24 (70%) are pts with other GI cancer. 2% of pts with NGS testing had a potentially actionable mutation identified. Conclusions: NGS testing is standard of care for pts with stage IV GI cancer that wish to pursue therapy. ERN was minimally helpful in increasing NGS testing. This may be in part due to the effect of the practice's emphasis on NGS testing, which increased its baseline prospective testing rate. Increased use of a team based approach in the office would be a key element to increasing compliance with the current workflow as well as use of pathways which embed the NGS testing into the treatment plan. A more robust EMR would also be vital in increasing NGS testing rates by the use of automatic reminders or order sets. Better support of the physician and use of multiple touch points is necessary until full automation is utilized for NGS testing.

Multi-Omics Reveal the Immunological Role and the Theragnostic Value of miR-216a/GDF15 Axis in Human Colon Adenocarcinoma.

Colon adenocarcinoma (COAD) is the most common type of gastrointestinal cancer and is still the third leading cause of cancer-related mortality worldwide. Accurate screening tools for early diagnosis and prediction of prognosis and precision treatment strategies are urgently required to accommodate the unmet medical needs of COAD management. We herein aimed to explore the significance of the microRNA (miR)-216a/growth differentiation factor 15 (GDF15) axis in terms of clinical value, tumor immunity, and potential mechanisms in COAD by using multi-omic analysis. The gene expression levels of miR-216a and GDF15 showed an increase in the COAD group compared to those of the normal group. The expression of miR-216a presented a negative correlation with GDF15 in COAD tumor tissue. The use of an in vitro luciferase reporter assay and bioinformatic prediction revealed that miR-216a-3p acted toward translational inhibition on GDF15 by targeting its 3′untranslated region (UTR) site. High miR-216a expression was associated with decreased overall survival (OS), while the high expression of GDF15 was associated with increased OS. Enriched type 1 T-helper (Th1), enriched regulatory T (Treg), enriched eosinophils, and decreased nature killer T-cells (NKTs) in COAD tumor tissue may play counteracting factors on the tumor-regulatory effects of miR-216a and GDF15. In addition, high GDF15 expression had associations with suppressed immunoinhibitory genes and negative correlations with the infiltration of macrophages and endothelial cells. The enrichment analysis revealed that GDF15 and its co-expression network may be implicated in mitochondrial organization, apoptosis signaling, and endoplasmic reticulum (ER) stress response. The Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Therapeutics Response Portal (CTRP) analysis identified that Gemcitabine acted as a precision treatment for COAD when GDF15 expression was low. This study supports the miR-216a/GDF15 axis as a diagnostic/prognostic panel for COAD, identifies Th1, Treg, eosinophils, and NKTs as counteracting factors, indicates potential relationships underlying immunomodulation, mitochondrial organization, apoptotic signaling, and ER stress and unveil Gemcitabine as a potential drug for the development of treatment strategy when combined with targeting GDF15.

Correlations between P2RX1 Expression and Gastrointestinal Cancers Prognosis and Immune Infiltration Based on Bioinformatics Analysis

This study was conducted to explore the correlations between the expression, methylation, and various clinicopathological factors of purinergic P2X1 receptor (P2RX1) and the prognosis of patients with gastrointestinal tumors. The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases were used to analyze the expression of P2RX1 in different types of gastrointestinal cancers. Kaplan-Meier analysis and univariate Cox regression analysis were used to analyze the correlations between P2RX1 expression and the prognosis of various gastrointestinal tumors. Correlations between P2RX1 expression and N6 methyladenine (m6A)-related genes as well as immune checkpoint genes were analyzed by R packages (R version: 4.0.3) based on TCGA database. The association between P2RX1 methylation level and the prognosis of patients with gastrointestinal cancers was analyzed using the MethSurv database. In order to explore the biological functions of P2RX1 in hepatocellular carcinoma, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis were carried out using R software. In order to evaluate the correlations between P2RX1 and tumor immune infiltration, Spearman correlation test was performed. The correlations between P2RX1 expression and immune score as well as immune checkpoint genes were analyzed based on TCGA and Tumor Immune Estimation Resource (TIMER) databases. The expression of P2RX1 was found to be significantly downregulated in gastrointestinal tumors except in cholangiocarcinoma (P < 0.05). High expression of P2RX1 tended to present better prognosis in hepatocellular carcinoma (P < 0.05). It was noted that cg06475633 of P2RX1 presented a higher methylation level compared with other CpG sites in hepatocellular carcinoma. Overall, six CpGs of P2RX1 were associated with significant prognosis in patients with hepatocellular carcinoma (P < 0.05). Among all the 20 m6A-related genes, Wilms’ tumor 1-associating protein (WTAP) was the most strongly correlated with P2RX1 in hepatocellular carcinoma. Gene enrichment analysis showed that P2RX1 is widely involved in the proliferation, activation, organization, and differentiation of various immune cells. After investigating the TIMER database, P2RX1 was found to be tightly correlated with immune infiltrating cells in gastrointestinal tumors, especially with dendritic cells. Moreover, P2RX1 was found to be strongly positively associated with programmed cell death 1 (PD1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) in hepatocellular carcinoma (P < 0.05). In conclusion, the dual role of P2RX1 in cancers and its involvement in the recruitment as well as regulation of tumor infiltrating cells in gastrointestinal cancers may be appreciated through this study.

CRISPR/Cas9 in Gastrointestinal Malignancies

Gastrointestinal (GI) cancers such as colorectal cancer (CRC), gastric cancer (GC), esophageal cancer (EG), pancreatic duct adenocarcinoma (PDAC) or hepatocellular cancer (HCC) belong to the most commonly diagnosed types of cancer and are among the most frequent causes of cancer related death worldwide. Most types of GI cancer develop in a stepwise fashion with the occurrence of various driver mutations during tumor progression. Understanding the precise function of mutations driving GI cancer development has been regarded as a prerequisite for an improved clinical management of GI malignancies. During recent years, CRISPR/Cas9 has developed into a powerful tool for genome editing in cancer research by knocking in and knocking out even multiple genes at the same time. Within this review, we discuss recent applications for CRISPR/Cas9-based genome editing in GI cancer research including CRC, GC, EG, PDAC and HCC. These applications include functional studies of candidate genes in cancer cell lines or organoids in vitro as well as in murine cancer models in vivo, library screening for the identification of previously unknown driver mutations and even gene therapy of GI cancers.

Assessment of the Anti-Cancer Efficiency of Silver Moringa oleifera Leaves Nano-extract against Colon Cancer Induced Chemically in Rats.

Background:Colorectal cancer (CRC) categorized as the most common type of gastrointestinal cancers affected both genders equally. Chemotherapeutic drugs became limited due to their deleterious side effects. Therefore, efficiency of M. oleifera leaves extract increased by incorporating silver nanoparticles (Ag-NPs) then studied against colon cancer induced by azoxymethane (AOM) in rats. Methods:Different hematological and biochemical measurements in addition to specific tumor and inflammatory markers were quantified. Histopathological examination for Colonic tissues was performed. Native proteins and isoenzyme patterns were electrophoretically detected in addition to assaying expression of Tumor Protein P53 (TP53) and Adenomatous Polyposis Coli (APC) genes in colonic tissues.Results: M. oleifera nano-extract restored levels of the hematological and biochemical measurements in addition to levels of tumor and inflammatory markers to normalcy in both of nano-extract simult- and post-treated groups. Also, it minimized severity of the histopathological alterations in the simult-treated group and prevented it completely in the post-treated group. The lowest similarity index (SI%) values were noticed with electrophoretic protein (SI=61.54%), lipid (SI=0.00%) and calcium (SI=75.00%) moieties of protein patterns, catalase (SI=85.71%), peroxidase (SI=85.71%), α-esterase (SI=50.00%) and β-esterase (SI=50.00%) isoenzymes in addition to altering the relative quantities of total protein and isoenzyme bands in colon of cancer induced group. Moreover, levels of TP53 and APC gene expression increased significantly (P≤0.05) in colon cancer induced group. The nano-extract prevented the qualitative and quantitative alterations in the different electrophoretic patterns in addition to restoring levels of the gene expressions to normalcy in both of simult- and post-treated groups. Conclusion: M. oleifera nano-extract exhibited ameliorative effect against the biochemical, physiological and molecular alterations induced by AOM in nano-extract simult- and post-treated groups.

Gastrointestinal hemorrhage in the setting of gastrointestinal cancer: Anatomical prevalence, predictors, and interventions.

BACKGROUNDGastrointestinal hemorrhage (GIH) is a common complication with gastrointestinal cancers (GIC). There is no comprehensive research that examines GIH in different types of GIC. AIMTo study the prevalence, predictors, and interventions of GIH based on the anatomical location of GIC.METHODSThis is a retrospective analysis of the 2016-2018 National Inpatient Sample database, the largest inpatient care database in the United States. All adult inpatients (≥ 18-year-old) were included. ICD-10-CM codes were used to identify patients with GIH and GIC. Prevalence of GIH was obtained based on the anatomical location of GIC. Predictors of GIH in the GIC population were studied using multivariate analysis. Interventions including endoscopy were compared to the non-intervention group to determine the differences in inpatient mortality.RESULTSOut of a total of 18173885 inpatients, 321622 (1.77%) cases had a diagnosis of GIC. Within GIC patients, 30507 (9.5%) inpatients had GIH, which was significantly (P < 0.001) more than the prevalence of GIH in patients without GIC (3.4%). The highest to lowest GIH rates are listed in the following order: Stomach cancer (15.7%), liver cancer (13.0%), small bowel cancer (12.7%), esophageal cancer (9.1%), colorectal cancer (9.1%), pancreatic cancer (7.2%), bile duct cancer (6.0%), and gallbladder cancer (5.1%). Within gastric cancer, the GIH rate ranged from 14.8% in cardia cancer to 25.5% in fundus cancer. Within small bowel cancers, duodenal cancers had a higher GIH rate (15.6%) than jejunal (11.1%) and ileal cancers (5.7%). Within esophageal cancers, lower third cancers had higher GIH (10.7%) than the middle third (8.0%) or upper third cancers (6.2%). When studying the predictors of GIH in GIC, socioeconomic factors such as minority race and less favorable insurances (Medicaid and self-pay) were associated with significantly higher GIH on multivariate analysis (P < 0.01). Chemotherapy and immunotherapy were also identified to have a lower risk for GIH [odds ratios (OR) = 0.74 (0.72-0.77), P < 0.001]. Out of 30507 GIC inpatients who also had GIH, 16267 (53.3%) underwent an endoscopic procedure, i.e., upper endoscopy or colonoscopy. Inpatient mortality was significantly lower in patients who underwent endoscopy compared to no endoscopy [5.5% vs 14.9%, OR = 0.42 (0.38-0.46), P < 0.001].CONCLUSIONThe prevalence of GIH in patients with GIC varies significantly based on the tumor’s anatomical location. Endoscopy, which appears to be associated with a substantial reduction in inpatient mortality, should be offered to GIC patients with GIH. Nevertheless, the decision on intervention in the GIC population should be tailored to individual patient's goals of care, the benefit on overall care, and long-term survival.

Global Analysis of Microbiota Signatures in Four Major Types of Gastrointestinal Cancer.

The gut microbiota has been previously linked with tumorigenesis and gastrointestinal cancer progression; however, intra-tumor microbiota analysis has just emerged and deserves increasing attention. Based on the public databases of The Cancer Microbiome Atlas (TCMA) and The Cancer Genome Atlas (TCGA), this study identified the tissue/organ microbial signatures generated from 443 biosamples of four major gastrointestinal cancer types, including esophageal carcinoma (ESCA), which further includes esophageal adenocarcinoma (EAD) and esophageal squamous cell carcinoma (ESCC), stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and rectum adenocarcinoma (READ). According to partial least squares discrimination analysis (PLS-DA), the profile differences in microbial communities between the tumor and normal samples were not particularly noticeable across the four cancer cohorts, whereas paired comparison analyses revealed several specific differences in bacteria between tumor and normal samples in the EAD, STAD, and COAD samples. The taxa classified from the phylum to genus level revealed a trend of distinguishable microbial profiles between upper and lower gastrointestinal tumors. The Bacteroidetes/Firmicutes ratio in lower gastrointestinal tract tumors was nearly three times that in upper gastrointestinal tract tumors. We also determined the relative tissue/organ-prevalent microbes for each of the four cohorts at the order and genus levels. Microbe Alistipes, Blautia, Pasteurellales, and Porphyromonas compositions were correlated with the clinical characteristics of patients with gastrointestinal cancer, particularly colorectal cancer. Taken together, our findings indicate that microbial profiles shift across different gastrointestinal cancer types and that microbial colonization is highly site-specific. Composition of specific microbes can be indicative of cancer stage or disease progression. Overall, this study indicates that the microbial community and abundance in human tissues can be determined using publicly available data, and provides a new perspective for intra-tissue/organ microbiota research.

The recurring features of molecular subtypes in distinct gastrointestinal malignancies-A systematic review.

In colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC) and gastric cancer (GC) multiple studies of inter-tumor heterogeneity have identified molecular subtypes, which correlate with clinical features. Our aim was to investigate the attributes of molecular subtypes across three different gastrointestinal cancer types. We performed a systematic search for publications on molecular subtypes or classifications in PDAC and GC and compared the described subtypes with the established consensus molecular subtypes of CRC. Examining the characteristics of subtypes across CRC, PDAC and GC resulted in four categories of subtypes. We describe uniting and distinguishing features within a mesenchymal, an epithelial, an immunogenic and a metabolic and digestive subtype category. We conclude that molecular subtypes of CRC, PDAC and GC display relevant overlap in molecular features and clinical outcomes. This finding encourages quantitative studies on subtypes across different cancer types and could lead to a paradigm shift in future treatment strategies.

Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer.

Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC.Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan–Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression.Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation.Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

Cytotoxic and Proapoptotic Effects of Resveratrol in In Vitro Studies on Selected Types of Gastrointestinal Cancers.

Cancer diseases are currently one of the greatest health challenges in clinical medicine worldwide. Classic methods of treatment often lead to numerous side effects, including the development of multidrug resistance. For this reason, increasing hope is being placed on compounds of natural origin, mainly due to their pleiotropic effect on different types of cells, protective effect on normal cells and toxic effect on cancerous ones. The most studied group are the polyphenolic compounds, which include resveratrol. The effectiveness of polyphenols in the treatment and prevention of many diseases, including cancer of various origins, has become the basis of many scientific studies. The anticancer effect of resveratrol has been demonstrated at all stages of the carcinogenesis process. Additionally, whether administered by itself or in combination with cytostatics, it may play a significant role in the process of reversing multidrug resistance. A review of the effects of resveratrol in in vitro conditions proves that it has a stronger or weaker antiproliferative and proapoptotic effect on the cells of certain neoplasms of the gastrointestinal tract. Despite the differences in the effect of this compound on different types of cancer, a similar tendency can be observed especially regarding the correlation between the concentration of the compound and the incubation time on the one hand and the antitumour effect on the other hand. The information included in this review may prove helpful in planning in vivo and clinical studies in the future.

Comprehensive characterization of neurotransmitters and neuronal signaling (NT) pathway alterations in colorectal cancer (CRC).

3537 Background: Aberrant NT signaling has been shown to activate uncontrolled proliferation and dissemination in several gastrointestinal cancer types. Neurotransmitters have been shown to affect endothelial cells and immune cells in the tumor microenvironment to promote tumor progression. We previously showed that single nucleotide polymorphisms in the dopamine and GABA pathways are associated with outcome in patients with metastatic CRC receiving first-line treatment. Here we further evaluated the distribution and molecular context of NT pathway alterations in CRC. Methods: A total of 7,595 CRC tumors tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA (Next Seq, 592 genes or NovaSeq, WES) and RNA (NovaSeq, WTS) were analyzed. ssGSEA (single-sample gene set enrichment analysis) was used to calculate pathway enrichment scores (ES) of 7 NT gene sets (GABA, nicotinic, muscarinic, dopamine (DA), reelin, glial cell line-derived neurotrophic factor and neurotrophins). X2/Fisher-Exact was used for comparison and significance was determined as p-value adjusted for multiple comparison of ( q) &lt; 0.05. Results: ES based on sample sites showed a substantial heterogeneity in NT enrichment. Notably, when compared to primary tumors, all 7 gene sets were significantly enriched in brain metastases (mets; ES ratio 1.14-1.55), while abdomen, liver, and peritoneal mets displayed significant decreases in most NT gene sets. DA was enriched in ovarian and lung mets (ES ratio: 1.18 and 1.09, respectively), the latter also showing increased neurotrophins ES (1.06) (all q &lt; 0.05). When investigating primary tumors grouped according to overall ES by unsupervised clustering, right-sided and CMS4 CRCs were more prevalent in the high ES cluster compared to the low ES cluster (32 vs 29%, P = 0.02 and 46 vs 30%, P &lt; 0.001, respectively). In addition, tumors in the high ES cluster showed lower prevalence of TMB-H (≥ 10mt/MB) (7 vs 10%), MSI-H (6 vs 10%) and PD-L1 (2 vs 6%), while higher CNA rates were noted in 9 genes (all q &lt; 0.05). High ES tumors showed significant positive associations with microenvironment infiltration of B cells, T cells (NK, CD4+ and CD8+ T cells, but not Treg), M2 Macrophages, Myeloid Dendritic Cell, Neutrophils, and an inverse association with M1 Macrophages, regardless of MSI status ( q &lt; 0.05). Conclusions: This is the first and most extensive molecular profiling study to investigate NT signaling pathway alterations in CRC. Our data show a distinct distribution of pathway enrichment according to metastatic site, distinct molecular features in high vs low ES clusters in primary tumors (including CMS subtypes, TMB, MSI and PD-L1 rates), and differential immune cell infiltration. These findings support the role of NT signaling in the metastatic spread of CRC and modulation of tumor immune microenvironment.

Decoupling epithelial-mesenchymal transitions from stromal profiles by integrative expression analysis

Epithelial-to-mesenchymal transition (EMT) is the most commonly cited mechanism for cancer metastasis, but it is difficult to distinguish from profiles of normal stromal cells in the tumour microenvironment. In this study we use published single cell RNA-seq data to directly compare mesenchymal signatures from cancer and stromal cells. Informed by these comparisons, we developed a computational framework to decouple these two sources of mesenchymal expression profiles using bulk RNA-seq datasets. This deconvolution offers the opportunity to characterise EMT across hundreds of tumours and examine its association with metastasis and other clinical features. With this approach, we find three distinct patterns of EMT, associated with squamous, gynaecological and gastrointestinal cancer types. Surprisingly, in most cancer types, EMT patterns are not associated with increased chance of metastasis, suggesting that other steps in the metastatic cascade may represent the main bottleneck. This work provides a comprehensive evaluation of EMT profiles and their functional significance across hundreds of tumours while circumventing the confounding effect of stromal cells.

Identification of gene signatures and potential therapeutic targets for acquired chemotherapy resistance in gastric cancer patients.

Gastric cancer (GC) is the most common type of gastrointestinal cancer, and has been studied extensively. However, resistance to chemotherapeutic agents has become a major problem, leading to treatment failure. This study aimed to investigate the molecular mechanisms mediating acquired resistance to cisplatin and fluorouracil (CF) combination-based chemotherapy in GC patients. The microarray datasets (GSE14209, GSE30070) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) using the limma package in R/Bioconductor. Possible targets of the DEMs were predicted using miRWalk, and the putative miRNA-mRNA regulatory network was constructed using Cytoscape software. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses were then conducted and visualized using the Search Tool for Retrieval of Interacting Genes (STRING) and Cytoscape. The prognostic value of hub genes was revealed by Kaplan-Meier Plotter. The causal relationships and interactions between proteins were displayed using DisNor. Finally, similarity analysis was conducted using the Connectivity Map (CMap) profiles to predict a group of small molecules in GC treatment. A total of 394 DEGs and 31 DEMs were identified after analysis of pre- and post-treatment samples of clinical responders to CF therapy. TM9SF4, hsa-miR-185-5p, and hsa-miR-145-5p were found to be critical in the miRNA-mRNA regulatory network. The DEGs were found to be mainly enriched in the processes of ribonucleoprotein complex assembly, catalytic activity acting on RNA, mitochondrial matrix, and thermogenesis. The DEMs were predominantly found to be involved in single-stranded RNA binding and endoplasmic reticulum lumen. HDAC5, DDX17, ILF3, and SDHC were identified as hub genes in the PPI network. Of these, HDAC5, DDX17, and ILF3 were found to be closely related to the overall survival of GC patients. DisNor identified the first neighbors of the key genes. Furthermore, CMap profiles predicted a group of small molecules, including several histone deacetylase inhibitors (HDACIs), menadione, and mibefradil, which could serve as promising therapeutic agents to reverse acquired resistance to CF therapy. Our findings reveal new targets and alternative therapies to overcome the acquired resistance of GC patients to CF treatment.

Identification of cluster of differentiation molecule-associated microRNAs as potential therapeutic targets for gastrointestinal cancer immunotherapy.

Cluster of differentiation molecules are markers of immune cells that have been identified as a potential immunotherapeutic target for cancer treatment. MicroRNAs are small non-coding RNAs that act as tumor suppressors or oncogenes whose importance in diagnosis, prognosis, and treatment of gastric and colorectal cancers has been widely reported. However, their association with cluster of differentiation molecules in gastrointestinal cancers has not been well studied. Therefore, our study aimed to analyze the relationship between microRNAs and cluster of differentiation molecules in gastrointestinal cancers, and to identify cluster of differentiation molecule-associated microRNAs as prognostic biomarkers for gastrointestinal cancer patients. Targetscan, Starbase, DIANA microT, and miRDB were used to investigate microRNA profiles that might be correlated with cluster of differentiation molecules in gastrointestinal cancers. Moreover, The Cancer Genome Atlas data analysis was used to investigate the association between cluster of differentiation molecules and microRNA expression in patients with gastric, colon, rectal, pancreatic, and esophageal cancers. The Kaplan-Meier plotter was used to identify the association between overall survival and cluster of differentiation molecule-associated microRNA expression in gastrointestinal cancer patients. miR-200a, miR-559, and miR-1236 were negatively associated with CD86, CD81, and CD160, respectively, in almost all types of gastrointestinal cancers, which were further verified in the in vitro studies by transfecting microRNA mimics in gastric cancer, colon cancer, pancreatic, and esophageal cell lines. Our study showed that miR-200a, miR-1236, and miR-559 are identified as cluster of differentiation-associated microRNAs in gastrointestinal cancers, providing a novel perspective to identify new therapeutic targets for cancer immunotherapy in gastrointestinal cancer patients.

Analysis of the PD-1 Ligands Among Gastrointestinal Cancer Patients: Focus on Cancer Immunity.

Many types of gastrointestinal cancer have shown promising outcomes after checkpoint blockade immunotherapy; however, it remains largely unclear about the expression profiles of programmed death 1 (PD-1) ligands (CD274 and PDCD1LG2) in the context of human pan-cancer. This work comprehensively analyzed the expression pattern of the PD-1 ligands and the clinical significance in the prognosis prediction among the seven types of gastrointestinal malignancies collected from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) database. Furthermore, the correlation of CD274/PDCD1LG2 with cancer immunity was also explored. The patients with liver hepatocellular carcinoma (LIHC) receiving cytokine-induced killer (CIK) cell immunotherapy at our cancer center were enrolled. CD274 and PDCD1LG2 displayed inconsistent gene expression levels among the diverse cancer cell lines. Typically, the abnormal expression level of CD274 and PDCD1LG2 was detected in both esophageal carcinoma (ESCA) and stomach adenocarcinoma (STAD), where PDCD1LG2 was related to the overall survival (OS) of the patients in ESCA (p = 0.015) and STAD (p = 0.025). High-serum CD274 and PDCD1LG2 levels predicted a worse survival in the patients with LIHC receiving CIK therapy. More importantly, the expression level of CD274 and PDCD1LG2 was significantly correlated with the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE). In addition, we found that CD274 and PDCD1LG2 were correlated with gene markers in tumor-infiltrating immune cells. Furthermore, the expression of CD274 and PDCD1LG2 was correlated with tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) of different types of cancers. The present work comprehensively analyzed a RNA sequencing of the PD-1 ligands across the seven distinct types of gastrointestinal cancers, which provided clues for further studies in cancer immunity and development.

Sarcopenia predicts worse postoperative outcomes and decreased survival rates in patients with colorectal cancer: a systematic review and meta-analysis.

Previous studies have shown an association of sarcopenia with adverse short- and long-term outcomes in multiple gastrointestinal cancer types. We aimed to investigate the prognostic value of sarcopenia on the postoperative outcomes and survival rates of patients with colorectal cancer (CRC). A systematic literature search was performed using the PubMed, Embase, Cochrane, Google Scholar, and Scopus databases. We included studies that compared postoperative outcomes or survival rates in sarcopenic and non-sarcopenic patients with CRC. A total of 44 observational studies, comprising 18,891 patients, were included. The pooled prevalence of sarcopenia was 37% (n = 7009). The pooled analysis revealed an association between sarcopenia and higher risk of total postoperative complications (23 studies, OR = 1.84; 95% CI 1.35-2.49), postoperative severe complications (OR = 1.72; 95% CI 1.10-2.68), postoperative mortality (OR = 3.21; 95% CI 2.01-5.11), postoperative infections (OR = 1.40; 95% CI 1.12-1.76), postoperative cardiopulmonary complications (OR = 2.92; 95% CI 1.96-4.37), and prolonged length of stay (MD = 0.77; 95% CI 0.44-1.11) after colorectal cancer surgery. However, anastomotic leakage showed comparable occurrence between sarcopenic and non-sarcopenic patients (OR = 0.99; 95% CI 0.72 to 1.36). Regarding survival outcomes, sarcopenic patients had significantly shorter overall survival (25 studies, HR = 1.83; 95% CI = 1.57-2.14), disease-free survival (HR = 1.55; 95% CI = 1.29-1.88), and cancer-specific survival (HR = 1.77; 95% CI 1.40-2.23) as compared with non-sarcopenic patients. Among patients with colorectal cancer, sarcopenia is a strong predictor of increased postoperative complications and worse survival outcomes.

Genomic profiling of gastrointestinal cancers by comprehensive tumor-normal sequencing.

109 Background: Gastrointestinal cancers (GIC) account for 26% of global cancer incidence and 35% of cancer-related deaths. We investigated the molecular landscape and therapeutic targets across 18 types of GIC using whole exome (WES) and whole transcriptome sequencing (WTS). Methods: GEM ExTra assay was performed on 603 paired samples (ages 18-90 years, median = 61 years). Targeted sequence coverage was 180X for germline DNA and 400X for tumor DNA. Reportable somatic alterations included single base substitutions, indels, Copy Number Alterations, gene fusions, alternate transcripts, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. Germline subtraction identified somatic-specific alterations. Results: Analysis of 603 GIC patient samples, including esophageal, gastric cancer (GC), biliary tract (BT), pancreatic cancer (PC), colorectal cancer (CRC), and other cancers, identified 434 actionable targets. The median number of alterations was 3 per GIC patient. The 5 most common actionable alterations were in APC, KRAS, CDKN2A, ARID1A and PIK3CA. Activation of Wnt signaling was found in 264/603 (44%), with the majority being in CRC cases. Alterations in cell cycle genes including CDKN2A, CDK4/6 and others were noted in 129/603 (21%) cases, with the majority in PC, suggesting benefit from CDK4/6 inhibitors. Activation of PI3K/PTEN/Akt/mTOR pathway was noted in 105/603 (17%), with the majority harbored in CRC, suggesting benefit from targeting this pathway. ERBB2 amplification and mutations were noted in 22/603 (4%) across different GIC tumor types. Alterations in homologous recombination genes predicting platinum and PARP inhibitor response was noted in 181/603 (30%) samples distributed across GIC subtypes. KRAS (G12C) mutation was found in 7% of all KRAS mutations across GIC subtypes, thus allowing patients to enroll in clinical trials with G12C-specific inhibitors. The majority of cases with MSI- and TMB-high status were identified in GC and CRC tumors and may be predictive of response to immunotherapy. WTS identified actionable fusions, including FGFR1/2/3 and novel NRG1 fusions in BT cancers. Conclusions: Our study revealed actionable targets used in patient selection for precision therapies, in addition to other mutational profiles of clinical significance. Overall, comprehensive genomic profiling enabled detection of established and novel actionable alterations, including fusions, which may have gone undetected using hotspot panels.

Pneumatosis Intestinalis in Patients on Chemotherapy or Molecular Targeted Therapy: Report of 3 Cases

Pneumatosis intestinalis (PI) is a radiological term to describe the presence of gas in the bowel wall. It can occur as a primary disease or secondary to various other causes ranging from benign conditions to life-threatening diseases. We present three cases of PI in patients being treated for different types of gastrointestinal cancer. The diagnosis was made incidentally on follow-up CT scanning for two patients, who had only mild gastrointestinal symptoms. For the last patient, it was diagnosed in the setting of fever and clostridium difficile infection. A conservative treatment was advocated and follow-up imaging showed resolution of the PI in two out of three cases. It is important to distinguish between chemotherapy induced PI and other life-threatening causes of PI, which often require urgent surgery. After resolution, risks and possible benefits of restarting of the culprit agent should be outweighed.

DNase1L3 suppresses hepatocellular carcinoma growth via inhibiting complement autocrine effect.

Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer and currently lacks effective treatment strategies. The present study revealed that deoxyribonuclease 1 like 3 (DNase1L3) expression levels were significantly downregulated in numerous types of gastrointestinal cancer, and especially in HCC. Tissue microarrays were further used to illustrate that DNase1L3 expression levels were frequently downregulated in HCC tissues compared with normal liver tissues. In addition, DNase1L3 expression levels were identified to be significantly associated with tumor size (p=0.0028), tumor thrombus formation (p<0.01), and a poorer overall survival (p=0.005) and disease-free survival (p=0.006) of HCC. Gene Ontology functional term enrichment analysis of biological processes discovered that DNase1L3 was significantly associated with complement activation. Further studies demonstrated that the ectopic expression of DNase1L3 suppressed cell growth and inhibited the PI3K/AKT signaling pathway activation following C3a receptor agonist treatment. In conclusion, the findings of the present study suggested, for the first time, that DNase1L3 may serve as a biomarker for the prognosis of patients with HCC, and may suppress HCC growth via inhibiting the PI3K/AKT signaling pathway.