Association of metabolic syndrome and frailty with postoperative complications in older gastric cancer patients: A body composition perspective.

OBJECTIVES: To compare the characteristics of body compositions between metabolic syndrome (MetS) and frailty, and determine the independent and overlapping of MetS and frailty with postoperative complications among older patients with gastric cancer. DESIGN: A prospectively observational study. SETTING AND PARTICIPANTS: Two hundred and eighty six older patients from 60 to 80 years undergoing radical gastrectomy for the first time. MEASUREMENTS: MetS was diagnosed by the criteria from the 2020 edition of Chinese guideline for the prevention and treatment of type 2 diabetes mellitus, and frailty was defined by frailty phenotype. An InBody770 impedance analyzer was used to measure body compositions and with 10 fat- and muscle-related indicators being included in this study. Based on the presence of frailty and MetS, patients were divided into the frailty group, MetS group, frailty+MetS group, and normal group, and the body compositions indicators of these groups were compared. Clavien-Dindo classification was used to grade the severity of postoperative complications. Univariate and multivariate regression models were performed to explore the independent and joint association of MetS and frailty with postoperative complications. RESULTS: The incidence rate of MetS, frailty, and frailty+MetS being 20.3%, 15.7%, and 4.2% respectively. Compared with the normal group, both fat and muscle compositions were decreased significantly in the frailty group (p < 0.05), while the statistically significant difference of fat-to-muscle mass ratio (FMR) and skeletal muscle mass to visceral fat area ratio (SVR) were not observed (p > 0.05). In contrast, except SVR, the other indicators of the MetS group were higher than the normal group (p < 0.05). As to the frailty+MetS group, there was a significant increase in fat compositions and FMR, as well as a significant decline in SVR (p < 0.05), while the difference of muscle compositions was not statistically significant (p > 0.05). There was an association of frailty with postoperative total (OR = 3.068, 95% CI: 1.402-6.713) and severe (OR = 9.423, 95% CI: 2.725-32.589) complications, but no association was found of MetS alone. MetS coexisting with frailty was associated with the highest risk of both total (OR = 3.852, 95% CI: 1.020-14.539) and severe (OR = 12.096, 95% CI: 2.183-67.024) complications. CONCLUSIONS: Both frailty and MetS coexisting with frailty had adverse effects on postoperative complications, which appeared greatly different characteristics in body compositions and therefore reinforced the importance of targeted nutritional or metabolic intervention. Although MetS alone were not significantly associated with postoperative complications, it is essential to focus on the causal relationship and development trend between MetS and frailty to prevent MetS from shifting into frailty, considering the highest risk in their coexistence state.

Pharmacological manipulation of TRPC5 by kaempferol attenuates metastasis of gastrointestinal cancer via inhibiting calcium involved in the formation of filopodia.

The thermo-sensory receptor, transient receptor potential channel 5 (TRPC5), a non-selective calcium ion (Ca2+)-permeable ion channel, has been implicated in cancer initiation and progression. However, its specific role in gastrointestinal cancer remains unclear. This study demonstrates that TRPC5 is significantly overexpressed in gastrointestinal tumors and is inversely associated with patient prognosis. TRPC5 overexpression triggers a substantial elevation in intracellular Ca2+ levels ([Ca2+]i), driving actin cytoskeleton reorganization and facilitating filopodia formation. Furthermore, kaempferol, a compound sourced from traditional Chinese medicine, is identified as a TRPC5 inhibitor that effectively suppresses its activity, thereby impeding gastrointestinal cancer metastasis. These findings underscore the potential of TRPC5 as a therapeutic target for metastasis inhibition, with kaempferol emerging as a promising natural inhibitor that could be optimized for clinical use in preventing cancer metastasis.

Glucagon-like peptide-1 receptor agonists and risk of gastrointestinal cancers: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used for glucose lowering and weight-loss. However, their association with gastrointestinal cancer remains uncertain. This meta-analysis assesses the risk of gastrointestinal cancer in patients treated with GLP-1 RAs. METHODS: We searched Medline/PubMed, Embase, and Scopus databases from inception to November 15, 2023, for randomized controlled trials (RCTs) with at least 24 weeks of safety follow-up. Pooled risk ratios (RRs) were calculated using fixed- and random-effect models. Risk of bias was assessed using the revised Cochrane risk-of-bias tool, and certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: We included 90 RCTs with 124,791 participants, with an average follow-up of 3.1 years per participant. No significant association was found between GLP-1 RAs and the risk of any gastrointestinal cancer (RRrandom=0.99, 95 % CI: 0.86-1.13), or site-specific gastrointestinal cancers including biliary tract (RR=0.98, 0.54-1.78), colorectal (RR=1.13, 0.92-1.39), gallbladder (RR=1.32, 0.43-4.00), gastric (RR=0.88, 0.58-1.33), hepatic (RR=0.79, 0.51-1.21), oesophageal (RR=0.70, 0.38-1.28), pancreatic (RR=1.05, 0.77-1.43), and small intestine cancer (RR=0.78, 0.20-3.04). The corresponding absolute risk differences excluded important impacts on risk. Additional analyses, limited to placebo-controlled trials, high-dose studies, or those with a follow-up duration of ≥5 years, confirmed these findings. Risk of bias was generally low and the certainty of evidence was high for all outcomes. CONCLUSIONS: This meta-analysis found no significant impact of GLP-1 RAs on gastrointestinal cancer risk. Long-term safety monitoring of these agents remains important. SYSTEMATIC REVIEW REGISTRATION: CRD42023476762.

Genomic-Based Early Detection Screening: A Literature Review of Prospective Trials and Emerging Strategies for Gastrointestinal Cancers.

Numerous genomic-based early detection screening tests are being developed. These tests have the potential to revolutionize current single-organ screening paradigms, especially in gastrointestinal cancers. In this review, we underscore the performance of these genomic-based early detection tests based on prospective clinical trials. Moreover, we discuss a professional advancement for gastroenterologists in the diagnostic assessment of individuals who are cancer signal positive.

Role of chemokine receptors in gastrointestinal mucosa.

Chemokine receptors are essential for the immune response in the oral and gut mucosa. The gastrointestinal mucosa is characterized by the presence of immune populations because it is susceptible to inflammatory and infectious diseases, necessitating immune surveillance. Chemokine receptors are expressed on immune cells and play a role in gastrointestinal tissue-homing, although other non-immune cells also express them for various biological functions. CCR9, CXCR3 and CXCR6 play an important role in the T cell response in inflammatory and neoplastic conditions of the gastrointestinal mucosa. However, CXCR6 could also be found in gastric cancer cells, highlighting the different roles of chemokine receptors in different pathologies. On the other hand, CCR4 and CCR8 are critical for Treg migration in gastrointestinal tissues, correlating with poor prognosis in mucosal cancers. Other chemokine receptors are also important in promoting myeloid infiltration with context-dependent roles. Further, CXCR4 and CXCR7 are also present in gastrointestinal tumor cells and are known to stimulate proliferation, migration, and invasion into other tissues, among other pro-tumorigenic functions. Determining the processes underlying mucosal immunity and creating tailored therapeutic approaches for gastrointestinal diseases requires an understanding of the complex interactions that occur between chemokine receptors and their ligands in these mucosal tissues.

Biologic activity and treatment resistance to gastrointestinal cancer: the role of circular RNA in autophagy regulation.

Circular RNAs (circRNAs) lack the 5'-end methylated guanine cap structure and 3' polyadenylate tail structure, classifying it as a non-coding RNA. With the extensive investigation of circRNA, its role in regulating cell death has garnered significant attention in recent years, establishing it as a recognized participant in cancer's biological processes. Autophagy, an essential pathway in programmed cell death (PCD), involves the formation of autophagosomes using lysosomes to degrade cellular contents under the regulation of various autophagy-related (ATG) genes. Numerous studies have demonstrated that circRNA can modulate the biological activity of cancer cells by influencing the autophagy pathway, exhibiting a dualistic role in suppressing or promoting carcinogenesis. In this review, we comprehensively analyze how autophagy-related circRNA impacts the progression of gastrointestinal cancer (GIC). Additionally, we discuss drug resistance phenomena associated with autophagy regulation in GIC. This review offers valuable insights into exploring potential biological targets for prognosis and treatment strategies related to GIC.

Parkinson's disease and the risk of gastrointestinal cancers: a two-sample Mendelian randomization study.

Background: The association between Parkinson's disease (PD) and gastrointestinal (GI) cancers remains unknown. This study aims to assess the causal effect of PD on colon cancer (CC), gastric cancer (GC), esophageal cancer (EC), and rectal cancer (RC) using the two-sample Mendelian randomization (MR) method. Methods: Five pairs of summary datasets of genome-wide association studies (GWAS) from publicly available studies [Integrative Epidemiology Unit (IEU) OpenGWAS project, FinnGen, and GWAS Catalog database] were enrolled. The inverse variance weighted (IVW) method was used as the primary outcome for MR analysis. Cochran Q-derived, MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods, and leave-one-out analysis were used to test heterogeneity and directional pleiotropy. Results: For the European population, no significant causal effect of PD on the risk of CC was found [odds ratio (OR) =0.9; 95%, confidence interval (CI): 1.00-1.11; P=0.42]. The same applied to the East Asian population (OR =1.05; 95% CI: 0.66-1.66; P=0.63). As for GC, no causal effect was found (OR =0.94, 95% CI: 0.89-0.99; P=0.22). Moreover, the genetic liability for PD was not associated with EC (OR =1.00; 95% CI: 0.99-1.00; P=0.32). Finally, no evidence was found for any causal effect of genetic liability for PD on an increased risk of RC (OR =1.00; 95% CI: 0.99-1.00; P=0.71). Conclusions: There is no causal effect of genetic liability for PD on an increased risk of GI cancer.

Particle therapy in gastrointestinal cancer-a narrative review.

Background and Objective: Radiation therapy is one of the main pillars in the treatment of gastrointestinal (GI) cancers, especially esophageal and anorectal malignancies. The worldwide standard of care is yet an irradiation with photons. Though not commonly used, charged particles offer some physical advantages with a highly conformal dose distribution, which allows an even better sparing of organs at risk. In addition to dosimetric advantages, heavy-ion beams like carbon ions may offer an additional set of biological advantages. Because particle therapy is not standard of care, data are scarce-especially concerning the use in GI malignancies. The aim of this review is to provide a compact overview of the currently available literature. Methods: PubMed and Web of Science databases were searched for publications on particle radiotherapy in GI cancer (e.g., proton therapy in esophageal cancer, carbon ion radiotherapy in pancreatic cancer). Key Content and Findings: Here we present a review of the current data on particle therapy with regard to esophageal, pancreatic, hepatic and anorectal malignancies. Conclusions: Data on particle therapy in GI cancer are scarce. Nevertheless, the current literature shows some promising results. Further clinical evidence, especially randomized trials, is crucial to augment the role of particle radiotherapy in GI cancer.

Dizziness and impaired walking balance in aging patients during chemotherapy.

INTRODUCTION: Older adults are at risk of adverse effects during chemotherapy including nausea and fatigue, but many also suffer from dizziness and peripheral neuropathy. This may lead to balance and walking impairments and increased risk of falls and affect health-related quality of life. Moreover, these symptoms are often underreported with inadequate awareness among health professionals leading to deficient focus on the need for targeted assessment and rehabilitation. We aimed to examine the prevalence of dizziness, impaired walking balance, and neuropathy and falls in older adults ≥65 years with gastrointestinal cancer receiving chemotherapy and the associations between these symptoms. Further, we aimed to examine the quantity of patients reporting these symptoms to the oncologist. MATERIALS AND METHODS: This is a cross-sectional study among patients ≥65 years with gastrointestinal cancers who have completed three or more series of chemotherapy. The prevalence of dizziness, impaired walking balance, neuropathy, and reporting of these adverse effects was examined through structured questionnaires. RESULTS: Of two hundred patients (57 % male, mean age 74.4 years) the prevalence of dizziness was 54 % and the prevalence of patients experiencing impaired walking balance was 48 %. Symptoms of neuropathy was present in 32 % of patients and 11 % experienced falls during chemotherapy. Symptoms of neuropathy was associated with experiencing dizziness: odds ratio (OR) 1.98 (95 % confidence interval [CI]: 1.06; 3.71) and impaired balance: OR 3.61 (95 % CI: 1.87; 6.96). Less than half the patients (48 %) told the oncologist about these symptoms. DISCUSSION: Dizziness and impaired walking balance during chemotherapy are underreported yet profound symptoms among older patients with cancer. Dizziness and impaired balance should be systematically assessed during chemotherapy among older patients.

Cancer incidence (2000-2020) among individuals under 35: an emerging sex disparity in oncology.

BACKGROUND: Aggressive malignancies, such as pancreatic cancer, are increasingly impacting young, female populations. Our investigation centered on whether the observed trends in cancer incidence were unique to pancreatic cancer or indicative of a broader trend across various cancer types. To delve deeper into this phenomenon, we analyzed cancer incidence trends across different age and sex groups. Furthermore, we explored differences in cancer incidence within specific young subgroups aged 18 to 26 and 27 to 34, to better understand the emerging incidence trend among young individuals. METHODS: This study collected cancer incidence data from one of the Surveillance, Epidemiology, and End Results cancer registry databases (SEER22), with 10,183,928 total cases from 2000 to 2020. Data were analyzed through Joinpoint trend analysis approach to evaluate sex- and age-specific trends in cancer incidence. Exposure rates were reported as Average Annual Percentage Changes (AAPCs). RESULTS: The analysis revealed significant age and sex-specific disparities, particularly among individuals aged 18-26 and 27-34. Pancreatic cancer incidence rates increased more in females aged 18-26 (AAPC, 9.37% [95% CI, 7.36-11.41%]; p < .0001) than in males (4.43% [95% CI, 2.36-6.53%]; p < .0001). Notably, among gender, age, and other malignancies, young females had the highest AAPCs for pancreatic cancer. Additionally, the incidence of gastric cancer, myeloma, and colorectal malignancies also showed higher AAPCs in young females compared to males. CONCLUSIONS: Recognizing emerging risk populations for highly lethal malignancies is crucial for early detection and effective disease management.

The role of lymphocyte-C-reactive protein ratio in the prognosis of gastrointestinal cancer: a systematic review and meta-analysis.

Objective: The lymphocyte-to-C-reactive protein (LCR) ratio, an immune-inflammatory marker, shows prognostic potential in various cancers. However, its utility in gastrointestinal malignancies remains uncertain due to inconsistent findings. This systematic review and meta-analysis synthesizes recent evidence to elucidate the association between LCR and prognosis in gastrointestinal cancer patients, aiming to clarify LCR's potential role as a prognostic biomarker. Methods: We searched PubMed, Embase, Cochrane, and Web of Science databases up to May 2024 to evaluate the association between LCR and prognosis in gastrointestinal cancer patients. The main outcomes included overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS). We also analyzed secondary parameters such as geographical region, study duration, sample size, LCR threshold, and patient characteristics (age, gender, tumor location, and TNM stage). Results: This meta-analysis of 21 cohort studies (n=9,131) finds a significant association between reduced LCR levels and poor prognosis in gastrointestinal cancer. Lower LCR levels were associated with worse overall survival (HR=2.01, 95% CI=1.75-2.31, P<0.001), recurrence-free survival (HR=1.90, 95% CI=1.32-2.76, P<0.001), and disease-free survival (HR=1.76, 95% CI=1.45-2.13, P<0.001). Subgroup analyses by cancer type, timing, and LCR threshold consistently confirmed this relationship (P<0.05). Conclusion: LCR may serve as a prognostic marker in gastrointestinal cancer patients, with lower LCR levels associated with poorer prognosis. However, more high-quality studies are needed to validate these findings, considering the limitations of the current evidence. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023486858.

Duodenal adenocarcinoma at stage IV: A critical look at diagnostic pathways and treatment modalities.

Duodenal adenocarcinoma is a rare and aggressive gastrointestinal malignancy that frequently presents with symptoms like gastric outlet obstruction and biliary obstruction, leading to delayed diagnosis and challenging prognosis. This case report explores the clinical presentation, diagnostic hurdles, and therapeutic management of late-stage duodenal adenocarcinoma in a 53-year-old woman with no significant prior medical history. The patient presented with severe epigastric pain radiating to the right upper quadrant, nausea, and decreased appetite. Elevated liver enzymes and imaging revealed multiple liver masses and a primary duodenal mass. Biopsies confirmed moderately differentiated adenocarcinoma. Tumor markers were evaluated during the staging phase, showing markedly elevated levels. The patient underwent systemic chemotherapy with FOLFOX but faced complications, including pulmonary emboli and neurological symptoms. Management required a multidisciplinary approach, integrating palliative and supportive care to address symptoms and improve quality of life. The case highlights the necessity of considering duodenal adenocarcinoma when diagnosing persistent gastrointestinal symptoms. It highlights the need for a holistic treatment approach, including tailored chemotherapy regimens and vigilant monitoring of complications. Molecular profiling was crucial in guiding treatment decisions, although MSI, HER2, and PD-1 were negative, and the tumor showed no mismatch repair protein deficiency. This article emphasizes the importance of early integration of palliative care and the value of comprehensive pathological analysis in managing advanced duodenal adenocarcinoma, providing insights into diagnostic and therapeutic strategies for this complex case.

Changes in Skeletal Muscle Mass in the First 3 Months Following Gastrointestinal Cancer Surgery: A Prospective Study.

BACKGROUND: Surgical resection is the primary treatment for gastrointestinal (GI) cancers, but postoperative skeletal muscle loss (SML) is common and linked to poor prognosis. This study aims to identify patterns of muscle change, examine its association with quality of life (QoL), and explore predictors of SML in the first 3 months. PATIENTS AND METHODS: A prospective cohort study was conducted on patients newly diagnosed with GI cancer and undergoing surgery in China between September 2021 and May 2022. Skeletal muscle mass (SMM) and QoL were assessed at admission, 7 days, 1 month, and 3 months post-surgery. Demographic, clinical data, and biomarkers were collected. Missing data were imputed using multiple imputation. Data were analyzed using growth mixture modelling, bivariate analyses, and logistic regression. RESULTS: A total of 483 patients completed baseline assessment. Of the 242 patients with complete muscle assessments, 92% experienced SML. Three distinct patterns of muscle change were identified: 57% had normal preoperative SMM with mild postoperative SML, 16% had low preoperative SMM with moderate SML, and 27% had normal preoperative mass but severe postoperative SML. Moderate/severe SML was associated with more postoperative complications, poorer health, and higher symptom burden. Independent predictors included advanced age, preoperative sarcopenia, advanced cancer stage, and low prognostic nutrition index (PNI ≤ 45). The results did not change when using imputed values. CONCLUSIONS: Although SML is prevalent, patterns of muscle change are heterogeneous among patients. Advanced age, preoperative sarcopenia, advanced cancer stage, and cancer-related inflammation are predictors for moderate/severe SML, highlighting the need for early detection and management.

Gut microbial metabolites: Shaping future diagnosis and treatment against gastrointestinal cancer.

Gastrointestinal cancer is a worldwide health challenge due to its dramatically increasing prevalence and as a leading cause of cancer-related mortality. Increasing evidence has illustrated the vital role of gut microbes-derived metabolites in gastrointestinal cancer progression and treatment. Microbial metabolites are produced by the gut microbiota that utilizes both extrinsic dietary components and intrinsic host-generated compounds. Meanwhile, certain categories of metabolites such as short-chain fatty acids, bile acids, tryptophan, and indole derivatives, are linked to gastrointestinal malignancy. In this review, the major classes of microbial metabolites and their impacts on various gastrointestinal cancers including colorectal cancer, gastric cancer, and hepatocellular carcinoma, have been introduced. The application of microbial metabolites as predictive biomarkers for early diagnosis and prognosis of gastrointestinal cancer has also been explored. In addition, therapeutic potential of strategies that target microbial metabolites against gastrointestinal cancer is further evaluated.

Gastrointestinal Cancer Therapy and Cardiotoxicity.

OPINION STATEMENT: Gastrointestinal cancers are a heterogenous group of cancers that share common risk factors with cardiovascular disease. Therapy for gastrointestinal cancers have improved cancer-specific outcomes at the cost of cardiotoxicity. The most common cardiotoxic therapies utilized in gastrointestinal cancers include conventional chemotherapy (including fluoropyrimidines and anthracyclines), targeted therapies including anti-vascular endothelial growth factor (VEGF) therapy and tyrosine kinase inhibitors (TKI), and immunotherapy. It is important for clinicians managing patients with gastrointestinal cancers to be aware of potential cardiotoxicity associated with these agents.

Effects of Degreasing Pretreatment on Immunohistochemistry and Molecular Analysis of Gastrointestinal and Breast Cancer Samples.

Lymph node status is a key factor in determining stage, treatment, and prognosis in cancers. Small lymph nodes in fat-rich gastrointestinal and breast cancer specimens are easily missed in conventional sampling methods. This study examined the effectiveness of the degreasing pretreatment with dimethyl sulfoxide (DMSO) in lymph node detection and its impact on the analysis of clinical treatment-related proteins and molecules. Thirty-three cases of gastrointestinal cancer specimens from radical gastrectomy and 63 cases of breast cancer specimens from modified radical mastectomy were included. After routine sampling of lymph nodes, the specimens were immersed in DMSO for 30 minutes for defatting. We assessed changes in the number of detected lymph nodes and pN staging in 33 gastrointestinal cancer specimens and 37 breast cancer specimens. In addition, we analyzed histologic characteristics, Masson trichrome special staining, and immunohistochemistry (gastrointestinal cancer: MMR, HER2, and PD-L1; breast cancer: ER, PR, AR, HER2, Ki-67, and PD-L1). Molecular status was evaluated for colorectal cancer (KRAS, NRAS, BRAF, and microsatellite instability) and breast cancer (HER2) in gastrointestinal cancer specimens and the remaining 26 breast cancer specimens. Compared with conventional sampling, DMSO pretreatment increased the detection rate of small lymph nodes (gastrointestinal cancer: P < .001; breast cancer: P < .001) and improved pN staging in 1 case each of gastric cancer, colon cancer, and rectal cancer (3/33; 9.1%). No significant difference in the morphology, special staining, protein, and molecular status of cancer tissue after DMSO treatment was found. Based on these results and our institutional experience, we recommend incorporating DMSO degreasing pretreatment into clinical pathologic sampling practices.

Gastric Cancer Detection with Ensemble Learning on Digital Pathology: Use Case of Gastric Cancer on GasHisSDB Dataset.

Gastric cancer has become a serious worldwide health concern, emphasizing the crucial importance of early diagnosis measures to improve patient outcomes. While traditional histological image analysis is regarded as the clinical gold standard, it is labour intensive and manual. In recognition of this problem, there has been a rise in interest in the use of computer-aided diagnostic tools to help pathologists with their diagnostic efforts. In particular, deep learning (DL) has emerged as a promising solution in this sector. However, current DL models are still restricted in their ability to extract extensive visual characteristics for correct categorization. To address this limitation, this study proposes the use of ensemble models, which incorporate the capabilities of several deep-learning architectures and use aggregate knowledge of many models to improve classification performance, allowing for more accurate and efficient gastric cancer detection. To determine how well these proposed models performed, this study compared them with other works, all of which were based on the Gastric Histopathology Sub-Size Images Database, a publicly available dataset for gastric cancer. This research demonstrates that the ensemble models achieved a high detection accuracy across all sub-databases, with an average accuracy exceeding 99%. Specifically, ResNet50, VGGNet, and ResNet34 performed better than EfficientNet and VitNet. For the 80 × 80-pixel sub-database, ResNet34 exhibited an accuracy of approximately 93%, VGGNet achieved 94%, and the ensemble model excelled with 99%. In the 120 × 120-pixel sub-database, the ensemble model showed 99% accuracy, VGGNet 97%, and ResNet50 approximately 97%. For the 160 × 160-pixel sub-database, the ensemble model again achieved 99% accuracy, VGGNet 98%, ResNet50 98%, and EfficientNet 92%, highlighting the ensemble model's superior performance across all resolutions. Overall, the ensemble model consistently provided an accuracy of 99% across the three sub-pixel categories. These findings show that ensemble models may successfully detect critical characteristics from smaller patches and achieve high performance. The findings will help pathologists diagnose gastric cancer using histopathological images, leading to earlier identification and higher patient survival rates.

Exploiting the role of O6-methylguanine-DNA-methyltransferase (MGMT) in gastrointestinal cancers.

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.

Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives.

Gastrointestinal tumors, the second leading cause of human mortality, are characterized by their association with inflammation. Currently, progress in the early diagnosis and effective treatment of gastrointestinal tumors is limited. Recent whole-genome analyses have underscored their profound heterogeneity and extensive genetic and epigenetic reprogramming. Epigenetic reprogramming pertains to dynamic and hereditable alterations in epigenetic patterns, devoid of concurrent modifications in the underlying DNA sequence. Common epigenetic modifications encompass DNA methylation, histone modifications, noncoding RNA, RNA modifications, and chromatin remodeling. These modifications possess the potential to invoke or suppress a multitude of genes associated with cancer, thereby governing the establishment of chromatin configurations characterized by diverse levels of accessibility. This intricate interplay assumes a pivotal and indispensable role in governing the commencement and advancement of gastrointestinal cancer. This article focuses on the impact of epigenetic reprogramming in the initiation and progression of gastric cancer, esophageal cancer, and colorectal cancer, as well as other uncommon gastrointestinal tumors. We elucidate the epigenetic landscape of gastrointestinal tumors, encompassing DNA methylation, histone modifications, chromatin remodeling, and their interrelationships. Besides, this review summarizes the potential diagnostic, therapeutic, and prognostic targets in epigenetic reprogramming, with the aim of assisting clinical treatment strategies.

Immune checkpoint reprogramming via sequential nucleic acid delivery strategy optimizes systemic immune responses for gastrointestinal cancer immunotherapy.

Monoclonal antibodies targeting immune checkpoints have been widely applied in gastrointestinal cancer immunotherapy. However, systemic administration of various monoclonal antibodies does not often result in sustained effects in reversing the immunosuppressive tumor microenvironment (TME), which may be due to the spatiotemporal dynamic changes of immune checkpoints. Herein, we reported a novel immune checkpoint reprogramming strategy for gastrointestinal cancer immunotherapy. It was achieved by the sequential delivery of siPD-L1 (siRNA for programmed cell death ligand 1) and pOX40L (plasmid for OX40 ligand), which were complexed with two cationic polymer brush-grafted carbon nanotubes (dense short (DS) and dense long (DL)) designed based on the structural characteristics of nucleic acids and brush architectures. Upon administrating DL/pOX40L for the first three dosages, then followed by DS/siPD-L1 for the next three dosages to the TME, it upregulated the stimulatory checkpoint OX40L on dendritic cells (DCs) and downregulated inhibitory checkpoint PD-L1 on tumor cells and DCs in a sequential reprogramming manner. Compared with other combination treatments, this sequential strategy drastically boosted the DCs maturation, and CD8+ cytotoxic T lymphocytes infiltration in tumor site. Furthermore, it could augment the local antitumor response and improve the T cell infiltration in tumor-draining lymph nodes to reverse the peripheral immunosuppression. Our study demonstrated that sequential nucleic acid delivery strategy via personalized nanoplatforms effectively reversed the immunosuppression status in both tumor microenvironment and peripheral immune landscape, which significantly enhanced the systemic antitumor immune responses and established an optimal immunotherapy strategy against gastrointestinal cancer.