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Gastrointestinal cancers are one of the most frequent cancers and a leading cause of cancer deaths worldwide. We provide an overview of the most important practice-changing trials that were either published or presented at the international scientific meetings in 2021–2023. Highlights included reports on three phase III trials (CONCORDE/PRODIGE 26, ARTDECO, and a study by Xu et al.) that evaluated dose escalation in the definitive setting for locally advanced oesophageal cancers, as well as two phase III trials that evaluated the role of chemotherapy (neo-AEGIS) and targeted therapy (NRG/RTOG 1010) in the neoadjuvant setting for adenocarcinoma oesophageal cancers or gastroesophageal junction cancer. CheckMate 577 evaluated nivolumab in patients who had residual pathological disease after neoadjuvant chemoradiation followed by complete resection. The use of radiation therapy for borderline and locally advanced pancreatic cancer is also discussed (SMART and CONKO-007 trials). Stereotactic body radiation therapy followed by sorafenib was compared to sorafenib alone in patients with hepatocellular carcinoma in the NRG/RTOG 1112 study. New options in the management of rectal cancer are emerging such as total neoadjuvant treatment (PRODIGE 23, RAPIDO, PROSPECT), organ preservation (OPRA, OPERA), and the role of immunotherapy in patients with DNA mismatch-repair deficient/microsatellite instability. Finally, preliminary results of the ACT 4 trial that evaluated de-escalation in anal cancer are presented. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) cancers are a group of malignancies that globally account for a significant portion of cancer incidence and cancer-related death. Survival outcomes for esophageal, gastric, pancreatic, and hepatobiliary cancers remain poor, but new treatment paradigms are emerging with the advent of immune checkpoint inhibitor (ICI) therapy. This review characterizes patient-related prognostic factors that influence the response to ICI therapy. We performed an analysis of the landmark randomized clinical trials in esophageal, gastric, colorectal, hepatocellular, pancreatic, and biliary tract cancers in terms of patient demographic factors. A literature review of smaller retrospective studies investigating patient-related factors was completed. The immunological bases for these associations were further explored. The key predictive factors identified include age, sex, performance status, geography, body mass index, sarcopenia, gut microbiome, various biochemical factors, and disease distribution. [ABSTRACT FROM AUTHOR]

Purpose: Gallium-68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) is an emerging promising tumor tracer. This study aims to evaluate the diagnostic efficiency of 68Ga-FAPI PET in gastrointestinal cancer, and to determine its potential impact on clinical management. Methods: Patients with malignancies were prospectively enrolled in a clinical trial to evaluate the diagnostic value of 68Ga-FAPI PET. One hundred twenty patients with gastrointestinal malignancies (121 68Ga-FAPI PET scans) between June 2020 and May 2021 were retrospectively analyzed. Initial staging of untreated patients and restaging of treated patients were evaluated. The treatment scheme promoted by imaging was determined according to NCCN guidelines. Final diagnosis and treatment reference standards were determined by a dedicated multidisciplinary team. The diagnostic performance and treatment guidance of 68Ga-FAPI PET were compared with those of conventional imaging (CI) and 18F-FDG PET. Results: The diagnostic accuracy of 68Ga-FAPI PET was much higher than that of CI and 18F-FDG PET (95.0% vs. 65.1% and 69.0%, respectively, both p < 0.001). 68Ga-FAPI PET revised diagnosis in 30.3% and 26.2% of patients compared with CI and 18F-FDG PET. The accordance rate of 68Ga-FAPI PET-guided treatment in comparison with the reference standard was significantly higher than that of CI and 18F-FDG PET (96.7% vs. 75.2% and 76.2%, respectively, both p < 0.001). 68Ga-FAPI PET changed treatment in 22.9% and 23.8% of patients compared with CI and 18F-FDG PET. Conclusions: 68Ga-FAPI PET showed remarkable diagnostic performance in gastrointestinal cancer, resulting in more accurate staging and guidance for timely treatment revision, thereby having a critical impact on clinical management. Trial registration: NCT04554719. Registered September 8, 2020—retrospectively registered, http://clinicaltrails.gov/show/NCT04554719 [ABSTRACT FROM AUTHOR]

Colon cancer is the leading cause for the malignancy in the gastrointestinal tract. Autophagy is a self-degradation process of the unnecessary, injured and aged organelles and proteins in the cell, which is followed by recovering of degraded products. Apoptosis is a programmed cell death which is characterized by membrane blebbing, chromosome condensation and nuclear fragmentation. Apoptosis and autophagy can occur frequently in a cell, predominantly in a series preceding apoptosis through autophagy by the formation of autophagosomes. In current research, the impact of autophagy inhibition and apoptosis activation were found to be the targeted strategies to treat colon cancer. This study is focused on the apoptotic potential of RA-V, a natural cyclopeptide through the inhibition of protective autophagy in colon cancer cells. Growth inhibitory properties were observed in the RA-V treated (125 μM) colo 320DM cells using cell viability assay. RA-V induced apoptosis of colo 320DM cells at the maximum concentration of 125 μM, which was observed using DAPI and Annexin - PI staining methods. In this study we also examined the mechanistic role of RA-V (125 μM) in and colo 320DM cells in the presence of Rapamycin (mTOR inhibitor) and chloroquine (autophagy inhibitor) using MDC and AO staining methods. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The influence of sedation on the endoscopic detection rate of upper gastrointestinal (UGI) early cancer (EC) and precancerous lesions, including high-grade intraepithelial neoplasia (HGIN) and low-grade intraepithelial neoplasia, has not been assessed. The aim of this research is to assess whether the use of sedation can help improve the detection rate of UGI EC and precancerous lesions. The second objective is to evaluate its potential influencing factors. METHODS: The study includes 432,202 patients from a multicenter database from January 2012 to July 2019. Information on endoscopic findings and histology biopsies was obtained from endoscopy quality-control system. Associations of sedation with the detection rate of EC and precancerous lesions were assessed. RESULTS: The sedation group has a higher detection rate of UGI EC and HGIN compared with the no-sedation group, whereas the detection rate of low-grade intraepithelial neoplasia was similar between the 2 groups. There were more cases examined by using staining, image enhancement, or magnifying techniques in the sedation group (P < 0.001). And, the mean observation time was also longer in the sedation group (P < 0.001). The type 0-IIb esophageal HGIN and EC cases were significantly increased in the sedation group. No significant difference was detected on lesion subtypes for gastric HGIN and EC according to the Paris classification. More gastric HGIN and EC were detected at gastric body in the sedation group (P = 0.001). DISCUSSION: Sedation may improve the endoscopic detection rate of EC and HGIN in the UGI tract probably through enhancing the use of accessary endoscopic techniques, prolonging observation time, and taking more biopsies in different locations (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/AJG/B926). [ABSTRACT FROM AUTHOR]

Although surgery was the standard treatment for early gastrointestinal cancers, endoscopic resection is now a standard treatment for early gastrointestinal cancers without regional lymph node metastasis. High-definition white light endoscopy, chromoendoscopy, and image-enhanced endoscopy such as narrow band imaging are performed to assess the edge and depth of early gastrointestinal cancers for delineation of resection boundaries and prediction of the possibility of lymph node metastasis before the decision of endoscopic resection. Endoscopic mucosal resection and/or endoscopic submucosal dissection can be performed to remove early gastrointestinal cancers completely by en bloc fashion. Histopathological evaluation should be carefully made to investigate the presence of risk factors for lymph node metastasis such as depth of cancer invasion and lymphovascular invasion. Additional treatment such as radical surgery with regional lymphadenectomy should be considered if the endoscopically resected specimen shows risk factors for lymph node metastasis. This is the first Korean clinical practice guideline for endoscopic resection of early gastrointestinal cancer. This guideline was developed by using mainly de novo methods and encompasses endoscopic management of superficial esophageal squamous cell carcinoma, early gastric cancer, and early colorectal cancer. This guideline will be revised as new data on early gastrointestinal cancer are collected. [ABSTRACT FROM AUTHOR]

O6‐carboxymethylguanine (O6‐CMG) is a highly mutagenic alkylation product of DNA, triggering transition mutations relevant to gastrointestinal cancer. However, precise localization of a single O6‐CMG with conventional sequencing platforms is challenging. Here nanopore sequencing (NPS), which directly senses single DNA bases according to their physiochemical properties, was employed to detect O6‐CMG. A unique O6‐CMG signal was observed during NPS and a single‐event call accuracy of >95 % was achieved. Moreover, O6‐CMG was found to be a replication obstacle for Phi29 DNA polymerase (Phi29 DNAP), suggesting this lesion could cause DNA sequencing biases in next generation sequencing (NGS) approaches. [ABSTRACT FROM AUTHOR]

Abstract Over the last 15 years there has been a change in how we understand the impact of the interaction between the tumour and the host on cancer outcomes. From the simplistic view that the make-up of tumours cells largely determines their aggressiveness to a more complex view that the interaction between the products of tumour and host cell signal transduction pathways is crucial in determining whether the tumour cell is eliminated or survives in the host. Of the host cells, those with an immune/inflammatory function are most well documented to inhibit or promote tumour cell proliferation and dissemination. It is only in the last few years that there has been greater recognition of the impact of intracellular, cellular and systemic immune/inflammatory phenotypes on patient outcomes independent of current tumour staging and that these phenotypes are useful in informing oncological research and practice. In the present review we will examine the importance of inflammatory phenotypes at the intra-cellular, cellular and systemic levels on outcomes in patients with gastrointestinal cancer with focus on colorectal cancer. Based on these phenotypes we will examine and discuss the prospects for therapeutic intervention. Highlights • The development and progression of colorectal cancer is heterogenous in nature. • Tumourogenesis occurs via systemic, cellular and intracellar mechanisms. • NF-κB and JAK-STAT signalling pathways represent key signalling cascades. • Components of signalling pathways are promising therapeutic targets. [ABSTRACT FROM AUTHOR]

Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and "under development" anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives. [ABSTRACT FROM AUTHOR]

Purpose: Severe gastrointestinal (GI) toxicity is a common adverse effect following 5-fluorouracil (5-FU)-based chemotherapy treatment. The presence of severe GI toxicity leads to treatment revisions, sub-optimal therapy outcomes, and decreases to patients' quality of life. There are no adequate predictors for 5-FU-induced severe GI toxicity risk. The Toll-like receptor/interleukin-1 (TIR) domain innate immune signalling pathway is known to be a mediating pathway in the development of GI toxicity. Hence, genetic variability in this signalling pathway may alter the pathophysiology of GI toxicity and, therefore, be predictive of risk. However, little research has investigated the effects of TIR domain innate immune signalling pathway single nucleotide polymorphism (SNPs) on the risk and development of severe GI toxicity.Methods: This critical review surveyed the literature and reported on the in vitro, ex vivo and in vivo effects, as well as the genetic association, of selected TIR domain innate immune signalling pathway SNPs on disease susceptibility and gene functioning.Results: Of the TIR domain innate immune signalling pathway SNPs reviewed, evidence suggests interleukin-1 beta (IL1B) and tumour necrosis factor alpha (TNF) SNPs have the greatest potential as predictors for severe GI toxicity risk. These results warrant further research into the effect of IL1B and TNF SNPs on the risk and development of severe GI toxicity.Conclusions: SNPs of the TIR domain innate immune signalling pathway have profound effects on disease susceptibility and gene functioning, making them candidate predictors for severe GI toxicity risk. The identification of a predictor for 5-FU-induced severe GI toxicity will allow the personalization of supportive care measures. [ABSTRACT FROM AUTHOR]

Introduction: Background and objective: malnutrition during cancer treatment is common in patients; therefore, nutritional intervention has an important role in cancer prognosis. Total parenteral nutrition is indicated for patients subjected to a major surgery with gastrointestinal complications. Nutritional support could be improved with glutamine (Gln). Therefore, in this work, the effect of parenteral glutamine in patients with gastrointestinal cancer undergoing surgery was studied. Material and methods: patients were classifi ed into two groups: non-supplemented and supplemented (Gln; 0.4 g/kg/day). Both groups received parenteral nutrition. One and seven days after surgery the nutritional status was evaluated. Hematic cytometry, protein metabolism and biochemical data were analyzed. A questionnaire was also applied to assess gastrointestinal function. Results: after the intervention, the nutritional status in both groups improved. However, the nutritional condition improved signifi cantly better (p = 0.008) in the supplemented group. According to the gastrointestinal function evaluation, the supplemented group changed from severe to mild dysfunction (p = 0.0001). The non-supplemented group progressed from moderate to severe dysfunction, but no changes in blood cell markers were observed. The supplemented group improved its concentration of lymphocytes (p = 0.014). The plasma albumin concentration did not change in groups, but prealbumin improved signifi cantly (p = 0.012) in the group that was supplemented with Gln. Conclusions: intravenous nutritional support supplemented with glutamine can improve gastrointestinal function, improving the absorption of nutrients, which leads to a better state of nutrition. It also has positive effects on plasma concentration of lymphocytes, monocytes and prealbumin. [ABSTRACT FROM AUTHOR]

Summary: Cancer immunotherapy has been increasingly applied in the treatment of advanced malignancies. Consequently, immune checkpoints have become a major concern. As PD‐1 is an important immunomodulatory protein, the blockade of PD‐1 and its ligand PD‐L1 is a promising tumour immunotherapy for human carcinoma. In this review, we first discuss the role of the PD‐1/PD‐L1 interaction in gastrointestinal tract cancers. Targeting PD‐1 and PD‐L1 in immune cells and tumour cells may show remarkable efficiency in gastrointestinal tract cancers. Second, the PD‐1/PD‐L1‐associated signalling pathway involved in cancer immunotherapy in gastrointestinal tract cancers is discussed. Most importantly, this review summarizes the PD‐1/PD‐L1‐targeted immunotherapy combinations with relevant signalling pathways, which may result in a breakthrough for the treatment of gastrointestinal tract cancers, such as gastric cancer, colorectal cancer and liver cancer. Meanwhile, the review provides a deeper insight into the mechanism of checkpoint blockade immunotherapies. [ABSTRACT FROM AUTHOR]

Abstract High-performance submucosal injection materials (SIMs) contribute to the success of endoscopic therapy for early-stage gastrointestinal neoplasms. This study aimed to identify the most important factor (viscoelastic parameter) that determines SIM performance and the ease of injection. To determine the ideal viscoelastic parameters of SIMs, submucosal elevation heights (SEHs) and the ease of submucosal injection [characterized by injection pressures (IPs)] were evaluated using a newly developed ex vivo model, in which a constant tension was applied to the studied specimen. The strongest positive correlation was observed between the loss modulus determined at an oscillation frequency of 0.1 rad/s and SEH (correlation coefficient > 0.9) and between the loss modulus at 10 rad/s and IP (correlation coefficient > 0.9). SIMs with high loss moduli (0.1 rad/s) also contributed to maintenance of the submucosal elevation. Moreover, the SEHs of pseudoplastic fluid SIMs (whose loss moduli increased slightly with increasing angular frequency) were greater than those of Newtonian fluid SIMs (whose loss modulus increased drastically with increasing angular frequency). In this study, the ideal viscoelastic SIM parameters were clarified. The loss modulus (0.1 rad/s) was the most important viscoelastic factor affecting SIM performance. Additionally, the development of pseudoplastic fluid SIMs may lead to the creation of next-generation SIMs, with a performance superior to that of sodium hyaluronate, which is currently used widely in endoscopic treatments. Graphical abstract Unlabelled Image Highlights • Submucosal injection materials (SIMs) are important for endoscopic treatment. • The viscoelastic parameter that determines SIM performance was identified. • Loss modulus (0.1 rad/s) was the most important parameter affecting SIM performance. • Pseudoplastic fluid SIMs can be a major candidate for next-generation SIM. [ABSTRACT FROM AUTHOR]

Background: The treatment of upper gastrointestinal cancer (UGIC) patients is complex. Patients are often elderly, comorbid as well as nutritionally depleted and treatment involves multimodality therapy incorporating chemotherapy, radiation therapy and surgery. The pre‐treatment information requirements of UGIC patients are not clear but crucially important in ensuring they complete treatment successfully. Methods: A systematic review of the English language literature was performed to determine the specific information needs of patients with UGIC. Results: Following abstract review and comprehensive analysis six articles were included. UGIC patients nominated information regarding post‐operative recovery, quality of life, expected survival, management of post‐operative symptoms and coping strategies for insurance and financial issues, relationships and family as being most important to them. Patients' families nominated information on the effects of diagnosis on patient well‐being over the ensuing months and detailed information on available support services as being most important. One‐on‐one consultations with senior medical staff were the preferred method of information transfer followed by web‐based information services. Conclusions: For effective treatment of UGIC patients, physicians and surgeons must address issues pertaining to quality of life, finance and relationships and may require specific training, or administrative support, in these areas. [ABSTRACT FROM AUTHOR]

Class III β-tubulin (TUBB3) is a component of microtubules of neuronal cells that is upregulated in various cancer entities. To better understand the role of TUBB3 in upper gastrointestinal tract cancer types, the present study assessed TUBB3 expression in tissue microarrays including 189 gastric and 428 esophageal cancer. TUBB3 expression was detected in 62.4% of gastric cancer, 73.8% of esophageal adenocarcinoma and 88.7% of esophageal squamous cell cancer, while control samples of normal esophageal and gastric epithelium were TUBB3-negative. TUBB3 positivity was not associated with the International Union Against Cancer classification, World Health Organization grading, lymph node involvement or distant metastasis in any entity. Of note, TUBB3 expression was associated with tumor localization and prognosis in gastric cancer, with the tumor stage in esophageal adenocarcinoma, and with the resection margin in esophageal squamous cell cancer. In conclusion, the substantial rate of positivity for TUBB3 already in early stages of gastric cancer in combination with the lack of a further increase in frequency with tumor stage, may suggest, that TUBB3 upregulation is rather relevant for cancer development than for cancer progression. TUBB3 might be a suitable prognostic biomarker in gastric cancer types. [ABSTRACT FROM AUTHOR]

Background: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains lack of clinical evidence. The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group recently launched a multicenter randomized clinical trial (CLASS02-01) to compare the safety of LTG for clinical stage I gastric cancer with the conventional open total gastrectomy (OTG).Methods: This CLASS02-01 trial is a prospective, multicenter, randomized, controlled, open, and non-inferiority trial. Two hundred patients who met the inclusion criteria and did not accord with the exclusion criteria will be randomly divided into LTG group (n = 100) and OTG group (n = 100). The primary purpose of this study is to evaluate the early operative morbidity and mortality of LTG compared with OTG for clinical stage I gastric adenocarcinoma. The second purpose is to evaluate the recovery course and compare the postoperative hospital stay of the patients enrolled in this study.Discussion: This CLASS02-01 trial is the first prospective randomized two-arm controlled study to determine the safety of LTG compared with OTG. Through this trial, we hope to show that experienced surgeons can safely perform LTG with lymphadenectomy for gastric cancer.Trial Registration: ClinicalTrials.gov ID: NCT03007550 . December 30, 2016. [ABSTRACT FROM AUTHOR]

Highlights • KRAS -mutant pancreatic and colorectal cancer is common and difficult to target. • Direct inhibition of K-Ras has been demonstrated in preclinical studies. • Combining MEK inhibitors with novel targeted agents may improve efficacy. • Immunotherapy has shown clinical promise in KRAS -mutant gastrointestinal cancers. Abstract KRAS mutations are common in pancreatic and colorectal cancers and are associated with lack of response to anti-epidermal growth factor receptor therapy. Ras is an established therapeutic target that has long eluded efforts to develop specific inhibitors, while targeting downstream signaling pathways has proven largely ineffective, highlighting a need for rational combination strategies to overcome resistance. Recently, renewed interest in directly targeting Ras has led to the development of several small-molecule inhibitors that bind directly to K-Ras or its effector proteins, downregulation of K-Ras expression using therapeutic antisense oligonucleotides or siRNAs, and targeting scaffold proteins such as kinase suppressor of Ras. Indirect approaches to inhibiting K-Ras include combining inhibitors of the mitogen-activated protein kinase pathway with novel targeted agents. Immunotherapy in early studies has also shown clinical promise. This review summarizes the current evidence for each of these approaches. [ABSTRACT FROM AUTHOR]

Purpose. Oxaliplatin is a platinum compound widely used in gastrointestinal cancer treatment but produces dose-limiting peripheral neuropathy. New insights into oxaliplatin-induced peripheral neuropathy (OIPN) assessment are needed to detect more effectively this condition. In this context, we conducted Canaloxa study, a prospective preliminary clinical trial that aimed to investigate how Electrochemical Skin Conductance (ESC), a parameter used in small fiber neuropathy assessment, could be helpful in OIPN diagnosis. Methods. Cancer patients treated for at least three months with oxaliplatin and suffering from clinically OIPN were included. Electrochemical Skin Conductance, thermal thresholds, and neuropathic pain were assessed in all included patients. Results. During one year, 36 patients were included. The main result was the correlation between ESC and Neuropathic Pain Symptom Inventory score for hands (rho value = -0.69, p < 0.0001) and feet (rho value = -0.79, p < 0.0001). ESC values were lower in neuropathic patients with painful symptoms than in ones without painful symptoms (p = 0.0003 and p < 0.0001 for hands and feet, respectively). No correlation was observed between ESC and thermal thresholds. Conclusion. These preliminary data suggest that ESC could be a useful objective marker of painful oxaliplatin-induced neuropathy and could complement the use of subjective clinical scales. This study was prospectively registered on clinicaltrials.gov (NCT02827916) before patient recruitment has begun. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing chemotherapy are highly burdened by side effects. These may be caused by the pharmacodynamics of the drug or be driven by psychological factors such as negative expectations or pre-conditioning, which reflect nocebo effects. As such, negative pre-treatment expectations or prior experiences might exacerbate the burden of chemotherapy side effects. Educating patients about this nocebo effect has been put forward as a potential strategy to optimize patients' pre-treatment expectations. In this study, we evaluate whether a briefing about the nocebo effect is efficacious in reducing side effects.Methods: In this exploratory study, a total number of n = 100 outpatients with newly diagnosed gastrointestinal cancers are randomized 1:1 to an information session about the nocebo effect (nocebo-education) or an attention control group (ACG) with matching interaction time. Assessments take place before the intervention (T1 pre), post-intervention (T1 post), and 10 days (T2) and 12 weeks (T3) after the initial chemotherapy. The primary outcomes are the patient-rated number and intensity of side effects at 10-days and at 12-weeks follow-up. Secondary outcomes include coping with side effects, tendency to misattribute symptoms, compliance intention, attitude towards the chemotherapy, co-medication to treat side effects and the clinician-rated severity of toxicity. Further analyses are conducted to investigate whether a potential beneficial effect is mediated by a change of expectations before and after the intervention.Discussion: Informing patients about the nocebo effect might be an innovative and feasible intervention to reduce the burden of side effects and strengthen patients' perceived control over adverse symptoms.Trial Registration: The trial is registered at the German Clinical Trials Register (ID: DRKS00009501 ; retrospectively registered on March 27, 2018). The first patient was enrolled on September 29, 2015. [ABSTRACT FROM AUTHOR]

Gastrointestinal cancers (GI), are a group of highly aggressive malignancies with heavy cancer‐related mortalities. Even if continued development of therapy methods, therapy resistance has been a great obstruction for cancer treatment and thereby inevitably leads to depressed final mortality. Peritumoral cancer associated fibroblasts (CAFs), a versatile population assisting cancer cells to build a facilitated tumor microenvironment (TME), has been demonstrated exerting a promotion influence on cancer proliferation, migration, invasion, metastasis, and also therapy resistance. In this review, we provide an update progress in describing how CAFs mediate therapy resistance in GI by various means, meanwhile highlight the crosstalk between CAFs and cancer cells and present some vital signaling pathways activated by CAFs in this resistant process. Furthermore, we discuss the current advances in adopting novel drugs against CAFs and how the knowledge contributing to improved therapy efficacy in clinical practice. In sum, CAFs create a therapy‐resistant TME in several aspects of GI progression, although some key problems about distinguishing CAFs subpopulations and controversial issues on pleiotropic CAFs in medication need to be solved for subsequent clinical application. Predictably, targeting therapy‐resistant CAFs is a promising adjunctive treatment to benefit GI patients. [ABSTRACT FROM AUTHOR]

Background: There are accumulating studies investigating the aberrant expression of microRNAs in tumor patients. As an important member of miR-17/92 cluster, miR-17-5 p has been identified as a potential prognostic factor for survival in tumor patients. We conducted this meta-analysis aimed to assess the effect of miR-17-5 p as a prognostic biomarker for gastrointestinal tumor patients. Materials and methods: Eligible studies were enrolled by searching the online databases of PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and WanFang Data until September 2017. We calculated pooled hazard ratios (HRs) and 95% CI of miR-17-5 p for overall survival and disease-free survival. Results: In the categorical variable analysis, we identified 11 studies with 1,279 patients. The pooled analyses suggested that overexpression of miR-17-5 p may predict poor overall survival (HR = 1.86, 95% CI: 1.55–2.25, P [ABSTRACT FROM AUTHOR]

Background: The gastrointestinal (GI) microbiota in healthy cats is altered in IBD. Little research has been performed to identify whether specific bacterial groups are associated with small cell GI lymphoma (LSA). Hypothesis: Mucosal bacteria, including Enterobacteriaceae and Fusobacterium spp., are abundant in intestinal biopsies of cats with small cell GI LSA compared to cats with IBD. Animals: Fourteen cats with IBD and 14 cats with small cell GI LSA. Methods: Retrospective case control study. A search of the medical records was performed to identify cats diagnosed with IBD and with GI LSA. Bacterial groups identified by FISH in GI biopsies were compared between cohorts and correlated to CD11b+ and NF‐κB expression. Results: Fusobacterium spp. (median; IQR bacteria/region) were higher in cats with small cell GI LSA in ileal (527; 455.5 – 661.5; P =.046) and colonic (404.5; 328.8 – 455.5; P =.016) adherent mucus, and combined colonic compartments (free mucus, adherent mucus, attaching to epithelium) (8; 0 – 336; P =.017) compared to cats with IBD (ileum: 67; 31.5 – 259; colon: 142.5; 82.3 – 434.5; combined: 3; 0 – 34). Bacteroides spp. were higher in ileal adherent mucus (P =.036) and 3 combined ileal compartments (P =.034) of cats with small cell GI LSA. There were significant correlations between Fusobacterium spp. totals and CD11b+ cell (P =.009; rs.476) and NF‐κB expression (P =.004; rs.523). Conclusions: The bacterial alterations appreciated might be influential in development of small cell GI LSA, and should drive further studies to elucidate the effects of microbial‐mediated inflammation on GI cancer progression. [ABSTRACT FROM AUTHOR]

In this study, we aimed to investigate the effects of curcumin on cell activities of gastric cancer (GC), and the connection between curcumin and P53, as well as, PI3K signaling. This study was conducted with two cell lines SGC‐7901 and BGC‐823, both were exposed to curcumin at the concentrations of 0, 10, 20, and 40 μm. MTT assay, flow cytometry (FCM) assay, transmission electron microscopy (TEM) were used to study the underlying mechanisms of curcumin in respective of proliferation, apoptosis, and autophagy. Western blot assay was also employed to detect impacts of curcumin on tophosphatidylinositol‐3 kinase (PI3K) and P53 signaling pathways‐related proteins. MTT assay displayed that curcumin inhibited GC cell proliferation. FCM results indicated that curcumin induced the apoptosis of GC cells. TEM revealed that curcumin induced autophagy in GC cells. Western blot results showed that curcumin activated P53 signaling pathway and inhibited PI3K signaling pathway. Curcumin may inhibit proliferation and induce the autophagy and apoptosis in GC cells. Additionally, curcumin activated the P53 signaling pathway by up‐regulating P53 and P21, which also inhibited PI3K pathway through down‐regulating PI3K, p‐Akt, and p‐mTOR. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the comparative efficacy and safety of polysaccharides from Auricularia auricula (Huaier) for patients with gastrointestinal cancers (GICs) through a systematic review and network meta-analysis. We performed a network meta-analysis to identify evidence from clinical trials. We searched databases for publications up to February 2018. The prespecified primary efficacy outcomes were clinical therapeutic effects, which included the treatment response rate, 0.5-year overall survival rate, 1-year overall survival rate, 2-year overall survival rate, KPS improved rate and AFP decreased rate. The safety outcomes were the side effects of Huaier. The secondary efficacy outcome was immune function. Subgroup analyses and meta-regression were performed according to the various cancer types in all of the efficacy and safety outcomes. The study is registered with PROSPERO (CRD42018086481). A total of 33 trials, involving 2884 patients and 10 treatment arms, were eligible. Huaier significantly increased the treatment response rate (2.48, 1.83–3.35) and survival rate (0.5-year, 1-year and 2-year) and improved immune function without increasing the incidence of adverse effects. Significant efficacy was observed in most subgroups. Network meta-analysis revealed that Huaier was very suitable for combination therapy with TACE and 125 I particle implantation. Similarly, Huaier also had a good adjuvant therapeutic effect on enhancing platinum (L-OHP and DDP) and adriamycin (ADM). Huaier offers clear advantages for patients with GICs. Moreover, patients should be encouraged to accept Huaier treatment, especially HCC patients undergoing combination therapy with TACE and 125 I particle implantation. [ABSTRACT FROM AUTHOR]

Inhibiting component of therapy with (−)-epigallocatechin-3-gallate (EGCG) is low bioavailability of fresh tea polyphenols that outcome from insecurity under stomach related circumstances, insufficient transcellular transport. As needs are, fucose- carboxymethyl chitosan (FU-CMC) graft EGCG with gold nanoparticles (GNPs) (FU-CMC-EGCG-GNPs) nanocomposites were prepared and managed peritumorally to assess their anticancer action. The physicochemical properties of as-prepared nanocomposite were evaluated by FTIR spectroscopy, UV–visible absorption spectra, XRD, FESEM-EDX and HRTEM-SAD. Additionally, the viability and cell uptake assays revealed that the as-prepared nanocomposite successfully repressed the propagation of gastric tumor cells. In vivo anticancer treatment of FU-CMC-EGCG-GNPs nanocomposites showed more anticancer action contrasted with pure EGCG. Immuno-histological investigations established a superior numeral of apoptotic tissues in the as-prepared FU-CMC-EGCG-GNPs nanocomposites contrasted with pure EGCG. Overall, the as-prepared FU-CMC-EGCG-GNPs nanocomposite affords a proficient medicine delivery stage for chemotherapy. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy often induces gastrointestinal symptoms such as anorexia, nausea, and vomiting. Antiemetic agents are effective in inhibiting nausea and vomiting, but patients still experience anorexia. We previously reported that chemotherapeutic agent-induced anorexia is associated with an increase of inflammatory cytokines. Other studies also reported that antagonism of the histamine H 4 receptor is anti-inflammatory. In this study, we investigated the involvement of the H 4 receptor in the development of chemotherapy-induced anorexia in mice. Cisplatin-induced anorexia occurred within 24 h of its administration and continued for 3 days. The early phase (day 1), but not the delayed phase (days 2 and 3), of anorexia was inhibited by the daily injection of a 5-HT 3 receptor antagonist (granisetron). However, a corticosteroid (dexamethasone) or selective H 4 receptor antagonist (JNJ7777120) abolished the delayed phases of anorexia. Cisplatin significantly increased TNF-α mRNA expression in the hypothalamus and spleen, and the period of expression increase paralleled the onset period of anorexia. In addition, pretreatment with JNJ7777120 completely inhibited the increased expression. These results suggest that TNF-α mRNA expression via H 4 receptors may contribute to the development of cisplatin-induced anorexia, and that H 4 receptor antagonists are potentially useful treatments. [ABSTRACT FROM AUTHOR]

Aims Gastrointestinal cancers are a kind of deadly malignancy afflicting close to a million peoples worldwide. 5-Fluorouracil (5-Fu) is a main chemotherapeutic agent for cancer treatment. However, prolonged exposure of 5-Fu to cancer cells may cause chemoresistance and decrease the therapeutic potential of 5-Fu. Main methods Replication protein A (RPA) is a component of the origin recognition complex. In our study, we explored the role of RPA1 in hepatocellular carcinoma cell SMMC-7721, gastric cancer cell SGC-7901 and colorectal cancer HT-29 via lentiviral particles infection. Flow cytometry assay was used to examine the effect of RPA1 on cell proliferation, cell cycle and apoptosis. Western blot was employed to determine the role of RPA1 on Caspase 3 expression. Key findings Immunohistochemstry results showed that RPA1 was highly expressed in colorectal cancer tissues. Only 5-Fu or the knockdown of RPA1 suppressed cell clone formation, induced cell cycle arrest at the G1 phase and promoted cell apoptosis by regulating the protein level of Caspase 3. And the combination of the application of 5-Fu and RPA1 silencing significantly enhanced the above effects. Significance RPA1 serves as an oncogene during gastrointestinal cancers progression. These studies reveal a new target for gastrointestinal cancers therapy, and the combination of 5-Fu and silencing of RPA1 provides a new attractive therapeutic measure for gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Purpose: Glutamine (Gln) is essential for the proliferation of most cancer cells, making it an appealing target for cancer therapy. However, the role of Gln in gastric cancer (GC) metabolism is unknown and Gln-targeted therapy against GC remains scarce. The aim of this study was to investigate the relevance of Gln in GC growth and targeting.Methods: Expression of Gln transporter ASCT2 and glutamine synthetase (GS) in the parental and molecularly engineered GC cells or in human GC specimens was determined by RT-PCR and western blot analysis or immunohistochemistry. Cell proliferation and survival was assessed by CCK-8 assay and colony formation assay. Intracellular Gln content was measured by a HPLC system. Effects of ASCT2 and/or GS inhibitor on tumor growth were investigated in xenograft models.Results: A significant heterogeneity of GC cells was observed with respect to their response to the treatment of ASCT2 inhibitor benzylserine (BenSer). Gln deprivation did not affect the BenSer-resistant cell growth due to endogenous GS expression, whose inhibition remarkably reduced cell proliferation. The differential in vitro sensitivity correlated with overall intracellular Gln content. Combined therapy with both ASCT2 and GS inhibitors produced a greater therapeutic efficacy than the treatment of either inhibitor alone. Furthermore, 77% human GC tissues were found to express moderate and high levels of ASCT2, 12% of which also co-expressed relatively high levels of GS.Conclusion: Gln mediates GC growth and the therapeutic efficacy of Gln-targeted treatment relies on distinct ASCT2 and GS expression pattern in specific gastric cancer groups. [ABSTRACT FROM AUTHOR]

DNA methylation is an important epigenetic modification that alters gene expression; DNA hypomethylation contributes to tumorigenesis through multiple processes. In the present study, the methylation of long interspersed element-1 (LINE-1) in 95 gastric cancer (GC) tissues and matched adjacent normal tissues was investigated by pyrosequencing. LINE-1 methylation was compared with the expression of ubiquitin-like with PHD and ring-finger protein 1 (UHRF1), an essential regulator of DNA methylation, using reverse transcription-quantitative polymerase chain reaction. Significant hypomethylation of LINE-1 and overexpression of UHRF1 were observed in GC tissues compared with the matched controls (P<0.001 and P=0.001, respectively). LINE-1 hypomethylation was inversely correlated with UHRF1 overexpression in GC tissues (r=−0.026, P=0.028). In addition, LINE-1 hypomethylation in GC was significantly associated with Lauren's histological classification, tumor differentiation and background intestinal metaplasia (P=0.014, P=0.042 and P=0.034, respectively). These results suggest that LINE-1 hypomethylation may be a potential biomarker for GC and it is indirectly regulated by UHRF1 overexpression. [ABSTRACT FROM AUTHOR]

The objective of the present study was to investigate the cytotoxic effects of sodium citrate on human gastric adenocarcinoma epithelia AGS cells. Numerous cytotoxicity- associated sodium citrate-induced effects were assessed, including cell viability and proliferation, cytokine expression and caspase activity. In vitro studies demonstrated that incubation with sodium citrate (>3.125 mM) inhibited AGS cell viability and proliferation in a dose-dependent manner. Incubation with sodium citrate for 24 h revealed that the levels of interleukin-1β (IL-1β), IL-8 and tumor necrosis factor increased with an increasing of dose of sodium citrate, whereas the IL-6 levels exhibited only a slight alteration. In addition, increases in caspase-3 and -9 activities were associated with increased duration of treatment and dosage of sodium citrate. Collectively, the results of the present study demonstrated that treatment with sodium citrate at higher concentrations or for longer durations exerts a cytotoxic effect on AGS cells via the induction of the intrinsic apoptosis pathway and the alteration in the levels of certain cytokines. [ABSTRACT FROM AUTHOR]

Endoscopic submucosal dissection (ESD) was first conceptually described almost 30 years ago in Japan and is now widely practiced throughout East Asia. ESD expands the boundaries of endoscopic resection (ER) by allowing en bloc resection of large early neoplastic lesions within the gastrointestinal tract (GIT). This offers advantages over other ER techniques by facilitating definitive histological staging and curative treatment of early cancer in selected cases. Indeed, the experience of ESD in Eastern countries is significant, and excellent outcomes from high‐volume centers are reported. The potential benefits of ESD are recognized by Western endoscopists, but its adoption has been limited. A number of factors contribute to this, including epidemiological differences in GIT neoplasia between Western and Eastern populations and limitations in training opportunities. In this review, we discuss the role of ESD, its current status and the future in Western endoscopic practice. [ABSTRACT FROM AUTHOR]

Background/Aims: Outcomes of endoscopic submucosal dissection (ESD) for undifferentiated-type early gastric cancer (EGC) need to be further evaluated. We aimed to simulate the outcomes of ESD for undifferentiated-type EGC from a surgical database. Methods: Among 802 patients who underwent gastrectomy with endoscopic biopsy for poorly differentiated adenocarcinoma (PD-type) or signet ring cell carcinoma (SRC-type), ESD candidates meeting the expanded indication (n=280) were selected by reviewing the endoscopic images. According to the surgical pathologic results, the outcomes of the ESD simulation were evaluated. Results: Among the candidates, 104 (37.1%) were PD-type and 176 (62.9%) were SRC-type. The curative resection (CR) rate was 42.1%. Among the patients with CR, three patients (2.5%) showed lymph node metastasis (LNM). Three EGCs with CR and LNM were mucosal cancers ≥1.0 cm in size. The CR rate was higher in the SRC-type than in the PD-type (48.3% vs 31.7%, respectively, p=0.007). In the SRC-type, the CR rate was increased, with a smaller size criterion for the ESD indication, but was similar between the 1.0 cm and 0.6 cm criteria (63.3% and 63.6%, respectively), whereas the CR rate was below 50% in all of the different tumor size criteria (2.0 to 0.6 cm) in the PD-type. Conclusions: In undifferentiated- type EGC, ESD should be considered in selected patients with tumor sizes <1 cm and SRC histology. [ABSTRACT FROM AUTHOR]

Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers—either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutropenia and hand-and-foot syndrome. Secondly, we performed detailed analyses of the HLA region on the same phenotypes after imputing the HLA alleles and amino acids. No protein-altering variants, or sets of protein-altering variants collapsed into genes, were associated with the main outcomes after Bonferroni correction. We found evidence that the HLA region was enriched for associations with Hand-and-Foot syndrome (p = 0.023), but no specific SNPs or HLA alleles were significant after Bonferroni correction. Larger studies will be required to characterize the genetic contribution to ADRs to 5FU. Future studies that focus on the HLA region are likely to be fruitful. [ABSTRACT FROM AUTHOR]

Background: Calcification in primary gastric cancer is very rare. In this report, we describe the computerized tomography (CT) changes in calcification in a patient with locally advanced signet-ring gastric cancer treated with chemotherapy.Case Presentation: A 49-year-old man presented with 5 months' history of abdominal pain, anorexia, and rapid weight loss. He had undergone Billroth-II subtotal gastrectomy for a bleeding gastric ulcer 30 years ago. Abdominal CT showed irregular thickening of the gastric wall and miliary calcifications. Histologic examination of specimen obtained by endoscopic biopsy showed poorly differentiated calcified signet-ring gastric cancer. The patient was clinically staged T4N2M0 and treated with docetaxel, cisplatin, and fluorouracil (DCF)/oxaliplatin and S-1 (XLOX)/S-1. After five cycles of chemotherapy, the general condition of the patient improved and tumor markers (CEA, CA125, CA199) decreased. However, follow-up CT scans showed continuing increase in the calcification.Conclusions: To conclude, in this case report we have described the dynamic changes in calcification in a gastric cancer patient receiving chemotherapy. One explanation for the observed increase in calcifications could be that the ischemic necrosis resulting from chemotherapy creates an alkaline environment, which promotes deposition of calcium salts. Our theory needs to be confirmed with histological evidence from a large series of patients. Nevertheless, we hope that these findings will improve understanding of the mechanism of calcification in gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Survival rates for upper gastrointestinal (GI) cancer are poor since many are diagnosed at advanced stages. Fast track endoscopy has been introduced to prompt diagnosis for patients with alarm symptoms that could be indicative of upper GI cancer. However, these symptoms may represent benign conditions and little is known about the predictive values of alarm symptoms of upper GI cancer in the general population.Methods: The study is a nationwide cohort study of 60,562 individuals aged 45 years or above randomly selected from the Danish general population. Participants were invited to complete a survey comprising of questions on several symptom experiences, including alarm symptoms for upper GI cancer within the past four weeks. The participants were asked about specific symptoms (repeated vomiting, difficulty swallowing, signs of upper GI bleeding or persistent and recent-onset abdominal pain) and non-specific symptoms (nausea, weight loss, loss of appetite, feeling unwell and tiredness). We obtained information on upper GI cancer diagnosed in a 12-month period after completing the questionnaire from the Danish Cancer Registry. We calculated positive predictive values and positive likelihood ratios for the association between alarm symptom and subsequent upper GI cancer.Results: A total of 33,040 individuals above 45 years completed the questionnaire, yielding a response rate of 54.6%. Respondents were fairly respresentative of the study sample. During the follow-up period, 18 people were diagnosed with upper GI cancer. The number of incident cancers was similar among eligible non-respondents. Two thirds of the respondents with an upper GI malignancy had experienced one or more alarm symptoms. The positive predictive value for being diagnosed with upper GI cancer after reporting a least one alarm symptom was 0.1% (95% CI:0.0-0.1%). The positive likelihood ratio was 4.4 for specific alarm symptoms and 1.1 for non-specific alarm symptoms.Conclusions: We found that positive predictive values of alarm symptoms of upper GI cancer experienced in the general population are low. It is important knowledge that despite denoted alarm symptoms even patients with specific alarm symptoms of upper GI cancer have a low risk of being diagnosed with upper GI cancer. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The aim of this study is to investigate the clinicopathological characteristics, as well as explore the prognostic accuracy of the proposed new classification in gastrointestinal NENs (GI‐NENs) patients. Methods: Patients diagnosed with GI‐NENs were retrospectively indentified from existing databases of the pathological institute at our institution from January 2009 to November 2015. Results: We identified 414 patients with GI‐NENs, 250 cases were diagnosed as neuroendocrine tumor G1 (NET G1), 25 as neuroendocrine tumor G2 (NET G2), 53 as neuroendocrine tumor G3 (NET G3), 55 as neuroendocrine carcinoma G3 (NEC G3), and 31 as mixed adenoneuroendocrine carcinoma (MANEC); the overall survival (OS) rate at three years were 94.9%, 91.7%, 74.3%, 62.7% and 38.1%, respectively. The difference in progression‐free survival (PFS) duration among the patients with NET G1, NET G2, NET G3, NEC G3, and MANEC was statistically significant (P < 0.001). However, the PFS of NEC G3 and MANEC was low and similar (P = 0.090). In multivariate analysis of patients with GI‐NENs, surgical margin, comorbidity, proposed new classification and tumor location were useful predictors of OS (P < 0.05). Conclusion: Our findings suggest that the proposed new classification can accurately reflect the clinical outcome, together with surgical margin, comorbidity, and tumor location may be meaningful prognostic factors for the OS of GI‐NENs. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is the fourth most common malignant tumor globally. The highest incidence of GC is found in Eastern Asia, particularly in China. It is therefore imperative to further elucidate the molecular pathogenesis of GC in order to identify new biomarkers and targets for effective therapy. In the present study, we determined whether miR-148a was aberrantly downregulated in gastric cancer tissues and significantly correlated with aggressive clinicopathological characteristics in the MGC-803, HGC-27 and GES-1 cell lines using reverse transcription-quantitative PCR and western blot analysis. The cell lines were obtained from 60 patients who presented at our hospital between September 2010 and July 2015. The results showed that, miR-148a was aberrantly downregulated in GC tissues and its expression was relatively lower in the MGC-803 and HGC-27 GC cell lines than in the normal gastric epithelial cell line, GES-1. The clinicopathological analysis revealed that a decrease of miR-148a was significantly correlated with lymph-node metastasis (P<0.01) and tumor node metastasis (TNM) stage (P<0.05). The transwell assay showed that the re-expression of miR-148a significantly reduced cell migratory and invasive abilities in vitro (P<0.01). The luciferase assay confirmed that, DNA methyltransferase 1 (DNMT1) was a direct and functional target of miR-148a. The miR-148a inhibitor increased the expression of DNMT1 in HGC-27 cells and the re-expression of miR-148a reduced the expression of DNMT1 in MGC-803 cells as confirmed by western blot analysis. Furthermore, we found that the re-expression of DNMT1 reversed the inhibition of cell migration and invasion induced by miR-148a. Taken together, we demonstrated that miR-148a suppresses cell invasion and migration in gastric cancer by regulating DNMT1 expression. The miR-148a/DNMT1 axis may therefore be a new potential target for GC therapy. [ABSTRACT FROM AUTHOR]

The three cell lines, designated as gastric cancer (GC)1401, GC1415 and GC1436 were derived from peritoneal effusions from patients with gastric adenocarcinoma. Cell lines were established in tissue culture and in immunodeficient, non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. All cell lines were cultured in Dulbecco's modified Eagle's medium supplemented with 5% fetal bovine serum. These cell lines were grown as an adherent monolayer with doubling time ranging between 25 h (GC1436 cell line) and 30-34 h (GC1401 and GC1415, respectively). All cells showed morphological features of epithelial-like cells, forming sheets of polygonal cells. Chromosomal analysis showed that the modal numbers ranged from 52 (GC1401), 51-56 (GC1415) and 106 (GC1436). High heterogeneity, resulting from several structural and numerical chromosomal abnormalities were evident in all cell lines. The surface marker expression suggested a tumor origin of the cells, and indicated the intestinal phenotype of a GC (CD10+, MUC1). All three cell lines were tumorigenic but not metastatic, in vivo, in NOD/SCID mice. The lack of metastatic potential was suggested by the lack of aldehyde dehydrogenase 1A1 activity. In conclusion, these newly established GC cell lines widen the feasibility of the functional studies on biology of GC as well as drug testing for potential therapeutic purposes. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that nicotinamide N-methyltransferase (NNMT) is aberrantly expressed in a number of tumors. In the present study, it was demonstrated that the gene and protein levels of NNMT were significantly increased in gastric cancer cells. Furthermore, upregulation of NNMT significantly increased the expression of mesenchymal markers, including a-smooth muscle actin (SMA), vimentin and fibronectin, but decreased the levels of epithelial cadherin. Since transforming growth factor (TGF)-β1 may serve a key function in epithelial-mesenchymal transition (EMT), the effects of NNMT on the expression of TGF-β1 were investigated in BGC-823 cells. The results demonstrated that overexpression of NNMT significantly induced the expression of TGF-β1. However, knockdown of NNMT inhibited the expression of TGF-β1, mothers against decapentaplegic homolog (Smad)2 and α-SMA. Additionally, pre-incubation with TGF-β1 partially eliminated NNMT-mediated changes in EMT. Collectively, the results demonstrated that upregulation of NNMT in gastric cancer cells may increase the expression of TGF-β1, therefore activating TGF-β1/Smad signaling, which in turn promotes EMT. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs/miRs) are endogenous small non-coding RNAs that post-transcriptionally regulate the expression of genes and serve crucial roles in diverse biological processes. The present study aimed to examine the miRNA expression profile and drug resistance in the SGC7901 cell line and its isogenic drug-resistant counterpart, SGC7901/cisplatin (DDP) cell line. The potential role of miR-17-5p in modulating drug resistance in gastric cancer cells was investigated. Different levels of miRNA expression between SGC7901/DDP and SGC7901 cells were analyzed by miRNA microarray and validated by quantitative polymerase chain reaction. It was indicated that the downregulation of miR-17-5p sensitized SGC7901/DDP cells to anticancer drugs. A decreased luciferase activity of p21 3'-untranslated region-based reporter in miR-17-5p-transfected SGC7901/DDP cells suggested that p21 may be a direct target gene of miR-17-5p. Western blot analysis and flow cytometric assay revealed that the downregulation of miR-17-5p increases the sensitivity of SGC7901/DDP cells to DDP-induced apoptosis. Taken together, these results demonstrated that miR-17-5p may perform a role in the development of drug resistance in gastric cancer cells, at least partially by modulating apoptosis via targeting p21. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common cancers globally with high rates of morbidity and mortality. Purified Omphalia lapidescens protein (pPeOp) is a protein extracted from the sclerotium of Omphalia lapidescens. The present study aimed to investigate the effects of pPeOp on the viability, migration, cell cycle progression and apoptosis of SGC-7901 cells. The expression of numerous proteins, namely matrix metallopeptidase (MMP)2, MMP9, p53, caspase-3, B-cell lymphoma (Bcl)-2, cyclin A2, cyclin B1, cyclin D1, cyclin dependent kinase (CDK)1, CDK2 and CDK4, were investigated using western blot analysis and reverse transcription-quantitative polymerase chain reaction. The results of the present study demonstrated that treating SGC-7901 cells with pPeOp markedly suppressed their migration, induced their apoptosis and arrested their progression in S phase. pPeOp also downregulated the expression of migration-associated proteins (MMP2 and MMP9) and cyclin-associated proteins (cyclin A2, cyclin B1, cyclin D1, CDK1, CDK2 and CDK4) in a dose-dependent manner. Cells treated with pPeOp significantly upregulated caspase-3 and p53 and downregulated Bcl-2. Finally, the impact of pPeOp on three key nodes of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway were investigated and it was revealed that expression levels of JAK1, JAK2 and STAT3 were significantly downregulated following treatment. [ABSTRACT FROM AUTHOR]

The autophagy involved in the occurrence, development and prognosis of human epidermal growth factor receptor 2 (HER2) gene-amplified cancer also controls the resistance of this type of cancer to the monoclonal antibody, trastuzumab (Tzb). In the present study, Tzb resistance was established in HER2-positive NCI-N87 cell lines (Tzb-refractory cells). The cell viability, clonogenic assay, ratios of light chain 3 II/I, sequestosome 1 expression, and the phosphorylation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR) were investigated in the parental and Tzb-refractory cells. The viability of parental NCI-N87 and Tzb-refractory cells with an autophagy inhibitor or inducer was also examined. The results of the present study indicated that autophagic flux may have an important function in the resistance of HER2-positive human gastric cancer NCI-N87 cells to Tzb. Tzb resistance in NCI-N87 cells prevents cell apoptosis via autophagic flux inhibition. Tzb may activate the Akt/mTOR pathway to inhibit autophagic flux in gastric cancer cell lines. Everolimus, an mTOR inhibitor, may inhibit cell viability, indicating that the mTOR pathway may serve a function in HER2-positive gastric cancer and that the resistance of HER2-positive gastric cancer to Tzb may, at least partially, be due to activation of the mTOR pathway. [ABSTRACT FROM AUTHOR]

Background Photodynamic therapy (PDT) exploits the reaction between photosensitizer and irradiated light to generate potentially therapeutic reactive oxygen species such as singlet oxygen in cancer cells. We have reported several sugar-conjugated chlorins that express stronger antitumor effects in PDT than talaporfin sodium (TS), a second-generation photosensitizer clinically used in Japan. In this study, we developed a novel glucose-conjugated chlorin e6 (G-chlorin e6) and evaluated its antitumor effects. Methods G-chlorin e6 was synthesized with a core photosensitizer chlorin e6 conjugated to glucose. We measured the half maximal inhibitory concentration (IC 50 ) to compare the PDT effects of G-chlorin e6 and TS, and flow cytometry was performed to examine the accumulation of G-chlorin e6 in cancer cells. We also compared the accumulation of G-chlorin e6 between normal immortalized esophageal epithelial cells and esophageal cancer cells. Antitumor effects of G-chlorin e6 PDT were finally analyzed in allograft tumor mouse models. Results PDT in vitro using G-chlorin e6 elicited 9, 000–34,000 times stronger antitumor effects than TS, and there was 70–190 times more G-chlorin e6 accumulated than TS by flow cytometry. G-chlorin e6 accumulated more selectively in esophageal cancer cells than in esophageal immortalized epithelial cells, and in an allograft model, PDT with G-chlorin e6 showed very strong antitumor effects and a 40% complete response (CR) rate. Conclusions G-chlorin e6 showed excellent tumor selectivity, and PDT using G-chlorin e6 revealed the strongest anti-tumor effects among all sugar-conjugated chlorins that we have studied. G-chlorin e6 is considered to be the best photosensitizer for next-generation PDT. [ABSTRACT FROM AUTHOR]

Background In 2016, everolimus was approved by Health Canada for the treatment of unresectable, locally advanced or metastatic, well-differentiated, non-functional, neuroendocrine tumours (NET) of gastrointestinal (GI) or lung origin in adult patients with progressive disease. This analysis evaluated the cost-effectiveness of everolimus in this setting from a Canadian societal perspective. Methods A partitioned survival model was developed to compare the cost per life-year (LY) gained and cost per quality-adjusted life-year (QALY) gained of everolimus plus best supportive care (BSC) versus BSC alone in patients with advanced or metastatic NET of GI or lung origin. Model health states included stable disease, disease progression, and death. Efficacy inputs were based on the RADIANT-4 trial and utilities were mapped from quality-of-life data retrieved from RADIANT-4. Resource utilization inputs were derived from a Canadian physician survey, while cost inputs were obtained from official reimbursement lists from Ontario and other published sources. Costs and efficacy outcomes were discounted 5% annually over a 10-year time horizon, and sensitivity analyses were conducted to test the robustness of the base case results. Results Everolimus had an incremental gain of 0.616 QALYs (0.823 LYs) and CA$89,795 resulting in an incremental cost-effectiveness ratio of CA$145,670 per QALY gained (CA$109,166 per LY gained). The probability of cost-effectiveness was 52.1% at a willingness to pay (WTP) threshold of CA$150,000 per QALY. Conclusions Results of the probabilistic sensitivity analysis indicate that everolimus has a 52.1% probability of being cost-effective at a WTP threshold of CA$150,000 per QALY gained in Canada. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Heat‐shock protein‐90 (HSP90) chaperone machinery is critical to the folding, stability and activity of several client proteins including many responsible for tumour initiation, progression and metastasis. Overexpression of HSP90 is correlated with poor prognosis of GI cancer. Key findings: Pharmacological inhibitors of HSP90 suppress tumorigenic effects of HSP90 by suppressing angiogenesis, survival, metastasis and drug resistance in GI cancer. This review summarizes the role of HSP90 inhibitors in the treatment of GI cancer. Summary: We have presented different antitumour mechanisms of HSP90 inhibitors in cancer treatment. Suppression of HSP90 signalling via specific and novel pharmacological inhibitors is a potentially novel therapeutic approach for patients with GI cancer for a better understanding and hence a better management of this disease. [ABSTRACT FROM AUTHOR]

MiR-93-5p has been previously found to be associated with gastric cancer (GC) tumorigenesis; however, the current understanding of its function in this context remains largely incomplete. In the present study, we showed that miR-93-5p was upregulated in GC tissues. We also demonstrated that miR-93-5p overexpression promoted the proliferation, migration, invasion, and chemoresistance of SGC-7901 cells in vitro, and conversely, that endogenously silencing miR-93-5p expression induced the opposite effects in HGC-27 cells. Overexpression of miR-93-5p was found to inactivate the Hippo pathway, and furthermore, miR-93-5p knockdown activated Hippo signaling. MiR-93-5p upregulation was also shown to inhibit the expression of two well-characterized Hippo pathway regulators, protocadherin Fat 4 (FAT4), and large tumor suppressors 2 (LATS2), at both the mRNA and protein level. Additionally, the results of bioinformatics analyses and luciferase reporter assays indicated that miR-93-5p directly targets the 3′-UTR of FAT4 and LATS2. Taken together, these results demonstrate that miR-93-5p promotes GC-cell progression via the inactivation of the Hippo signaling pathway, and thus, represents a potential therapeutic target for the treatment of GC. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient‐derived three‐dimensional ‘organoid’ models. Methods: A PubMed search was conducted to identify relevant articles. An overview of the literature and published protocols is presented, and the implications of these models for patients with cancer, surgeons and oncologists are explained. Results: Organoid culture methods have been established for healthy and diseased tissues from oesophagus, stomach, intestine, pancreas, bile duct and liver. Because organoids can be generated with high efficiency and speed from fine‐needle aspirations, biopsies or resection specimens, they can serve as a personal cancer model. Personalized treatment could become a more standard practice by using these cell cultures for extensive molecular diagnosis and drug screening. Drug sensitivity assays can give a clinically actionable sensitivity profile of a patient's tumour. However, the predictive capability of organoid drug screening has not been evaluated in prospective clinical trials. Conclusion: High‐throughput drug screening on organoids, combined with next‐generation sequencing, proteomic analysis and other state‐of‐the‐art molecular diagnostic methods, can shape cancer treatment to become more effective with fewer side‐effects. [ABSTRACT FROM AUTHOR]

Gastric cancer is the third leading cause of cancer-associated mortality worldwide and is one of the most common malignancies in China. However, the molecular mechanisms underlying the tumorigenesis of gastric cancer remain largely unclear. Long non-coding (Lnc)RNAs have been demonstrated to serve significant roles in the tumorigenesis of various types of cancer. The present study aimed to explore the role of the LncRNA mediator of DNA damage checkpoint protein 1-antisense RNA (MDC1-AS), the antisense transcript of MDC1, in human gastric cancer. The results revealed that the expression of MDC1-AS in human gastric cancer was significantly suppressed in vivo and in vitro. In addition, overexpression of MDC1-AS in the poorly differentiated gastric cancer cell line MKN28 significantly inhibited cell proliferation and metastasis, while the knockdown of MDC1-AS in well-differentiated MKN45 gastric cancer cells significantly increased proliferation and metastasis. The knockdown of MDC1 relieved the inhibitory effect of MDC1-AS on MKN28 cell proliferation and metastasis, while the over-expression of MDC1 attenuated the stimulatory effect of MDC1-AS knock-down in MKN45 cells. Thus, the present study demonstrated that MDC1-AS had an inhibitory on gastric tumorigenesis through an MDC1-dependent mechanism. This indicates that MDC1-AS is a potential novel therapeutic target for the diagnosis and treatment of human gastric cancer in the clinic. [ABSTRACT FROM AUTHOR]