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Background: Comorbidities may complicate medical situations and have an impact on the treatment decisions and poor survival of cancer patients. How comorbidities cluster together and ultimately affect patients' outcomes in gastrointestinal tract cancer (GTC) is a poorly understood area. Methods: In a multicenter prospective observational study from 2012 to 2021, we grouped the comorbidities of patients with GTC by latent class analysis, obtaining two comorbidity classes. Cox regression models were initially used to predict mortality. LASSO techniques were used to reduce the dimension. The final model included the comorbidity classes and nine more predictors. Additionally, the performance of different simple multimorbidity measures were compared using the Bayesian information criterion (BIC), ROC curves and C-index. Finally, the performance of the final model was analyzed using ROC curves, calibration curves and decision curves. The nomogram was drawn to evaluate the model. Results: We included 10,019 patients and obtained two comorbidity classes. Class 2 patients have a higher incidence of comorbidities, and a lower survival rate compared to Class 1 (P < 0.001). Compared to models containing the number of comorbidities or only a single comorbidity, the final model with the comorbidity classes has the highest AUC and C-index, as well as the lowest BIC, indicating this model has the best predictive performance. Conclusion: We identified two classes of comorbidities that were associated with overall survival in patients with GTC. The combination of different comorbidities class plays a vital role in the prognosis of GTC. [ABSTRACT FROM AUTHOR]

Background: The collagen-rich tumor stroma plays a crucial role in biliary tract cancer (BTC). Collagen biomarkers of type I collagen (reC1M), type III collagen (PRO-C3), type IV collagen (C4G), type VIII collagen (PRO-C8), type XI collagen (PRO-C11), type XVII collagen (PRO-C17) and type VIII collagen (TUM) may be used as potential non-invasive biomarkers. Methods: We measured the seven biomarkers of collagen turnover in sera of 72 patients with BTC at baseline and after first and second chemotherapy cycle (CTX). Markers were also assessed in sera of 50 healthy controls and compared to levels of patients at baseline. The diagnostic and prognostic value of the markers was evaluated for overall survival (OS) and progression-free survival (PFS). Results: Patients had a median age of 65 years (IQR 57–70), while healthy controls were younger, with a median age of 46 years (IQR 38–54). The majority of patients (62%) were diagnosed with intrahepatic bile duct adenocarcinoma. Except C4G, all collagen turnover markers were significantly (p < 0.001) increased in serum from patients with BTC compared to healthy controls. PRO-C3 was the best marker to discriminate between patients with BTC and controls, reaching an area under a receiver operating characteristic (AUROC) of 0.98 (95% CI 0.95; 0.99) with a sensitivity (92%) and specificity (94%) balanced cutoff of 77.3 ng/ml. Patients with high levels (cohort separated by median split) of PRO-C8 (HR 2.85, 95% CI 1.42; 5.73) followed by C3M (HR 2.33, 95% CI 1.2; 4.5), PRO-C3 (HR 3.09, 95% CI 1.5; 6.36) and CA 19–9 (HR 2.52, 95% CI 1.37; 4.64) as reference biomarker had a shorter OS. Notably, only the novel marker PRO-C8 was also predictive of PFS (HR 3.26, 95% CI 1.53; 6.95). Associations with survival outcomes remained significant after adjusting for relevant risk factors (CA 19–9 and CEA at baseline, age, presence of metastases, weight, height and gender). Conclusion: The collagen turnover markers PRO-C8, C3M, PRO-C3 and the established biomarker CA 19–9 were prognostic for OS in patients with BTC while only PRO-C8 was also predictive for PFS. PRO-C3 showed the best diagnostic performance to discriminate between patients with BTC and controls. Trial registration: Trial registration number and date of registration NCT00661830 (NCT number) 15 April 2008 Trial registry The complete registry can found under: https://clinicaltrials.gov/study/NCT00661830?tab=table#administrative-information (last accessed 01/2025) Principal investigator and study sponsor Markus Moehler, MD Johannes Gutenberg University Mainz [ABSTRACT FROM AUTHOR]

Appendiceal Adenocarcinoma (AA) is a rare gastrointestinal cancer with no FDA-approved targeted therapies. Here, we retrospectively compare BRAF-mutant AA and colorectal cancer (CRC). BRAF mutation is rare in AA (3%). Unlike CRC, BRAFV600E AA is not associated with poor prognosis, female sex, microsatellite instability, mucinous histology, or poor differentiation. In both cancers, BRAFV600E but not atypical BRAF mutations are mutually exclusive with other Ras-activating mutations. BRAFV600E + EGFR inhibition shows efficacy in BRAFV600E AA (disease control rate = 80%, median progression-free survival = 7.1 months). [ABSTRACT FROM AUTHOR]

Background: Sarcopenia, which is characterized by the progressive loss of skeletal muscle mass, strength, and functionality, adversely affects cancer outcomes. This study aims to evaluate the development and progression of sarcopenia in patients with gastrointestinal cancer undergoing chemotherapy and its impact on comprehensive geriatric assessment outcomes in older participants. Methods: This cross-sectional study included 351 gastrointestinal cancer patients from October 2018 to December 2019. Pre- and post-chemotherapy measurements were taken for 243 participants. Sarcopenia was assessed using EWGSOP-2 criteria, including muscle mass, strength, and performance evaluations. A comprehensive geriatric assessment was conducted for patients aged 65 years and older. Results: The median age of participants was 57.84 years, with 31.7% being female and 29.2% being aged 65 years or older. A significant increase in the prevalence of sarcopenia post-chemotherapy was observed. The factors significantly associated with sarcopenia included low hand grip strength (−0.264; p < 0.001) and slow gait speed (0.222; p = 0.007). The muscle mass and albumin levels of older patients declined significantly post-treatment. Conclusions: This study highlights a strong association between chemotherapy and sarcopenia in gastrointestinal cancer patients, emphasizing the need for early detection and tailored interventions. Comprehensive geriatric assessments can provide critical insights that improve patient outcomes during chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This research investigates the use of Artificial Intelligence (AI) in improving the diagnosis, treatment, and follow-up of metastatic gastrointestinal cancers. By analyzing studies published between 2010 and 2022, the research evaluates the potential of AI models in enhancing diagnostic accuracy, predicting treatment outcomes, and identifying biomarkers. The findings highlight the promise of AI, particularly machine learning and deep learning, in advancing clinical practice. However, the study also identifies challenges, such as the reliance on retrospective data, inconsistencies in imaging protocols, small sample sizes, and issues related to data preprocessing and model interpretability. These challenges hinder the broad clinical implementation of AI models. This research aims to inform future studies and guide the integration of AI into clinical settings, with the goal of improving patient outcomes and streamlining treatment strategies for gastrointestinal cancers. Background/Objectives: This systematic literature review examines the application of Artificial Intelligence (AI) in the diagnosis, treatment, and follow-up of metastatic gastrointestinal cancers. Methods: The databases PubMed, Scopus, Embase (Ovid), and Google Scholar were searched for published articles in English from January 2010 to January 2022, focusing on AI models in metastatic gastrointestinal cancers. Results: forty-six studies were included in the final set of reviewed papers. The critical appraisal and data extraction followed the checklist for systematic reviews of prediction modeling studies. The risk of bias in the included papers was assessed using the prediction risk of bias assessment tool. Conclusions: AI techniques, including machine learning and deep learning models, have shown promise in improving diagnostic accuracy, predicting treatment outcomes, and identifying prognostic biomarkers. Despite these advancements, challenges persist, such as reliance on retrospective data, variability in imaging protocols, small sample sizes, and data preprocessing and model interpretability issues. These challenges limit the generalizability, clinical application, and integration of AI models. [ABSTRACT FROM AUTHOR]

Cryptosporidium parvum (C. parvum) is an apicomplexan protozoan known as a frequent cause of diarrhea. Because of its severe outbreaks and the association with different types of gastrointestinal cancers, it became an urgent need to develop effective solutions against that parasite. In the current study, the complete proteome of C. parvum was analyzed, and after applying several filtration steps, two proteins, namely Glycoprotein 60 (gp40/15) and thrombospondin-related adhesive protein (TRAP C-1), were selected as the protein candidates for epitope prediction. Next, CTL, HTL and BCL epitopes of each protein candidate were defined, and the best epitopes of each category were assembled alongside suitable linkers and adjuvants to initiate a potential multitope vaccine construct finally. That construct was evaluated for several properties, including its antigenicity, allergenicity, stability, secondary and tertiary structure, and the ability of that 3D predicted model to bind to TLR4. Furthermore, the stability of the constructed vaccine ligand in the TLR4 receptor was deeply investigated through a molecular dynamics simulation. The current study describes the stages of the multitope construct design. It demonstrates the results of that construct computational evaluation where the generated scores support the nomination of that potential vaccine as a solution for C. parvum infection, and further wet lab experiments are required to validate our current findings. The current study applied the proteome filtration steps of reverse vaccinology to obtain the most promising protein candidates for a vaccine design against C. parvum. Our protein candidates, gp40/15 and TRAP C-1 were further subjected to the immunoinformatics tools for epitope mapping to define the most promising CTLs, HTLs, and BCLs of each protein, and the best candidates were combined to generate a multitope vaccine construct. Based on the positive results of assessing the immunological and chemical characteristics of that multitope potential vaccine, we recommend it as a promising solution for C. parvum infection. [ABSTRACT FROM AUTHOR]

Multidrug resistance (MDR) development against cytotoxic drugs by tumor cells is one of the main causes of treatment failure in gastrointestinal cancers, a group of cancers of great relevance due to their prevalence and/or mortality. This phenomenon is mediated by diverse mechanisms, including the overexpression of members of the superfamily of membrane transporters of the ATP-binding cassette (ABC). Most of these molecules, including P-glycoprotein (P-gp or MDR1/ABCB), MDR-associated protein 1 (MRP1/ABCC1), MRP2, and breast cancer resistance protein (BCRP/ABCG2), are integrated in the cell membrane, acting as drug efflux pumps. Despite the use of various MDR modulators as adjuvants to improve the chemotherapy response, the results have not been satisfactory. Natural products from plants, such as flavonoids, alkaloids, terpenoids, and coumarins, are capable of modifying drug resistance, suggesting an improvement in the antitumoral effect of the current treatments without generating side effects. This review aims to provide an overview of the most recent studies in relation to plant-derived molecules and extracts that modulate resistance to antitumor drugs and that could be applied in the future in clinical practice to improve the treatment of patients with gastrointestinal cancer. [ABSTRACT FROM AUTHOR]

Background: Historically, housing policies have perpetuated the marginalization and economic disinvestment of redlined neighborhoods. Residential segregation persists nowadays in the form of contemporary redlining, promoting healthcare disparities. The current study sought to assess the effect of redlining on oncological outcomes of patients with gastrointestinal cancer and identify mediators of the association. Methods: Patients with colorectal or hepatobiliary cancer were identified from the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2007–2019). The contemporary redlining index, a measure of mortgage lending bias, was assessed relative to disease stage at diagnosis, receipt of appropriate treatment, textbook outcome, and mortality. Mediation analysis was used to identify socioeconomic, structural, and clinical mediating factors. Results: Among 94,988 patients, 32.2% resided in high (n = 23,872) and highest (n = 6,791) redlining census tracts compared with 46.2% in neutral and 21.6% in low redlining tracts. The proportion of Black, Hispanic, and White patients experiencing high and highest redlining was 65.9%, 41.6%, and 27.9%, respectively. Highest redlining was associated with 18.2% higher odds of advanced disease at diagnosis, greater odds of not undergoing surgery for localized disease (adjusted odds ratio [aOR] 1.363, 95% confidence interval [CI] 1.219–1.524) or not receiving chemotherapy for advanced disease (aOR 1.385, 95% CI 1.216–1.577), and 26.7% lower odds of textbook outcome achievement. Mediation analysis for appropriate treatment quantified the proportion of the association driven by socioeconomic status, racial/ethnic minority status, racial/economic segregation, primary care shortage, and housing/transportation. Conclusions: Contemporary redlining contributed both directly, and via downstream factors, to disparities in oncological care and outcomes of patients with gastrointestinal cancer. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal tract (GIT) cancers are the most lethal cancers with a high incidence and poor prognosis. Vascular endothelial growth factor (VEGF) glycoprotein plays an essential role in tumour neovascularization, especially in cancers of the gastrointestinal tract. There are numerous functional polymorphisms reported in the VEGF which lead to either upregulation or downregulation of VEGF expression. Objective: The present review focuses on the role of VEGF functional polymorphisms in influencing the risk and prognosis of various GIT cancers. Method of study: This systematic review was done by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, and Participant, Intervention, Comparison, Outcomes and Studies (PICOS) criteria were followed for designing the study. A total of 183 articles were retrieved from Google Scholar, PubMed and ScienceDirect using various keywords. After full-text evaluation and applying the literature selection criteria, 108 articles were selected in the review. The role of VEGF promoter polymorphisms in influencing various transcription factor binding sites (TFBS) in the VEGF promoter was studied by performing an in silico analysis. Results: This review article summarized the findings of the studies on the associations of VEGF promoter polymorphisms with various GIT cancers. The effect of the VEGF promoter polymorphisms on cancer risk and prognosis varied between different ethnicities and different GIT cancers. The in silico analysis revealed that the VEGF polymorphisms alter the TFBS, leading to attenuation of the functional activity of the transcription factors which might have importance in the GIT cancer development. Conclusion: VEGF is as an important biomarker for studying the disease susceptibility, progression and prognosis in GIT cancers. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) infection is a typical microbial agent that interferes with the complex mechanisms of gastric homeostasis by disrupting the balance between the host gastric microbiota and mucosa-related factors, ultimately leading to inflammatory changes, dysbiosis, and gastric cancer (GC). We searched this field on the basis of PubMed, Google Scholar, Web of Science, and Scopus databases. Most studies show that H. pylori inhibits the colonization of other bacteria, resulting in a less variety of bacteria in the gastrointestinal (GI) tract. When comparing the patients with H. pylori– positive and H. pylori –negative GC, the composition of the gastric microbiome changes with increasing abundance of H. pylori (where present) in the gastritis stage, whereas, as the gastric carcinogenesis cascade progresses to GC, oral and intestinal-type pathogenic microbial strains predominate. H. pylori infection induces a premalignant milieu of atrophy and intestinal metaplasia, and the resulting change in gastric microbiota appears to play an important role in gastric carcinogenesis. The effect of H. pylori –induced GC on GI microbiota is discussed in this review. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the incidence and risk factors of postoperative fever (POF) in gastrointestinal cancer (GIC), discuss the influence of POF on short-term clinical outcomes, and predict anastomotic leakage (AL) based on POF characteristics. Methods: Overall, 1362 patients that underwent radical resection for GIC were retrospectively analyzed. POF was defined as a postoperative temperature ≥38°C during hospitalization. Patients were divided according to whether they experienced POF. The influence of POF on short-term clinical outcomes was analyzed using propensity score matching. A subgroup analysis was conducted to examine the relationship between different POF characteristics and AL or infection-related complications. Results: POF occurred in 172 patients (12.6%). Overall, 115 patients (66.9%) had fever ≥38.6°C, while 105 (61.0%) had fever at postoperative day (POD) 2, and 73 (42.4%) had POF multiple times. Multivariate analysis showed that patients with a preoperative albumin level < 37 g/L (odds ratio [OR]=1.57, p=0.016), operative time >195min (OR=1.55, p=0.020), and radical gastrectomy (OR=1.84, p=0.009) were more likely to develop POF. Compared to patients without fever, drainage tube indwelling time, duration of antibiotic use, and hospital stay were prolonged, while AL and infection-related complications were more common in patients with POF. POF ≥38.6°C (OR=1.74, p=0.039) and PCT >0.7 ng/mL (OR=2.99, p=0.022) at POD 3 were early predictors of AL. Conclusion: POF was closely related to preoperative albumin levels, operative time, and type of operation, and it delayed postoperative recovery in patients with GIC. And POF ≥38.6°C and PCT >0.7 ng/mL at POD 3 were independent predictors of AL. [ABSTRACT FROM AUTHOR]

Background: Nutritional management in patients after gastrointestinal cancer surgery has changed throughout the 2000s. However, its evolution has not been formally studied. This study aimed to evaluate changes in nutritional management using real-world data. Methods: Patient data from 2011 to 2022 were extracted from a nationwide medical claims database. Patients were divided into four groups based on their year of hospital admission: period I, 2011–2013; II, 2014–2016; III, 2017–2019; IV, 2020–2022. For each period, feeding routes in all patients and prescribed doses of parenteral energy and amino acids in fasting patients during postoperative days (POD) 1–7 were determined. The results of the four different periods were compared using statistical trend tests. Results: The study cohort was comprised of 365,125 patients. During POD 1–3, the proportion of patients administered any oral intake increased over time (I, 40.3%; II, 47.1%; III, 49.4%; IV, 54.2%; P < 0.001), while that of patients receiving parenteral nutrition (PN) decreased (I, 60.1%; II, 55.0%; III, 50.3%; IV, 45.5%; P < 0.001). Of 19,661 patients with PN alone (i.e., neither oral intake nor enteral nutrition) during POD 1–7, the median (interquartile range) prescribed doses on POD 7 of energy (kcal/kg) [I, 15.3 (10.3–21.9); II, 13.9 (8.4–20.0); III, 13.2 (7.7–19.2); IV, 12.9 (7.0–18.7); P < 0.001] and amino acids (g/kg) [I, 0.65 (0.30–0.94); II, 0.58 (0.24–0.89); III, 0.56 (0.00–0.86); IV, 0.56 (0.00–0.87); P < 0.001] both decreased over time. Conclusion: From 2011 to 2022, more patients who underwent gastrointestinal cancer surgery in Japan were administered early oral intake, while fewer patients were administered early PN. Overall, the energy and amino acid doses prescribed in PN were far below the guideline recommendations. [ABSTRACT FROM AUTHOR]

Introduction: Gastrointestinal (GI) cancers represent a significant global health burden, and the need for more effective treatment options is exceptionally pressing. The present meta-analysis aimed to explore the efficacy and safety of the combination of nivolumab and ipilimumab in treating GI cancers. Methods: A systematic search of four databases (PubMed, Embase, Web of Science, and Cochrane Library) was conducted for articles on the treatment of GI cancers with nivolumab combined with ipilimumab, published from 2014 up to 30 August 2024. The inclusion criteria were designed according to the principles of Participants, Intervention, Control, Outcomes, and Study (PICOS). The control group was chemotherapy or nivolumab monotherapy or nivolumab in combination with other drugs. We extracted data from 10 randomized controlled trials and utilized a random effects model to assess the objective response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). The data analysis was conducted using Review Manager version 5.4 and Stata version 12.0. Results: Overall, the combination of nivolumab and ipilimumab demonstrated superior outcomes, including a higher ORR (OR = 1.69, P = 0.01), prolonged mOS (MD = 1.74, P = 0.04) and extended mDOR (MD = 5.64, P < 0.00001) compared to the control group. Subgroup analysis demonstrated that the ORR (OR = 1.75, P = 0.02) and mOS (MD = 5.02, P = 0.003) were significantly improved in patients with esophageal cancer. Notably, the ORR in patients with biliary cancer was significantly lower (OR = 0.11, P = 0.04). Additionally, the ORR was significantly higher in the NIVO1 + IPI3group (OR = 2.82, P = 0.01) and NIVO3 + IPI1 group (OR = 1.62, P = 0.01). Regarding safety, there was no statistically significant difference between the combination regimen and the control group in terms of any grade (OR = 0.72, P = 0.26) or grade 3-4 TRAEs (OR = 1.36, P = 0.14). Conclusions: Nivolumab in combination with ipilimumab demonstrated significant efficacy in GI cancers (especially esophageal cancer) without causing more adverse reactions. However, its efficacy in biliary cancer still needs to be further proven. Systematic review registration: https://www.crd.york.ac.uk/prospero/ , identifier CRD42024590994. [ABSTRACT FROM AUTHOR]

Relationships between cellular senescence and gastrointestinal cancers have gained prominence in recent years. The currently accepted theory suggests that cellular senescence and cancer occurrence exhibit "double-edged sword" effects. Cellular senescence is related to cancer via four "meta-hallmarks" i.e., genomic instability, epigenetic alterations, chronic inflammation, and dysbiosis, along with two "antagonistic hallmarks" i.e., telomere attrition and stem cell exhaustion. These relationships are characterized by both agonistic and antagonistic elements, but the existence of an intricate dynamic balance remains unknown. Non-coding RNAs (ncRNAs) have vital roles in post-transcriptional regulation, but how they participate in agonistic and antagonistic relationships between cellular senescence and gastrointestinal cancers remains to be fully investigated. In this article, we systematically review how ncRNAs (including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circularRNAs (circRNAs)) participate in interactions between cellular senescence and gastrointestinal cancers. Our aim is to elucidate a triangular relationship between "ncRNAs–senescence–gastrointestinal cancers" which considered these three elements as an equal important standing. We are keen to identify prognostic or therapeutic targets for gastrointestinal cancers from, i.e., aging-related ncRNAs, or discover novel strategies to treat and manage in the elderly. We seek to clarify complex relationships where ncRNAs participate in "senescence–gastrointestinal cancers" interactions. [ABSTRACT FROM AUTHOR]

Background: Medullary carcinoma of the small intestine is an exceptionally rare subtype of gastrointestinal cancer, characterized by its solid growth pattern and lack of glandular structures, which complicate timely diagnosis. During the COVID-19 pandemic, diagnostic delays for rare cancers became increasingly common due to the prioritization of COVID-related cases and patient reluctance to seek medical attention. Methods and Result: We present the case of a 70-year-old male initially misdiagnosed with COVID-19, whose persistent symptoms led to the eventual discovery of medullary carcinoma. Imaging studies revealed focal lesions in the liver, spleen, and thickened small intestinal walls, prompting surgical resection of a 16 cm intestinal segment. Histopathological examination confirmed medullary carcinoma with lymph node and liver metastases, supported by immunohistochemistry, which showed positive markers (calretinin, pancytokeratin, cytokeratin 7) and excluded other malignancies. Conclusions: The diagnostic delay, exacerbated by the pandemic, highlights the challenges of distinguishing rare cancers from more common conditions during global health crises. This case underscores the importance of advanced diagnostic techniques, such as immunohistochemistry, for accurate identification. Maintaining robust cancer diagnostic pathways during emergencies is crucial to avoid delays in treatment. Future research should focus on improving screening methods for rare cancers and developing resilient healthcare systems to mitigate similar challenges in future crises. [ABSTRACT FROM AUTHOR]

The pentose phosphate pathway (PPP), traditionally recognized for its role in generating nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate (R5P), has emerged as a critical metabolic hub with involvements in various gastrointestinal (GI) cancers. The PPP plays crucial roles in the initiation, development, and tumor microenvironment (TME) of GI cancers by modulating redox homeostasis and providing precursors for nucleotide biosynthesis. Targeting PPP enzymes and their regulatory axis has been a potential strategy in anti-GI cancer therapies. In this review, we summarize the regulatory mechanisms of PPP enzymes, elucidate the relationships between the PPP and TME's elements, and discuss the therapeutic potential of targeting the PPP in GI cancers. [ABSTRACT FROM AUTHOR]

Background: The lack of predictive biomarkers contributes notably to the poor outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). Cancer-associated fibroblasts (CAFs) are the key components of the prominent PDAC stroma. Data on clinical relevance of CAFs entering the bloodstream, known as circulating CAFs (cCAFs) are scarce. Here, we developed a combined liquid biopsy assay to detect cCAFs and circulating tumor cells (CTCs) in metastatic PDAC (mPDAC) and other metastatic gastrointestinal malignancies (mGI). In addition, we evaluated plasma hyaluronan (HA) levels as a complementary surrogate biomarker of the stromal extent in patients with PDAC. Methods: A sequential liquid biopsy assay based on a two step-enrichment, combining marker dependent and independent cell enrichment, was established for cCAF and CTC detection and validated in mPDAC and mGI patients. The enriched cells were identified by multiplex immunofluorescence. HA measurement was performed by ELISA on blood samples from healthy blood donors (HD), localized and late-stage PDAC patients. Results: cCAFs (≥ 1cCAFs/7.5 mL blood) were detected in 95.4% of mPDAC and in 78.2% of mGI patients, with significantly higher numbers in mPDAC compared to mGI patients (mean number 22.7 vs. 11.0; P = 0.0318). mPDAC patients with ≥ 15 cCAFs/7.5 mL blood had a significant shorter median overall survival (mOS 3.2 months (95% confidence interval (CI) 0.801–5.855) vs. 14.2 months (95% CI 6.055–22.332); P = 0.013), whereby CTC levels were not associated with mOS. In mGI neither cCAFs nor CTCs had a significant impact on OS. HA plasma levels in mPDAC patients were significantly higher compared to HD (mean 123.0 ng/mL vs. 74.45 ng/mL, P = 0.015). High HA in localized and late-stage PDAC were associated with a significantly shorter mOS (mOSlocalized PDAC: 12.6 months vs. 23.5 months (P = 0.008); mOSmPDAC: 1.8 months vs. 5.3 months (P = 0.004)). Conclusions: Our liquid biopsy assay provides robust detection of cCAFs in mPDAC and mGI patients. The measurement of both circulatory stromal parameters, cCAFs and HA, adds valuable clinical information as they are associated with an unfavorable outcome in PDAC. These results highlight that stromal characteristics unique to PDAC could be leveraged to fill the current gap in discovering predictive biomarkers. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is a common gastrointestinal cancer, and even though oxaliplatin chemotherapy is effective, there is a high likelihood of relapse, indicating the presence of oxaliplatin-resistant CRC. Therefore, it is crucial to comprehend the molecular mechanisms of oxaliplatin resistance and develop effective strategies to counter drug resistance. Numerous studies have demonstrated the close association between microRNAs (miRNAs) and drug resistance in CRC. In this study, we aimed to identify the essential exosomal and cellular miRNA related to oxaliplatin resistance in the CRC cell line HCT-116. Methods: The miRNA expression profile of CRC cells with resistance to oxaliplatin was analyzed. The effectiveness of diagnostics and biomarker potency of miRNAs were evaluated by receiver operating characteristic (ROC) analysis. Target miRNAs were identified, and the enrichment analysis was assessed based on Gene Ontology (GO), Reactome, and Human Disease Ontology (DO). In vitro experiments, oxaliplatin-resistant HCT-116 cells (HCT116-OXA) were developed, and the exosomes were isolated and characterized from HCT116-OXA and HCT116 cells. The expression of the selected miRNAs was evaluated in HCT116-OXA cells and their exosomes, and they were compared to HCT-116 cells using quantitative real-time PCR. Results: This study revealed that a combination of miR-4326, miR-3615, miR-7974, miR-130b-3p, and miR-454-3p exhibited the highest area under the curve (AUC), sensitivity, specificity, and superior diagnostic and predictive performance. In vitro experiments, HCT116-OXA cells displayed reduced early and late apoptosis, a bypass of S phase arrest, prolonged doubling time, and higher IC50 compared to parental cells. The expression of miR-454-3p, miR-130b-3p, miR-7974, miR-3615, and miR-4326 was decreased in HCT116-OXA cells as compared to sensitive cells. However, a significantly higher expression of miR-130b-3p and miR-4326 was observed in the isolated exosomes of HCT116-OXA cells as compared to the sensitive cells. Conclusions: The low expression of miR-454-3p, miR-7974, and miR-3615 in CRC cells or high expression of miR-130b-3p and miR-4326 in isolated exosomes could predict the response to oxaliplatin therapy. This indicates the potential of these specific miRNAs to serve as predictive markers for the response to oxaliplatin therapy. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusion Primary liver cancer (PLC) is projected to be the third leading cause of cancer mortality in the United States in 2040. We examine the burden of PLC in the United States, stratified by sex, state and aetiological risk factors.Data on PLC prevalence, incidence, death and disability–adjusted life years (DALYs) were extracted from the Global Burden of Disease Study 2021. Changes in these parameters were calculated using the Joinpoint regression model.There were 47,970 cases, 31,450 incident cases, 24,770 deaths and 576,920 DALYs from PLC in the United States. The highest prevalence (16,980), incidence (12,040), death (9840) and DALYs (213,410) from PLC were due to chronic hepatitis C virus infection. From 2000 to 2021, PLC incidences increased by 141%, and PLC deaths increased by 136%. Age–standardised incidence rates (ASIRs) and death rates (ASDRs) per 100,000 population for PLC increased, primarily driven by alcohol–related liver disease (ALD) (ASIR: annual percent change [APC]: +2.40%; ASDR: APC: +2.22%) and metabolic dysfunction–associated steatotic liver disease (MASLD) (ASIR: APC: +2.32%; ASDR: APC: +2.04%).The burden of PLC in the United States has risen in the past two decades, driven mainly by ALD and followed by MASLD. These findings offer policymakers an accurate assessment of the PLC burden and emphasise the need for targeted risk factor mitigation, especially regarding alcohol related policy. [ABSTRACT FROM AUTHOR]

Objective: We conducted this study to investigate the relationship between serum uric acid (SUA) levels and the risk of upper gastrointestinal cancer. Methods: We conducted a prospective cohort study with 475659 cancer-free participants from the UK Biobank. All subjects were grouped into quartiles, and we used a Cox proportional hazards model to analyze the association between SUA levels and the risk of upper gastrointestinal cancer and explore the potential sex-specific relationship. Results: Of the 475659 participants, 883 eventually developed upper gastrointestinal cancers over a median follow-up period of 6.7 years. We observed that SUA level was positively correlated with the risk of female oral cancer (hazard ratio Quartile 4 vs Quartile 1 (95% CI): 2.05(1.03,4.06)) and negatively associated with the risk of esophageal cancer in the general population (hazard ratio Quartile 3 vs Quartile 1 (95% CI): 0.65(0.45,0.93)). The risk of gastric cancer in males showed a U-shaped trend, decreasing and then increasing as SUA levels increased (hazard ratio Quartile 3 vs Quartile 1 (95% CI): 0.51(0.32,0.81)). The risk of small intestine cancer in females showed a trend of increasing and then decreasing with increasing SUA levels (hazard ratio Quartile 3 vs Quartile 1 (95% CI): 3.34(1.10,10.13)). Interaction analysis indicated that various factors, such as age, sex, smoking and drinking status, family history of cancer and BMI might play an important role in the relationship between SUA and cancer. Conclusion: SUA levels are positively associated with the risk of oral cancer risk in females and negatively associated with the risk of esophageal cancer in the general population. Both low and high SUA levels were associated with increased risk of gastric cancer, supporting a U-shaped association. [ABSTRACT FROM AUTHOR]

The gut microbiome plays an important role in the carcinogenesis of luminal gastrointestinal malignancies and response to antineoplastic therapy. Preclinical studies have suggested a role of intratumoral gammaproteobacteria in mediating response to gemcitabine-based chemotherapy in pancreatic ductal adenocarcinoma (PDAC). To our knowledge, this is the first study to evaluate the impact of the PDAC microbiome on chemotherapy response using samples from human pancreatic tumor resections. We performed 16S rRNA gene amplification and sequencing on both formalin-fixed paraffin-embedded (FFPE) and fresh frozen human PDAC resection samples. We analyzed frozen samples from 26 patients with resected PDAC and examined tumor and tumor-adjacent normal tissue. These patients represented nine long-term survivors (LTS) and nine short-term survivors (STS) after neoadjuvant gemcitabine therapy and eight control patients who did not receive any neoadjuvant therapy prior to resection. We also included FFPE samples from five patients, including tumor samples (3 samples per patient), tumor-adjacent normal tissue (2 per patient) and tumor-adjacent paraffin (1 per patient). Within frozen tissue, total DNA yields were high, but bacterial DNA was generally low, comparable to those seen in negative controls. In FFPE tissue, DNA yields were low and bacterial abundances were comparable in paraffin, tumor and normal PDAC samples. Gammaproteobacteria concentrations did not correlate with outcomes in patients treated with neoadjuvant gemcitabine-based chemotherapy. Our study found low microbial biomass in pancreatic tumor tissue, with no detectable association between bacterial taxa and chemotherapy outcomes. These results suggest a limited role of the microbiome in gemcitabine-based chemotherapy response in PDAC. Preclinical studies have implicated the pancreatic tumor microbiome in driving response to therapy. Cytidine deaminase, an enzyme produced by gammaproteobacteria, can metabolize gemcitabine and has been hypothesized to inhibit pancreatic tumor response to chemotherapy. Several clinical trials have evaluated the role of the tumor microbiome in pancreatic cancer treatment. We evaluated the impact of the pancreatic tumor microbiome on chemotherapy response using samples from human pancreatic tumor resections. We found a low microbial load that is partially attributable to contaminants and that gammaproteobacteria levels did not correlate with outcomes in patients with pancreatic cancer treated with gemcitabine-based chemotherapy. [ABSTRACT FROM AUTHOR]

(1) Background: Volumetric modulated arc therapy (VMAT) can deliver more accurate dose distribution and reduce radiotherapy-induced toxicities for postoperative cervical and endometrial cancer. This study aims to retrospectively analyze the relationship between dosimetric parameters of organs at risk (OARs) and acute toxicities and provide suggestions for the dose constraints. (2) Methods: A total of 164 postoperative cervical and endometrial cancer patients were retrospectively analyzed, and the endpoints were grade ≥ 2 acute urinary toxicity (AUT) and acute lower gastrointestinal toxicity (ALGIT). The normal tissue complication probability (NTCP) model was established using the logistic regression model. Restricted cubic spline (RCS) curves were used to explore the association between dosimetric parameters and toxicities. The receiver operating characteristic (ROC) curve, calibration curve, Akaike's corrected information criterion (AICc), decision curve analysis (DCA), and clinical impact curve (CIC) were analyzed to evaluate the performance of NTCP models. (3) Results: Bladder V40Gy was identified to develop the NTCP model of AUT, and the mean AUC was 0.69 (CI: 0.58–0.80). Three candidate predictors, namely the small intestine V30Gy, colon D45%, and rectum D55%, were identified to develop the NTCP model of ALGIT, and the mean AUC was 0.71 (CI: 0.61–0.80). Both models were considered to have relatively good discriminative accuracy and could provide a high net benefit in clinical applications. (4) Conclusions: We developed NTCP models to predict the probability for grade ≥ 2 AUT and ALGIT. We recommend that bladder V40Gy, the small intestine V30Gy, colon D45%, and rectum D55% be controlled below 42%, 20.4%, 16.9 Gy, and 32.0 Gy, respectively. [ABSTRACT FROM AUTHOR]

Cancer patients receiving non-endocrine therapies are at risk of hepatitis B virus (HBV) reactivation (HBVr). Guidelines recommend HBV screening prior to treatment. The Ottawa Hospital Cancer Center implemented a screening pilot for all patients receiving FOLFOX-based regimens between January and April 2023. We assessed the pilot from a quality improvement perspective. Charts were retrospectively reviewed, and patient and disease characteristics were collected. The primary endpoint was to identify the proportion of patients who underwent HBV screening prior to treatment start. Univariate analyses assessed the association between baseline characteristics and failure to screen. Quality metrics were also reviewed. There were 32/42 patients (76.2%) who completed screening, and 5 (11.9%) had a positive screen. The majority of eligible patients (59.5%) completed screening prior to the first treatment as intended. Four of five patients who tested positive were referred to Infectious Diseases. Of those, one received antivirals for chronic HBV. There were no treatment delays due to pending screening and no HBV reactivation. Receipt of prior systemic therapy was significantly associated with failure to screen (55 vs. 95%, OR 17.1 (95% CI 1.92–153), p = 0.011). The results of this pilot highlight the importance of building HBV screening into standardized treatment plans and engaging all team members to ensure high levels of screening. Prior systemic therapy receipt was associated with failure to screen, and thus, programs should include education on the necessity of screening as recommended by medical guidelines. [ABSTRACT FROM AUTHOR]

Purpose: Selecting the better techniques to harbor optimal motion management, either a stereotactic linear accelerator delivery using TrueBeam (TBX) or magnetic resonance–guided gated delivery using MRIdian (MRG), is time-consuming and costly. To address this challenge, we aimed to develop a decision-supporting algorithm based on a combination of deep learning-generated dose distributions and clinical data. Materials and Methods: We retrospectively analyzed 65 patients with liver or pancreatic cancer who underwent both TBX and MRG simulations and planning process. We trained three-dimensional U-Net deep learning models to predict dose distributions and generated dose volume histograms (DVHs) for each system. We integrated predicted DVH metrics into a Bayesian network (BN) model incorporating clinical data. Results: The MRG prediction model outperformed the TBX model, demonstrating statistically significant superiorities in predicting normalized dose to the planning target volume (PTV) and liver. We developed a final BN prediction model integrating the predictive DVH metrics with patient factors like age, PTV size, and tumor location. This BN model an area under the receiver operating characteristic curve index of 83.56%. The decision tree derived from the BN model showed that the tumor location (abutting vs. apart of PTV to hollow viscus organs) was the most important factor to determine TBX or MRG. It provided a potential framework for selecting the optimal radiation therapy (RT) system based on individual patient characteristics. Conclusion: We demonstrated a decision-supporting algorithm for selecting optimal RT plans in upper gastrointestinal cancers, incorporating both deep learning-based dose prediction and BN-based treatment selection. This approach might streamline the decision-making process, saving resources and improving treatment outcomes for patients undergoing RT. [ABSTRACT FROM AUTHOR]

Schematic diagram of Dehy suppressing GC cells. Created with BioRender.com. [Display omitted] • Dehy prominently suppresses GC progression in vitro and in vivo. • Dehy reduces de novo fatty acid synthesis and lipid pool by inhibiting ACLY. • Dehy targets IKKβ directly to promote the ubiquitination and degradation of ACLY. • GC cells trigger autophagy following lipid depletion, while this protective mechanism is blocked by Dehy. • Dehy enhances 5-FU efficacy in PDX models, indicating its potential in GC therapies. Dehydrocostus lactone (Dehy), a natural sesquiterpene lactone from Saussurea lappa Clarke, displays remarkable efficacy in treating cancer and gastrointestinal disorders. However, its anti-gastric cancer (GC) effect remains poorly understood. Our study aimed to elucidate the anti-GC effect of Dehy and its putative mechanism. The anti-GC effect was assessed with MTT, colony formation, wound healing and transwell invasion assays. Cell apoptosis rate was detected by Annexin V-FITC/PI binding assay. Network pharmacology analysis and XF substrate oxidation stress test explored the underlying mechanism and altered metabolic phenotype. Lipogenic enzyme expressions and neutral lipid pool were measured to evaluate cellular lipid synthesis and storage. Biolayer interferometry and molecular docking investigated the direct target of Dehy. Autophagosomes were observed by transmission electron microscopy and MDC staining, while the autophagic flux was detected by mRFP-GFP-LC3 transfection. The clinical significance of ACLY was confirmed by tissue microarrays. Patient-derived xenograft (PDX) models were adopted to detect the clinical therapeutic potential of Dehy. Dehy prominently suppressed GC progression both in vitro and in vivo. Mechanistically, Dehy down-regulated the lipogenic enzyme ACLY, thereby reducing fatty acid synthesis and lipid reservation. Moreover, IKKβ was identified as the direct target of Dehy. Dehy inhibited the phosphorylation of IKKβ, promoting the ubiquitination and degradation of ACLY, thereby resulting in lipid depletion. Subsequently, GC cells initiated autophagy to replenish the missing lipids, whereas Dehy impeded this cytoprotective mechanism by down-regulating LAMP1 and LAMP2 expressions, which disrupted lysosomal membrane functions, ultimately leading to apoptosis. Additionally, Dehy exhibited potential in GC clinical therapy as it enhanced the efficacy of 5-Fluorouracil in PDX models. Our work identified Dehy as a desirable agent for blunting abnormal lipid metabolism and highlighted its inhibitory effect on protective autophagy, suggesting the future development of Dehy as a novel therapeutic drug for GC. [ABSTRACT FROM AUTHOR]

Background Post-endoscopy upper gastrointestinal cancer (PEUGIC) is an important key performance indicator for endoscopy quality. We examined variation in PEUGIC rates among endoscopy providers in England and explored associated factors. Methods The was a population-based, retrospective, case–control study, examining data from National Cancer Registration and Analysis Service and Hospital Episode Statistics databases for esophageal and gastric cancers diagnosed between 2009 and 2018 in England. PEUGIC were cancers diagnosed 6 to 36 months after an endoscopy that did not diagnose cancer. Associated factors were identified using multivariable logistic regression analyses. Results The national PEUGIC rate was 8.5%, varying from 5% to 13% among endoscopy providers. Factors associated with PEUGIC included: female sex (odds ratio [OR] 1.29 [95%CI 1.23–1.36]); younger age (age >80 years, OR 0.52 [0.48–0.56], compared with ≤60 years); increasing comorbidity (Charlson score >4, OR 5.06 [4.45–5.76]); history of esophageal ulcer (OR 3.30 [3.11–3.50]), Barrett's esophagus (OR 3.21 [3.02–3.42]), esophageal stricture (OR 1.28 [1.20–1.37]), or gastric ulcer (OR 1.55 [1.44–1.66]); squamous cell carcinoma (OR 1.50 [1.39–1.61]); and UK national endoscopy accreditation status – providers requiring improvement (OR 1.10 [1.01–1.20]), providers never assessed (OR 1.24 [1.04–1.47]). Conclusion PEUGIC rates varied threefold among endoscopy providers, suggesting unwarranted differences in endoscopy quality. PEUGIC was associated with endoscopy findings known to be associated with upper gastrointestinal cancer and a lack of national endoscopy provider accreditation. PEUGIC variations suggest an opportunity to raise performance standards to detect upper gastrointestinal cancers earlier and improve outcomes. [ABSTRACT FROM AUTHOR]

Background and Aims: No studies have compared the effects of ketamine and dexmedetomidine on bowel recovery. We evaluated the effects of intraoperative low-dose ketamine or dexmedetomidine infusion on postoperative bowel recovery in patients undergoing gastrointestinal (GI) malignancy surgeries. Material and Methods: This placebo-controlled, randomized study was carried out in 84 American Society of Anesthesiologists II patients, aged 18–70 years, of either gender, undergoing elective open GI malignancy surgeries. Patients received intraoperative infusion of ketamine @ 0.1 mg kg-1 h-1 (KET), dexmedetomidine @ 0.25 μg kg-1 h-1 (DEX), or normal saline (placebo). Primary outcome was the time to first flatus and/or stool. Secondary outcomes included time to extubation, total analgesic requirement, postoperative pain scores, time to feeds, duration of intensive care unit (ICU) and hospital stay, and the incidence of adverse events. Continuous data were analyzed by the one-way analysis of variance (ANOVA) or the Kruskal–Wallis test. Categorical data were analyzed by the Chi-square test or the Fisher's exact test. Results: Median time to passage of flatus and/or stool was 3 [interquartile range (IQR) 2–3] days in the KET group, 2 [IQR 2–3] days in the DEX group, and 2 [IQR 2–3] days in the placebo group (P = 0.53 for placebo vs. KET, 0.81 for placebo vs. DEX, and 0.99 for KET vs. DEX). Pain scores and analgesic consumption were significantly less in the intervention groups versus placebo (P < 0.001). No difference was seen in other secondary outcomes. Conclusion: Low-dose ketamine or dexmedetomidine did not result in early bowel recovery despite lower pain scores and opioid consumption in patients undergoing open GI malignancy surgeries. [ABSTRACT FROM AUTHOR]

F-box and WD repeat domain-containing 7 (FBXW7), formerly known as hCdc4, hAGO Fbw7, or SEL10, plays a specific recognition function in SCF-type E3 ubiquitin ligases. FBXW7 is a well-established cancer suppressor gene that specifically controls proteasomal degradation and destruction of many key oncogenic substrates. The FBXW7 gene is frequently abnormal in human malignancies especially in gastrointestinal cancers. Accumulating evidence reveals that mutations and deletions of FBXW7 are participating in the occurrence, progression and treatment resistance of human gastrointestinal cancers. Considering the current therapeutic challenges faced by gastrointestinal cancers, elucidating the biological function and molecular mechanism of FBXW7 can provide new perspectives and references for future personalized treatment strategies. In this review, we elucidate the key molecular mechanisms by which FBXW7 and its substrates are involved in gastrointestinal cancers. Furthermore, we discuss the consequences of FBXW7 loss or dysfunction in tumor progression and underscore its potential as a prognostic and therapeutic biomarker. Lastly, we propose potential therapeutic strategies targeting FBXW7 to guide the precision treatment of gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Goldenberry and purple passion fruit contain bioactive compounds (BCs) that can prevent gastrointestinal cancers; hydrogel beads can protect and control their release in the gastrointestinal tract. This study aimed to develop an encapsulating material for fruit hydrogel beads (FHBs) to increase their bioaccessibility and to assess antiproliferative effects. A blend of goldenberry–purple passion fruit was encapsulated using ionic gelation and electrospraying. Through a mixture experimental design with sodium alginate (SA), hydroxypropylmethylcellulose (HPMC) and arabic gum (AG) as components, the following response variables were optimized: polyphenol bioaccessibility and encapsulation efficiency. Polyphenols and antioxidant activity were quantified before and after digestion. Antiproliferative effect was evaluated on Caco-2 colon cancer cells. Variations in formulation proportions had a significant effect (p < 0.05) on most responses. An SA-AG mixture in a 0.75:0.25 ratio maximized polyphenol bioaccessibility to 213.17 ± 19.57% and encapsulation efficiency to 89.46 ± 6.64%. Polyphenols and antioxidant activity were lower in FHBs than in the fruit blend (F). Both F and FHBs inhibited tumor cell proliferation by 17% and 25%, respectively. In conclusion, encapsulating BCs in hydrogel beads with SA-AG can enhance the effectiveness of polyphenols in food applications by improving their bioaccessibility and showing a more pronounced effect in inhibiting tumor cell proliferation. [ABSTRACT FROM AUTHOR]

Background/Objectives: Pembrolizumab, an immune checkpoint inhibitor targeting programmed death 1 (PD-1), is a widely employed therapy for various gastrointestinal (GI) cancers. We conducted a systematic review of clinical trials investigating pembrolizumab monotherapy in GI cancer patients to assess the spectrum and incidence of immune-related adverse events (irAEs) associated with pembrolizumab. Methods: A comprehensive search of PubMed/MEDLINE was performed to identify clinical trials investigating pembrolizumab monotherapy in GI cancer patients. Primary endpoints included the incidence of grade 3 or higher irAEs and the rate of treatment discontinuation due to irAEs. Secondary endpoints encompassed the incidence of any-grade irAEs, as well as specific irAEs. Results: Data extraction and analysis were performed on 25 articles. The analysis included 3101 patients with a median age of 62 years (range 53–68), with 30.2% being female. Tumor types encompassed were colorectal (12%), esophagogastric (46%), hepatocellular carcinoma (24%), and other GI tumor types (18%). The rate of treatment discontinuation due to irAEs was 6.8%. The most prevalent grade 3 or higher irAEs were hepatitis (3.6%), pneumonitis (0.8%), and colitis (0.7%). Death attributed to irAEs was infrequent (0.9%). Conclusions: In patients with GI cancers treated with pembrolizumab monotherapy, severe toxicities are infrequent, and irAEs leading to treatment discontinuation or death are uncommon. [ABSTRACT FROM AUTHOR]

Gastrointestinal tumors present a significant challenge for precision medicine due to their complexity, necessitating the development of more specific diagnostic tools and therapeutic agents. Recent advances have positioned coding and non-coding RNAs as emerging biomarkers for these malignancies, detectable by liquid biopsies, and as innovative therapeutic agents. Many RNA-based therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotides (ASO), have entered clinical trials or are available on the market. This review provides a narrative examination of the diagnostic and therapeutic potential of RNA in gastrointestinal cancers, with an emphasis on its application in precision medicine. This review discusses the current challenges, such as drug resistance and tumor metastasis, and highlights how RNA molecules can be leveraged for targeted detection and treatment. Additionally, this review categorizes specific diagnostic biomarkers and RNA therapeutic targets based on tissue type, offering a comprehensive analysis of their role in advancing precision medicine for gastrointestinal tumors. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) cancer is a prevalent disease and is recognized as the primary cause of cancer-related mortality globally. Therefore, there is an urgent need for novel diagnostic and treatment approaches for GC. The methylation of the O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter is a significant factor in the development of colorectal cancer (CRC), namely in roughly 30–40% of cases where the cancer has spread. MGMT plays a role in the repair of DNA damage caused by methylating drugs like temozolomide (TMZ) and chloroethylating compounds like carmustine. As a result, it contributes to the resistance of chemotherapy when these agents are utilized. Although MGMT's role in the development of CRC is well established, its prognostic significance remains a subject of debate. Only a limited number of research have been conducted to examine the prognostic significance of MGMT methylation, yielding varying outcomes. This review explores the structural functions and repair processes of MGMT, focusing on the putative structural and functional significance of the N-terminal domain of MGMT. It also investigates the advancement of cancer treatment techniques that specifically target MGMT. [ABSTRACT FROM AUTHOR]

Linmin Zhuge,1 Xinxin Chen,1 Xinyi Li,1 Zhoule Zhu2 1Department of Gastrointestinal Surgery, The second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Orthopedics (Spine Surgery), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Zhoule Zhu, Email 296127618@qq.comObjective: To observe the effect of cluster nursing based on multidisciplinary management strategy in perioperative venous thromboembolism (VTE) prevention and control in gastrointestinal cancer patients.Methods: A total of 263 gastrointestinal cancer patients admitted to our hospital between January 2022 and September 2023 were included in the study. The patients were stratified into a control group (n=118) and a quality improvement group (n=145). Routine nursing care was administered to the control group, while the quality improvement group received cluster nursing based on multidisciplinary management strategy.Results: The total incidence of VTE in the quality improvement group (11.7%) was significantly lower compared to the control group (26.3%). The correct rate of VTE assessment by nurses in the quality improvement group stood at 80.0%, significantly surpassing the control group rate of 61.0% (p < 0.001). The timeliness rates of VTE assessment within 24 hours of admission, before, and after surgery were 91.7%, 95.2%, and 95.9%, respectively, in the quality improvement group, as opposed to 89.8%, 86.4%, and 87.3% in the control group, indicating a significant improvement in timeliness rates before and after surgery (all p < 0.05). The quality improvement group demonstrated a significant increase in both the implementation rate of health education and VTE preventive measures (all p < 0.05).Conclusion: Cluster nursing based on multidisciplinary management strategy has the potential to significantly decrease the incidence of perioperative VTE in patients with gastrointestinal cancer and improve awareness of VTE prevention and treatment among both medical professionals and patients.Keywords: venous thromboembolism, gastrointestinal cancer, cluster nursing, multidisciplinary management

Alexandru Madalin Hasan,1 Simona Cavalu,1 Ahmed Y Kira,2 Rabab S Hamad,3 Mustafa Ahmed Abdel-Reheim,4 Elsayed A Elmorsy,5 Attalla F El-kott,6,7 Kareem Morsy,6,8 Ali S AlSheri,6 Sally Negm,9 Sameh Saber10 1Department of Preclinical Sciences, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, 410087, Romania; 2Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, Egypt; 3Biological Sciences Department, College of Science, King Faisal University, Al Ahsa, 31982, Saudi Arabia; 4Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia; 5Department of Pharmacology and Therapeutics, College of Medicine, Qassim University, Buraidah, 51452, Saudi Arabia; 6Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia; 7Department of Zoology, Faculty of Science, Damanhour University, Damanhour, Egypt; 8Department of Zoology, Faculty of Science, Cairo University, Cairo, Egypt; 9Department of Life Sciences, College of Science and Art, Mahyel Aseer, King Khalid University, Abha, 62529, Saudi Arabia; 10Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, 11152, EgyptCorrespondence: Ahmed Y Kira, Department of Pharmaceutics, Faculty of Pharmacy, ‎Delta University for Science and Technology, Gamasa, Egypt, +11152, Tel +2 01026462867, Fax +2 0502770140, Email ahmed.kira@deltauniv.edu.eg Mustafa Ahmed Abdel-Reheim, Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra, 11961, Saudi Arabia, Email m.ahmed@su.edu.saAbstract: Different types of cancers affect the gastrointestinal tract (GIT), starting from the oral cavity and extending to the colon. In general, most of the current research focuses on the systemic delivery of the therapeutic agents, which leads to undesired side effects and a limited enhancement in the therapeutic outcomes. As a result, localized delivery within gastrointestinal (GI) cancers is favorable in overcoming these limitations. However, the localized delivery via oral administration faces many challenges related to the complex structure of GIT (varied pH levels and transit times) as well as the harsh environment within tumor cells (hypoxia, efflux pumps, and acidity). To overcome these obstacles, nano-drug delivery systems (NDDs) have been designed and proved their potential by exploiting these challenges in favor of offering a specific delivery to the desired target. The current review begins with an overview of different GI cancers and their impact globally. Then, it discusses the current treatment approaches and their corresponding limitations. Additionally, the different challenges associated with localized drug delivery for GI cancers are summarized. Finally, the review discusses in detail the recent therapeutic and diagnostic applications of NDDs that have been conducted in oral, esophageal, gastric, colon, and liver cancers, aiming to offer valuable insights into the current and future state of utilizing NDDs for the local treatment of GI cancers. Keywords: gastrointestinal cancer, localized delivery, stimuli-responsive nanomaterials, gastro-retentive delivery systems

BackgroundGastrointestinal (GI) cancers impose a significant burden on global public health. Patients often experience mental health challenges due to physical changes and treatment-related symptoms, which can worsen their condition or delay recovery. Although research is mounting in this field, visual bibliometric analysis has not yet been conducted. This study aims to reveal the research hotspots and frontiers in this field using bibliometrics to guide future research.MethodsThe publications on GI cancer and mental health were retrieved in the Web of Science Core Collection from 2004 to 2024. VOS Viewer and CiteSpace, as commonly used bibliometric analysis tools, were employed to visualize the network structure of bibliometric data and uncover the evolving trends in scientific research fields. VOS Viewer was used to identify keyword co-occurrences, while CiteSpace was utilized to generate network visualizations, produce dual-map overlays of journals, and perform burst keyword analysis.ResultsA total of 1,118 publications were included for analysis. China had the highest number of publications in this field (341, 30.5%), while the United States held a central position (centrality = 0.48). The most productive author and institution were Floortje Mols and Tilburg University, respectively. Keyword analysis highlighted that “quality of life” (QoL) is a prominent research topic in the field, while “complications,” “cancer-related fatigue,” (CRF) “chronic stress,” and “epidemiology” have been identified as key areas for future research.ConclusionResearch interest in this field continues to grow. The research direction is mainly focused on personalized mental health interventions to improve QoL, as well as preoperative mental healthcare and ongoing care through internet-based multidisciplinary collaboration to reduce postoperative complications. More detailed clinical symptom assessment is needed to distinguish between CRF and mental health issues and to provide targeted intervention measures in the future. The mechanism of mental health effects on the occurrence and development of GI cancer will be a frontier.

IntroductionGastrointestinal (GI) cancers represent a significant global health burden, and the need for more effective treatment options is exceptionally pressing. The present meta-analysis aimed to explore the efficacy and safety of the combination of nivolumab and ipilimumab in treating GI cancers.MethodsA systematic search of four databases (PubMed, Embase, Web of Science, and Cochrane Library) was conducted for articles on the treatment of GI cancers with nivolumab combined with ipilimumab, published from 2014 up to 30 August 2024. The inclusion criteria were designed according to the principles of Participants, Intervention, Control, Outcomes, and Study (PICOS). The control group was chemotherapy or nivolumab monotherapy or nivolumab in combination with other drugs. We extracted data from 10 randomized controlled trials and utilized a random effects model to assess the objective response rate (ORR), median progression-free survival (mPFS), median overall survival (mOS), median duration of response (mDOR), and treatment-related adverse events (TRAEs). The data analysis was conducted using Review Manager version 5.4 and Stata version 12.0.ResultsOverall, the combination of nivolumab and ipilimumab demonstrated superior outcomes, including a higher ORR (OR = 1.69, P = 0.01), prolonged mOS (MD = 1.74, P = 0.04) and extended mDOR (MD = 5.64, P < 0.00001) compared to the control group. Subgroup analysis demonstrated that the ORR (OR = 1.75, P = 0.02) and mOS (MD = 5.02, P = 0.003) were significantly improved in patients with esophageal cancer. Notably, the ORR in patients with biliary cancer was significantly lower (OR = 0.11, P = 0.04). Additionally, the ORR was significantly higher in the NIVO1 + IPI3group (OR = 2.82, P = 0.01) and NIVO3 + IPI1 group (OR = 1.62, P = 0.01). Regarding safety, there was no statistically significant difference between the combination regimen and the control group in terms of any grade (OR = 0.72, P = 0.26) or grade 3-4 TRAEs (OR = 1.36, P = 0.14).ConclusionsNivolumab in combination with ipilimumab demonstrated significant efficacy in GI cancers (especially esophageal cancer) without causing more adverse reactions. However, its efficacy in biliary cancer still needs to be further proven.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024590994.

PurposeTo analyze the incidence and risk factors of postoperative fever (POF) in gastrointestinal cancer (GIC), discuss the influence of POF on short-term clinical outcomes, and predict anastomotic leakage (AL) based on POF characteristics.MethodsOverall, 1362 patients that underwent radical resection for GIC were retrospectively analyzed. POF was defined as a postoperative temperature ≥38°C during hospitalization. Patients were divided according to whether they experienced POF. The influence of POF on short-term clinical outcomes was analyzed using propensity score matching. A subgroup analysis was conducted to examine the relationship between different POF characteristics and AL or infection-related complications.ResultsPOF occurred in 172 patients (12.6%). Overall, 115 patients (66.9%) had fever ≥38.6°C, while 105 (61.0%) had fever at postoperative day (POD) 2, and 73 (42.4%) had POF multiple times. Multivariate analysis showed that patients with a preoperative albumin level < 37 g/L (odds ratio [OR]=1.57, p=0.016), operative time >195min (OR=1.55, p=0.020), and radical gastrectomy (OR=1.84, p=0.009) were more likely to develop POF. Compared to patients without fever, drainage tube indwelling time, duration of antibiotic use, and hospital stay were prolonged, while AL and infection-related complications were more common in patients with POF. POF ≥38.6°C (OR=1.74, p=0.039) and PCT >0.7 ng/mL (OR=2.99, p=0.022) at POD 3 were early predictors of AL.ConclusionPOF was closely related to preoperative albumin levels, operative time, and type of operation, and it delayed postoperative recovery in patients with GIC. And POF ≥38.6°C and PCT >0.7 ng/mL at POD 3 were independent predictors of AL.

The article from the New England Journal of Medicine discusses the efficacy of multimodal treatments for locally advanced esophageal adenocarcinoma. It compares perioperative chemotherapy with preoperative chemoradiotherapy and concludes that perioperative chemotherapy (specifically FLOT) led to improved overall survival compared to chemoradiotherapy. The study highlights the importance of tailoring treatment based on molecular subtypes and suggests that further advancements in systemic therapy may enhance survival rates for patients with esophageal adenocarcinoma. [Extracted from the article]

The article discusses a case of a 36-year-old man with MUTYH-associated polyposis (MAP) who developed a SMARCA4-deficient colonic tumor. The patient had a family history of colorectal cancer and presented with abdominal pain, rectal bleeding, and weight loss. Despite initial treatment, the patient developed metastatic colon cancer and eventually transitioned to comfort care. The article highlights the rarity and aggressiveness of SMARCA4-deficient colonic tumors and emphasizes the importance of surveillance and targeted therapeutic approaches for such cases. [Extracted from the article]

Multidrug resistance (MDR) development against cytotoxic drugs by tumor cells is one of the main causes of treatment failure in gastrointestinal cancers, a group of cancers of great relevance due to their prevalence and/or mortality. This phenomenon is mediated by diverse mechanisms, including the overexpression of members of the superfamily of membrane transporters of the ATP-binding cassette (ABC). Most of these molecules, including P-glycoprotein (P-gp or MDR1/ABCB), MDR-associated protein 1 (MRP1/ABCC1), MRP2, and breast cancer resistance protein (BCRP/ABCG2), are integrated in the cell membrane, acting as drug efflux pumps. Despite the use of various MDR modulators as adjuvants to improve the chemotherapy response, the results have not been satisfactory. Natural products from plants, such as flavonoids, alkaloids, terpenoids, and coumarins, are capable of modifying drug resistance, suggesting an improvement in the antitumoral effect of the current treatments without generating side effects. This review aims to provide an overview of the most recent studies in relation to plant-derived molecules and extracts that modulate resistance to antitumor drugs and that could be applied in the future in clinical practice to improve the treatment of patients with gastrointestinal cancer.

The article discusses the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and its alcohol-associated subtype (MetALD) with cancer risk, highlighting an increased risk of liver and gastrointestinal cancers in patients with these conditions. The authors suggest further exploration to enhance the clinical applicability of the new disease classification, focusing on developing precise tools for evaluating the impact of alcohol consumption on cancer risk and providing clearer guidance for clinicians. They also recommend future studies to optimize intervention strategies and address the global applicability of the classification, considering diverse metabolic profiles, lifestyle habits, and alcohol consumption patterns. Additionally, the authors emphasize the importance of incorporating genetic factors in future research to provide a comprehensive assessment of the carcinogenic mechanisms underlying MASLD and MetALD. [Extracted from the article]

The article discusses the issue of post-endoscopy upper gastrointestinal cancer (PEUGIC), where a high proportion of upper gastrointestinal cancers are missed during endoscopy, leading to delayed diagnosis and poorer prognosis. The study found that roughly 1 in every 10 UGI cancers were missed during a recently performed endoscopy, with a PEUGIC rate of 8.5% among endoscopy providers. Factors associated with a higher rate of missed cancers included clinical and endoscopic features, as well as the accreditation status of the endoscopy providers. The study emphasizes the need for improvement in the quality of endoscopy performance to reduce the rate of missed UGI cancers and improve patient outcomes. [Extracted from the article]

• Intestinal damage caused by colon cancer chemotherapy is highly correlated with tumor treatment outcomes. • 5-FU reduces intestinal proliferative cells, leading to acute intestinal injury. • IL-23/IL-17 and IL-22 in intestinal tissue increased significantly after 5-FU treatment. • 5-FU-induced upregulation of caspase3 and p-stat3 in intestinal tissue correlates with tumor response to 5-FU. • IL-22 promotes intestinal damage repair caused by 5-FU. 5-Fluorouracil (5-FU) is a primary chemotherapeutic agent for gastrointestinal cancers, known to improve survival but also cause significant intestinal damage, affecting patient quality of life. This study investigated the IL-23-IL-22 axis's role in moderating 5-FU-induced intestinal damage. We analyzed paracancerous tissue damage in colon cancer patients with different Tumor Regression Grade (TRG) and found a direct correlation between TRG and tissue damage severity, indicating that higher chemotherapy effectiveness is linked to increased tissue damage. In a 5-FU-treated mouse model, we observed severe intestinal damage and a reduction in proliferative cells. Transcriptome sequencing and immunofluorescence revealed that myeloid cells in damaged tissues produced IL-23, which activated ILC3s to secrete IL-22, promoting tissue repair and homeostasis. IL-22 supplementation in deficient mice significantly mitigated damage, underscoring the IL-22/IL-23 axis's potential as a therapeutic target to reduce chemotherapy-induced damage and enhance recovery. This research advances understanding of the biochemical responses to chemotherapy and suggests new avenues for developing therapies to maintain intestinal integrity during cancer treatment. [ABSTRACT FROM AUTHOR]

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives. [Display omitted] • Cancer therapies include surgery, chemoradiotherapy, targeted therapy, etc. • Targeted therapy focuses on the EGF/EGFR, VEGF/VEGFR, and HGF/c-MET pathways. • Targeted therapy has led to great achievements for GI cancer patients. • Targeted agents have been approved by the FDA, such as cetuximab, trastuzumab, etc. [ABSTRACT FROM AUTHOR]