Follow-up analysis and research of very low-risk and low-risk gastrointestinal stromal tumors after endoscopic resection.

Currently, due to limited long-term evidence, there remains some controversy surrounding the recommended postoperative monitoring strategy for primary low-risk gastrointestinal stromal tumors (GISTs). This study recruited a total of 532 patients diagnosed with very low-risk and low-risk GISTs who underwent endoscopic resection from 2015 to 2021, including 460 very low-risk patients and 72 low-risk patients. Descriptive statistical analysis was used to evaluate the clinical and pathological characteristics of GIST patients, and Kaplan-Meier methods were employed for survival analysis. The results showed that the 5-year recurrence-free survival rates for very low-risk and low-risk patients were 98.5% and 95.9%, respectively. The 5-year disease-specific survival rates for both groups were 100%. Additionally, the 5-year overall survival rates were 99.7% for very low-risk patients and 100% for low-risk patients (P = 0.69). Therefore, it is suggested that routine follow-up monitoring, including endoscopic surveillance and imaging, may not be necessary for very low-risk and low-risk GISTs after endoscopic resection.

Tata-box-binding protein-associated factor 15 as a new potential marker in gastrointestinal tumors.

In this editorial, the roles of tata-box-binding protein-associated factor 15 (TAF15) in oncogenesis, tumor behavior, and as a therapeutic target in cancers in the context of gastrointestinal (GI) tumors are discussed concerning the publication by Guo et al. TAF15 is a member of the FET protein family with a comprehensive range of cellular processes. Besides, evidence has shown that TAF15 is involved in many diseases, including cancers. TAF15 contributes to carcinogenesis and tumor behavior in many tumors. Besides, its relationship with the mitogen-activated protein kinases (MAPK) signaling pathway makes TAF15 a new target for therapy. Although, the fact that there is few studies investigating the expression of TAF15 constitutes a potential limitation in GI system, the association of TAF15 expression with aggressive tumor behavior and, similar to other organ tumors, the influence of TAF15 on the MAPK signaling pathway emphasize that this protein could serve as a new molecular biomarker to predict tumor behavior and target therapeutic intervention in GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic role of TAF15 in GI tumors, especially in tumors resistant to therapy.

Diagnostic efficacy of SEPT9 and PAX5 gene methylation in gastrointestinal cancer and precancerous lesions.

To assess the diagnostic efficacy of SEPT9 along with PAX5 gene methylation detection in gastrointestinal cancer and precancerous lesions, the peripheral blood of 62 patients with gastric cancer (GC) and 60 patients with no evidence of disease (as the control group) were retrospectively collected. The methylation rates of PAX5 and SEPT9 gene promoters in blood samples of GC group were detected by PCR. At the same time, the differences in methylation rates of genes in the two groups were compared, and the predictive value of plasma methylation PAX5 and SEPT9 in GC was evaluated by receiver operating characteristic (ROC) curve. We found that there were 41 cases of methylated PAX5 gene promoter region and 39 cases of methylated SEPT9 gene promoter region in GC group. The control group contained 14 cases of PAX5 gene promoter methylation and 12 cases of RNF¹80 gene promoter methylation. The occurrence of PAX5 promoter methylation was correlated with age of GC patients. There were statistically significant differences in mSEPT9 gene in patients with different TNM stages. Kaplan-Meier survival curve analysis revealed that the three-year overall survival rate of GC patients with PAX5 methylation was lower than that of GC patients without PAX5 methylation. No significant difference was discovered in 3-year overall survival rate between GC patients with SEPT9 methylation and those without SEPT9 methylation. Combined detection could not improve the diagnostic value of GC, but could promote diagnosis sensitivity. In summary, the risk of PAX5 and SEPT9 gene methylation in GC patients presents higher when compared with healthy people. PAX5 gene methylation is closely related to age, while SEPT9 is closely related to tumor TNM stage, and PAX5 gene methylation can decrease the survival rate of GC patients. Detection of PAX5 gene methylation level can assist in evaluating the prognosis of GC patients.

Endoscopic Characteristics of Small-Bowel Gastrointestinal Stromal Tumors Detected During Single-Balloon Enteroscopy: A Retrospective Analysis.

BACKGROUND/AIMS:  The endoscopic features of small-bowel gastrointestinal stromal tumors (GISTs) are not well defined. The objective of this study was to describe the endoscopic features of GISTs of the small intestine detected via single-balloon enteroscopy (SBE). MATERIALS AND METHODS:  Patients with surgically confirmed small intestinal GISTs from January 2014 to September 2022 were retrospectively analyzed. The hospital's electronic medical record system was used to retrieve the patients' data, including their demographics, clinical symptoms, hemoglobin on admission, endoscopic and computerized tomography findings, clinicopathological findings, and surgical management data. RESULTS:  In total, 46 GIST patients (23 men and 23 women) with overt bleeding were included, with a mean age of 52 years (23-80 years). The typical duration of the symptoms was 48 hours. Four patients (8.70%) had lesions in the duodenum, 32 (69.56%) had lesions in the jejunum, 8 (17.39%) had lesions in the ileum, and 2 (4.35%) had lesions around the junction of the jejunum and ileum. Out of the 46 patients, 27 underwent SBE, and GISTs were visualized in 25, while the lesions could not be visualized in the remaining 2. Submucosal round (n = 13), submucosal sessile (n = 8), and invasive/penetrating (n = 4) were among the endoscopic tumor features. Twenty patients exhibited submucosal protuberant lesions, with ulceration, vascular nodules/congestion, or erosion on the surface, and 5 patients presented ulcerative infiltrative lesions. The multiple logistic regression analysis indicated that the invasive/penetrating characteristics of GISTs under SBE evaluation are significantly correlated with the risk level of GIST malignancy (P < .05). CONCLUSION:  A variety of endoscopic characteristics could be observed during the preoperative SBE evaluation of small-intestine GISTs.

[Proteomic analysis of differentially expressed proteins in gastrointestinal neuroendocrine tumors and their liver metastasis].

Objective: To investigate the differences of protein expressions in the primary tumors, adjacent tissues, and metastatic tumors of gastrointestinal neuroendocrine neoplasms. Methods: Nine patients with gastrointestinal neuroendocrine tumors (GI-NENs) with liver metastasis who underwent surgery at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences from July 2015 to April 2019 were selected. The protein expressions of the primary tissues, liver metastatic tissues, and adjacent tissues were detected by the data independent acquisition (DIA) technology. P<0.05 and | log2FC|>0.5 (FC as the difference multiple) were used as the criteria to identify the differentially expressed proteins in the primary tissues vs adjacent tissues, primary tissues vs liver metastatic tissues, primary tissues with different degrees of differentiation, and liver metastatic tissues with different degrees of differentiation. The differentially expressed proteins were investigated by volcano map analysis, cluster analysis, Gene Ontology (GO) function analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Results: Compared with adjacent tissues, 85 proteins were downregulated and 42 proteins were upregulated in the primary tissues of gastric NENs. The differentially expressed proteins were mainly enriched in the biological processes related to the regulation of guanosidase triphosphate activity and the catabolism of deoxyribonucleoside monophosphate, the glycosaminoglycan biosynthesis chondroitin sulfate/dermatan sulfate, pantothenate, and CoA biosynthesis signaling pathways. 114 proteins were downregulated and 155 proteins were upregulated in the primary tissues of intestinal NENs. The differentially expressed proteins were mainly enriched in the biological processes related to glutathione metabolism and sulfur compound metabolism, collecting duct acid secretion, and taurine and hytaurine metabolism signaling pathways. Compared with the primary tissues of neuroendocrine cancers (NECs), 168 proteins were downregulated and 278 proteins were upregulated in G1-2 differentiation primary tissues. The differentially expressed proteins were significantly enriched in biological processes such as DNA metabolism and DNA replication, as well as replication, mismatch repair, and other pathways. Compared with the metastatic tissues of NECs, 95 proteins were downregulated and 97 proteins were upregulated in G1-2 differentiated metastases. The differentially expressed proteins were significantly enriched in the activity and catalytic activity of transcriptional coactivators, base excision repair, and protein efflux pathways. Compared with G1 differentiated primary tissues, 530 proteins were downregulated and 211 proteins were upregulated in G1 differentiated metastatic tissues. Compared with G2 differentiated primary lesions, 53 proteins were downregulated and 96 proteins were upregulated in G2 differentiated metastatic tissues. Compared with the primary lesions of NECs, 109 proteins were downregulated and 92 proteins were upregulated in the metastatic tissues of NECs. In G1 and G2 differentiated GI-NENs, there are many similar signal pathways enriched in differentially expressed proteins between primary lesions and metastases, while only one signal pathway enriched in differentially expressed proteins between primary and metastatic tissues of NECs is the same as that enriched in differentially expressed proteins between primary and metastatic tissues of GI-NENs, which is the drug metabolism signal pathway. The differentially expressed proteins in G1 differentiated primary and metastatic tissues were mainly expressed in cytoplasm (20.26%), mitochondria (18.67%), and nucleus (15.48%). The differentially expressed proteins in the primary and metastatic tissues of G2 differentiation were mainly expressed in the cytoplasm (20.24%), nucleus (18.25%), and cell membrane (15.08%). The differentially expressed proteins in the primary and metastatic tissues of NECs were mainly expressed in the nucleus (23.78%), cytoplasm (22.7%), and cell membrane (11.35%). Conclusion: The protein expressions of GI-NENs in the primary tissues, adjacent tissues, and metastatic tissues were significantly different in different sites and degrees of differentiation.

Interpretable artificial intelligence to optimise use of imatinib after resection in patients with localised gastrointestinal stromal tumours: an observational cohort study.

BACKGROUND: Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy. METHODS: In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011. FINDINGS: Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit. INTERPRETATION: If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings. FUNDING: National Cancer Institute.

Cystatin SN (CST1) Is a Poor Independent Prognostic Biomarker for Gastrointestinal Diffuse Large B-Cell Lymphoma.

BACKGROUND Gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common histological subtype of extra-nodal DLBCL, but the risk factors, prognostic biomarkers, histopathological classifications, and treatment strategies have not had significant progress. Emerging evidence shows that cystatin SN (CST1) is involved in tumor progression in several cancer types, but its role in GI-DLBCL has not been revealed. MATERIAL AND METHODS We established a cohort consisting of 84 patients with GI-DLBCL who underwent surgical resection. The expression of CST1 in the cohort was investigated by immunohistochemistry, which divided the patients into subgroups with low or high expression of CST1. Moreover, the CST1 expression in GI-DLBCL tissues or adjacent GI tissues were compared with RT-qPCR. The correlation between CST1 expression and clinicopathological factors was analyzed with the chi-square test. The prognostic significance of CST1 was estimated by univariate and multivariate analysis, and statistical significance was analyzed with the log-rank test. RESULTS CST1 was aberrantly upregulated in GI-DLBCL tissues compared with in non-tumor GI tissues. High expression of CST1 indicated poor prognosis of GI-DLBCL (P=0.012), and CST1 can be regarded as an independent prognostic biomarker of GI-DLBCL (hazard ratio=3.07). In our study, serum lactate dehydrogenase (P=0.002), performance status (P=0.003), Lugano stage (P=0.002), and International Prognostic Index (P=0.001) were also prognostic factors of GI-DLBCL. CONCLUSIONS CST1 is an independent prognostic biomarker of GI-DLBCL, indicating unfavorable prognosis. Our results suggested that CST1 detection can be a promising method to stratify high-risk patients and guide individual treatment.

Incorporating Tumor Genomic Profiling and Circulating Tumor Cell-derived Organoids into Clinical Practice for Gastrointestinal Cancers.

BACKGROUND/AIM: Precision medicine aims to revolutionize healthcare by tailoring treatment regimens. This study aimed to integrate comprehensive tumor genomic profiling (CTGP) by targeted-gene panel sequencing and drug screening by circulating tumor cell-derived organoids (CTOs) into clinical practice for the treatment of gastrointestinal (GI) cancers. PATIENTS AND METHODS: Nine patients with various GI cancers underwent CTGP and CTO drug sensitivity testing. CTGP results guided targeted therapy and immunotherapy, while CTO drug sensitivity predicted response to chemotherapy and targeted agents. The drug recommendations from two platforms were correlated with the treatment response to the suggested medications retrospectively. RESULTS: Five patients received therapies aligned with CTGP, including HER2-targeted treatment, immunotherapy, and BRAF/MEK dual inhibition, showing positive responses. CTO drug sensitivity predicted progression under regorafenib (low potential benefit) and good response to chemotherapy with high potential benefit. The combination of CTGP and CTO drug sensitivity may exhibit significant correlation with clinical outcomes during treatment with candidate drugs, demonstrating a sensitivity of 79% and an accuracy of 75%. This encompasses various treatment modalities, such as chemotherapy, targeted therapy, and immunotherapy. CONCLUSION: The present investigation elucidated the integration of CTGP and CTO drug sensitivity screening into clinical practice in a complementary manner, showcasing a significant correlation between treatment response and testing outcomes. Additional prospective evaluation of these two testing modalities in a large cohort is warranted to confirm whether the inclusion of CTO drug sensitivity screening confers enhanced survival benefits compared to utilizing CTGP alone.

Icariside I enhances the effects of immunotherapy in gastrointestinal cancer via targeting TRPV4 and upregulating the cGAS-STING-IFN-I pathway.

Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.

Survival of advanced/recurrent gastrointestinal stromal tumors treated with tyrosine kinase inhibitors in Taiwan: a nationwide registry study.

BACKGROUND: Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan. METHODS: Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival. RESULTS: A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89). CONCLUSIONS: We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.

HER-2 directed therapies across gastrointestinal tract cancers - A new frontier.

Gastrointestinal (GI) cancers are common and in the metastatic setting they have a poor prognosis. The current mainstay of treatment of GI cancers is chemotherapy; however, the biomarker-directed treatment landscape is evolving. HER-2 is overexpressed in a portion of GI cancers and is an emerging target for therapy, with recent FDA tumor agnostic approval for trastuzumab deruxtecan. Testing for HER-2 expression is not standardized across GI cancers, methodology requires further optimization and standardization as HER-2 targeted therapy emerges into the treatment landscape. There is established rationale for use of HER-2 targeted therapy in first line treatment of metastatic gastric cancer, and emerging evidence with variable benefit in bile duct, pancreatic and colorectal cancers.

A pilot study of the immune microenvironment of GI neuroendocrine carcinoma.

Gastroenteropancreatic high-grade (HG) neuroendocrine carcinoma (GEP-NEC) is an aggressive malignancy with limited treatment options and increasing incidence in the United States. Due to the rarity of the cancer and heterogeneity of the primary tumor location, data on GEP-NEC oncogenesis and its interaction with the host immune system are limited. A greater understanding of GEP-NEC and its tumor microenvironment (TME) would benefit efforts to develop more effective targeted therapies and rationally adapt immunotherapy to this disease. In this study, we profiled the expression of 770 unique genes using 21 biopsy samples from patients with GEP-NEC using the NanoString nCounter PanCancer IO 360 platform. Our results show several trends evident within the GEP-NEC TME. Greater expression of genes indicative of immune cell infiltration was present within the TME of patients <60 years of age and in patients with greater overall survival (OS). Tumors from patients with non-pancreatic NEC had diminished MHCII expression compared to pancreatic NEC, suggesting more prominent adaptive immune responses in the pancreatic GEP-NEC subtype. Patients with a >6 months OS had tumors with elevated NK cell gene signatures compared to patients with poor survival. Further, the analysis revealed numerous differentially expressed genes based on patient age, tumor location, response to treatment, and OS, which warrant future validation for assessing the relationship with clinical outcomes in patients.

The Discovery of GIT1/ß-Pix Inhibitors: Virtual Screening and Biological Evaluation of New Small-molecule Compounds with Anti-invasion Effect in Gastrointestinal Neoplasms.

Background and Objective: GIT1 (G-protein-coupled receptor kinase interacting protein-1) has been found to be highly related with cancer cell invasion and metastasis in many cancer types. ß-Pix (p21-activated kinase-interacting exchange factor) is one of the proteins that interact with GIT1. Targeting GIT1/ß-Pix complex might be a potential therapeutic strategy for interfering cancer metastasis. However, at present, no well-recognized small-molecule inhibitor targeting GIT1/ß-Pix is available. Thus, we aim to discover novel GIT1/ß-Pix inhibitors with simple scaffold, high activity and low toxicity to develop new therapeutic strategies to restrain cancer metastasis. Methods: GIT1/ß-Pix inhibitors were identified from ChemBridge by virtual screening. Briefly, the modeling of GIT1 was performed and the establishment of GIT1/ß-Pix binding pocket enabled the virtual screening to identify the inhibitor. In addition, direct binding of the candidate molecules to GIT1 was detected by biolayer interferometry (BLI) to discover the hit compound. Furthermore, the inhibitory effect on invasion of stomach and colon cancer cells in vitro was carried out by the transwell assay and detection of epithelial-mesenchymal transition (EMT)-related proteins. Finally, the binding mode of hit compound to GIT1 was estimated by molecular dynamics simulation to analyze the key amino residues to guide further optimization. Results: We selected the top 50 compounds from the ChemBridge library by virtual screening. Then, by skeleton similarity analysis nine compounds were selected for further study. Furthermore, the direct interaction of nine compounds to GIT1 was detected by BLI to obtain the best affinitive compound. Finally, 17302836 was successfully identified (KD = 84.1±2.0 µM). In vitro tests on 17302836 showed significant anti-invasion effect on gastric cancer and colorectal cancer. Conclusion: We discovered a new GIT1/ß-Pix inhibitor (17302836) against gastrointestinal cancer invasion and metastasis. This study provides a promising candidate for developing new GIT1/ß-Pix inhibitors for tumor treatment.

The role of sarcopenic obesity for the prediction of prognosis of patients with gastrointestinal cancer.

BACKGROUND: Sarcopenic obesity (SO) in patients with gastrointestinal cancer is associated with a poor prognosis. We aimed to investigate the prognostic impact of SO in patients with gastrointestinal cancer, as well as the diagnostic cut-off value of SO in patients with gastrointestinal cancer among Chinese population. METHODS: We conducted a consecutive cohort study. Between January 2017 and January 2019, 289 patients diagnosed with gastrointestinal cancer were included in our study. Skeletal muscle area, total fat area, and subcutaneous fat area were measured by CT scan. All patients were followed up for 5 years. Receiver operating characteristic curves (ROC) were adopted to determine the cut-off values of visceral fat obesity for the prediction of sarcopenia. Based on the cut-off values, patients with sarcopenia combined with visceral fat obesity were divided into the SO group, and the others were divided into the non-sarcopenic obesity (NSO) group. Kaplan-Meier curves and univariate and multivariate Cox proportional hazard models were employed to explore the associations of body composition profiles with 5-year overall survival and disease-specific survival. RESULTS: Obtained from Youden's Index for ROC for the prediction of 5-year survival, skeletal muscle mass index (SMI) ≤40.02 cm2/m2 with VFA ≥ 126.30 cm2 in men and SMI ≤32.05 cm2/m2 with VFA ≥72.42 cm2 in women indicate a risk of poor prognosis in patients diagnosed with gastrointestinal cancer. Patients with SO had poorer 5-year overall survival (OS) than patients with NSO (6.74% vs. 82.84%, p < 0.001), and poorer 5-year DFS (6.74% vs. 81.82%, p < 0.001). In multivariate analysis, we found that the long-term mortality risk was approximately 13-fold higher among patients in the SO group compared to those with no conditions. CONCLUSIONS: Preoperative assessment of SO is useful not only for monitoring nutritional status but also for predicting 5-year OS in gastrointestinal cancer patients.

Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.

Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). We previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. We hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo. TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.

Machine learning for the identification of neoantigen-reactive CD8 + T cells in gastrointestinal cancer using single-cell sequencing.

BACKGROUND: It appears that tumour-infiltrating neoantigen-reactive CD8 + T (Neo T) cells are the primary driver of immune responses to gastrointestinal cancer in patients. However, the conventional method is very time-consuming and complex for identifying Neo T cells and their corresponding T cell receptors (TCRs). METHODS: By mapping neoantigen-reactive T cells from the single-cell transcriptomes of thousands of tumour-infiltrating lymphocytes, we developed a 26-gene machine learning model for the identification of neoantigen-reactive T cells. RESULTS: In both training and validation sets, the model performed admirably. We discovered that the majority of Neo T cells exhibited notable differences in the biological processes of amide-related signal pathways. The analysis of potential cell-to-cell interactions, in conjunction with spatial transcriptomic and multiplex immunohistochemistry data, has revealed that Neo T cells possess potent signalling molecules, including LTA, which can potentially engage with tumour cells within the tumour microenvironment, thereby exerting anti-tumour effects. By sequencing CD8 + T cells in tumour samples of patients undergoing neoadjuvant immunotherapy, we determined that the fraction of Neo T cells was significantly and positively linked with the clinical benefit and overall survival rate of patients. CONCLUSION: This method expedites the identification of neoantigen-reactive TCRs and the engineering of neoantigen-reactive T cells for therapy.

Survival of patients with ruptured gastrointestinal stromal tumour treated with adjuvant imatinib in a randomised trial.

BACKGROUND: Patients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival. METHODS: We explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria. RESULTS: Most ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%). CONCLUSIONS: About one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture. CLINICAL TRIAL REGISTRATION: NCT00116935.