MicroRNA-431-5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF-ß1/SMAD2/3 signaling via ZEB1 in gastric cancer.

Accumulating evidence suggests that lymphangiogenesis plays a crucial role in lymphatic metastasis, leading to tumor immune tolerance. However, the specific mechanism remains unclear. In this study, miR-431-5p was markedly downregulated in both gastric cancer (GC) tissues and plasma exosomes, and its expression were correlated negatively with LN metastasis and poor prognosis. Mechanistically, miR-431-5p weakens the TGF-ß1/SMAD2/3 signaling pathway by targeting ZEB1, thereby suppressing the secretion of VEGF-A and ANG2, which in turn hinders angiogenesis, lymphangiogenesis, and lymph node (LN) metastasis in GC. Experiments using a popliteal LN metastasis model in BALB/c nude mice demonstrated that miR-431-5p significantly reduced popliteal LN metastasis. Additionally, miR-431-5p enhances the efficacy of anti-PD1 treatment, particularly when combined with galunisertib, anti-PD1 treatment showing a synergistic effect in inhibiting GC progression in C57BL/6 mice. Collectively, these findings suggest that miR-431-5p may modulate the TGF-ß1/SMAD2/3 pathways by targeting ZEB1 to impede GC progression, angiogenesis, and lymphangiogenesis, making it a promising therapeutic target for GC management.

Combined systemic inflammatory immune index and prognostic nutrition index as chemosensitivity and prognostic markers for locally advanced gastric cancer receiving neoadjuvant chemotherapy: a retrospective study.

BACKGROUND: The prognosis nutritional index (PNI) and the systemic inflammatory immunological index (SII) are characteristic indicators of the nutritional state and the systemic inflammatory response, respectively. However, there is an unknown combined effect of these indicators in the clinic. Therefore, the practicality of using the SII-PNI score to predict prognosis and tumor response of locally advanced gastric cancer (LAGC) following chemotherapy was the main focus of this investigation. METHODS: We retrospectively analyzed 181 patients with LAGC who underwent curative resection after neoadjuvant chemotherapy in a prospective study (NCT01516944). We divided these patients into tumour regression grade(TRG) 3 and non-TRG3 groups based on tumor response (AJCC/CAP guidelines). The SII and PNI were assessed and confirmed the cut-off values before treatment. The SII-PNI values varied from 0 to 2, with 2 being the high SII (≥ 471.5) as well as low PNI (≤ 48.6), a high SII or low PNI is represented by a 1 and neither is represented by a 0, respectively. RESULTS: 51 and 130 samples had TRG3 and non-TRG3 tumor responses respectively. Patients with TRG3 had substantially higher SII-PNI scores than those without TRG3 (p < 0.0001). Patients with greater SII-PNI scores had a poorer prognosis (p < 0.0001). The SII-PNI score was found to be an independent predictor of both overall survival (HR = 4.982, 95%CI: 1.890-10.234, p = 0.001) and disease-free survival (HR = 4.763, 95%CI: 1.994-13.903, p = 0.001) in a multivariate analysis. CONCLUSION: The clinical potential and accuracy of low-cost stratification based on SII-PNI score in forecasting tumor response and prognosis in LAGC is satisfactory.

Clinical implications of micro lymph node metastasis for patients with gastric cancer.

BACKGROUND: Lymph node size is considered as a criterion for possible lymph node metastasis in imageology. Micro lymph nodes are easily overlooked by surgeons and pathologists. This study investigated the influencing factors and prognosis of micro lymph node metastasis in gastric cancer. METHODS: 191 eligible gastric cancer patients who underwent D2 lymphadenectomy from June 2016 to June 2017 in the Third Surgery Department at the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Specimens were resected en bloc and the postoperative retrieval of micro lymph nodes was carried out by the operating surgeon for each lymph node station. Micro lymph nodes were submitted for pathological examination separately. According to the results of pathological results, patients were divided into the "micro-LNM (micro lymph node metastasis)" group (N = 85) and the "non micro-LNM" group (N = 106). RESULTS: The total number of lymph nodes retrieved was 10,954, of which 2998 (27.37%) were micro lymph nodes. A total of 85 (44.50%) gastric cancer patients had been proven to have micro lymph node metastasis. The mean number of micro lymph nodes retrieved was 15.7. The rate of micro lymph node metastasis was 8.1% (242/2998). Undifferentiated carcinoma (90.6% vs. 56.6%, P = 0.034) and more advanced Pathological N category (P < 0.001) were significantly related to micro lymph node metastasis. The patients with micro lymph node metastasis had a poor prognosis (HR for OS of 2.199, 95% CI = 1.335-3.622, P = 0.002). For the stage III patients, micro lymph node metastasis was associated with shorter 5-year OS (15.6% vs. 43.6%, P = 0.0004). CONCLUSIONS: Micro lymph node metastasis is an independent risk factor for poor prognosis in gastric cancer patients. Micro lymph node metastasis appears to be a supplement to N category in order to obtain more accurate pathological staging.

Prediction of occult peritoneal metastases or positive cytology using CT in gastric cancer.

OBJECTIVE: Accurate prediction of preoperative occult peritoneal metastasis (OPM) is critical to selecting appropriate therapeutic regimen for gastric cancer (GC). Considering the clinical practicability, we develop and validate a visible nomogram that integrates the CT images and clinicopathological parameters for the individual preoperative prediction of OPM in GC. METHODS: This retrospective study included 520 patients who underwent staged laparoscopic exploration or peritoneal lavage cytology (PLC) examination. Univariate and multivariate logistic regression results were used to screen model predictors and construct nomograms of OPM risk. The performance of the model was detected by using ROC, accuracy, and C-index. The bootstrap resampling method was considered internal validation of the model. The Delong test was used to evaluate the difference in AUC between the two models. RESULTS: Grade 2 mural stratification, tumor thickness, and the Lauren classification diffuse were significant predictors of OPM (p < 0.05). The nomogram of these three factors (compared with the original model) showed a higher predictive effect (p < 0.001). The area under the curve (AUC) of the model was 0.830 (95% CI 0.788-0.873), and the internally validated AUC of 1000 bootstrap samples was 0.826 (95% CI 0.756-0.870). The sensitivity, specificity, and accuracy were 76.0%, 78.8%, and 78.3%, respectively. CONCLUSIONS: CT phenotype-based nomogram demonstrates favorable discrimination and calibration, and it can be conveniently used for preoperative individual risk rating of OPM in GC. CLINICAL RELEVANCE STATEMENT: In this study, the preoperative OPM prediction model based on CT images (mural stratification, tumor thickness) combined with pathological parameters (the Lauren classification) showed excellent predictive ability in GC, and it is also suitable for clinicians to use rather than limited to professional radiologists. KEY POINTS: • Nomogram based on CT image analysis can effectively predict occult peritoneal metastasis in gastric cancer (training area under the curve (AUC) = 0.830 and bootstrap AUC = 0.826). • Nomogram model combined with CT features performed better than the original model (established using only clinicopathological parameters) in differentiating occult peritoneal metastasis of gastric cancer.

Inflammation and nutritional status indicators as prognostic indicators for patients with locally advanced gastrointestinal stromal tumors treated with neoadjuvant imatinib.

BACKGROUND: Previous studies have confirmed that preoperative nutritional-inflammatory indicators can predict prognosis in various malignancies. However, to the best of our knowledge, no study has investigated the assessment of systemic inflammatory immunity index (SII) combined with prognostic nutritional index (PNI) scores to predict prognosis after neoadjuvant treatment with imatinib in locally advanced gastrointestinal stromal tumours (LA-GIST). The aim of this study was to evaluate the predictive value of pretreatment SII-PNI scores in predicting recurrence after neoadjuvant therapy with imatinib in patients with LA-GIST. METHODS: We retrospectively analyzed 57 patients with LA-GIST who received imatinib neoadjuvant from January 2013 to March 2019. Patients were divided into recurrence and non-recurrence groups according to their follow-up status, and SII and PNI cut-offs were calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 544.6) and low PNI (≤ 47.2); score of 1, either high SII (≥ 544.6) or low PNI (≤ 47.2); score of 0, no high SII (≥ 544.6) nor low PNI (≤ 47.2). RESULTS: All patients received imatinib neoadjuvant therapy for a median treatment period of 8.5 months (ranging from 3.2 to 12.6 months), with 8 patients (14.04%) and 49 patients (85.96%) developing recurrence and non-recurrence, respectively. Patients with a high SII-PNI score had a significantly worse recurrence-free survival time than those with a low SII-PNI score (P = 0.022, 0.046), and had a poorer pathological response (P = 0.014). Multivariate analysis demonstrated that the SII-PNI score was an independent prognostic factor for prediction of recurrence-free survival (P = 0.002). CONCLUSION: The pre-treatment SII-PNI score can be used to predict the efficacy after neoadjuvant treatment with imatinib in patients with LA-GIST, which may be a promising predictor of recurrence-free survival time for patients.

Combined systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) predicts chemotherapy response and prognosis in locally advanced gastric cancer patients receiving neoadjuvant chemotherapy with PD-1 antibody sintilimab and XELOX: a prospective study.

BACKGROUND: Previous studies have confirmed that systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) can predict the prognosis and chemotherapy efficacy of various malignant tumors. However, to the best of our knowledge, no study investigated the SII combined with PNI score to predict the efficacy of anti-programmed death 1 (anti-PD-1) antibody sintilimab and XELOX regimen (capecitabine plus oxaliplatin) in the treatment of locally advanced gastric cancer. This study aims to evaluate the predictive value of pre-treatment SII-PNI score on the sensitivity of sintilimab immunotherapy combined with XELOX chemotherapy in patients with locally advanced gastric cancer. METHODS: We registered a prospective clinical study involving 30 locally advanced gastric cancer patients from March 2020 to July 2021. The pre-treatment SII and PNI were calculated from peripheral blood samples, and the cut-off value was calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 568.5) and low PNI (≤ 52.7); score of 1, either high SII or low PNI; score of 0, no high SII nor low PNI. RESULTS: All patients were evaluated by RECIST1.1 criteria after four cycles of sintilimab immunotherapy combined with XELOX chemotherapy, including 5 patients with TRG 3 and 25 patients with non-TRG 3. The SII-PNI score of non-TRG 3 patients was significantly lower than that of TRG 3 patients (P = 0.017). The medial progression free survival of patients with low SII-PNI score was significantly better than that of patients with high SII-PNI score (P < 0.001). Multivariate analysis showed that SII-PNI score was an independent prognostic factor for predicting progression-free survival (P = 0.003). CONCLUSION: The pre-treatment SII-PNI score is a significant indicator for predicting chemosensitivity of locally advanced patients after sintilimab immunotherapy combined with XELOX chemotherapy, which can help to identify high-risk groups and predict prognosis. TRIAL REGISTRATION: The registered name of the trial is "Prospective clinical study of sintilimab combined with chemotherapy for neoadjuvant therapy in locally advanced gastric cancer". Its Current Controlled Trials number is ChiCTR2000030414. Its date of registration is 01/03/2020.

Effect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced GIST.

BACKGROUND: Currently, the effect of skeletal muscle loss during neoadjuvant imatinib therapy on clinical outcomes in patients with locally advanced gastrointestinal stromal tumors (LA-GIST) remains unclear. This study aims to investigate the relationship between changes in skeletal muscle and postoperative complications, survival and tumor response in patients with LA-GIST during neoadjuvant therapy with imatinib. METHODS: We retrospectively analyzed pre- and post-treatment computed tomography images of 57 GIST patients who underwent radical surgery after neoadjuvant therapy with imatinib from January 2013 to March 2019. Skeletal muscle index (SMI) was measured at the L3 vertebral level in all patients. A cut-off value (SMI < 52.3 cm2/m2 and < 38.6 cm2/m2 for men and women, respectively) published in a previous study was used to define sarcopenia. Based on gender, we defined ΔSMI (%)/250 days above 9.69% for men and ΔSMI (%)/250 days above 7.63% for women as significant muscle loss (SML). Factors associated with postoperative complications and tumor response were analyzed using logistic regression, and predictors affecting patient prognosis were analyzed using Cox regression. RESULTS: Of the 57 patients, sarcopenia was present before and after neoadjuvant therapy in 20 (35.09%) and 28 (49.12%) patients, respectively. It was not associated with immediate or long-term clinical outcomes. However, patients with SML during neoadjuvant therapy had a higher incidence of postoperative complications (60.00% vs. 25.00%, p = 0.008), worse pathological regression (44.00% vs. 75.00%, p = 0.017) and worse 3-year survival (Male, 68.75% vs. 95.45%, p = 0.027; Female, 66.67% vs. 100.00%, p = 0.046) than patients without SML. CONCLUSION: The development of SML during neoadjuvant therapy in LA-GIST patients, rather than pre- and post-treatment sarcopenia, is a major prognostic factor for the long-term prognosis and is also associated with recent postoperative complication rates and pathological regression.

Comparison of the predictive performance of three lymph node staging systems for late-onset gastric cancer patients after surgery.

Introduction: Lymph node (LN) status is a vital prognostic factor for patients. However, there has been limited focus on predicting the prognosis of patients with late-onset gastric cancer (LOGC). This study aimed to investigate the predictive potential of the log odds of positive lymph nodes (LODDS), lymph node ratio (LNR), and pN stage in assessing the prognosis of patients diagnosed with LOGC. Methods: The LOGC data were obtained from the Surveillance, Epidemiology, and End Results database. This study evaluated and compared the predictive performance of three LN staging systems. Univariate and multivariate Cox regression analyses were carried out to identify prognostic factors for overall survival (OS). Three machine learning methods, namely, LASSO, XGBoost, and RF analyses, were subsequently used to identify the optimal LN staging system. A nomogram was built to predict the prognosis of patients with LOGC. The efficacy of the model was demonstrated through receiver operating characteristic (ROC) curve analysis and decision curve analysis. Results: A total of 4,743 patients with >16 removed lymph nodes were ultimately included in this investigation. Three LN staging systems demonstrated significant performance in predicting survival outcomes (P < 0.001). The LNR exhibited the most important prognostic ability, as evidenced by the use of three machine learning methods. Utilizing independent factors derived from multivariate Cox regression analysis, a nomogram for OS was constructed. Discussion: The calibration, C-index, and AUC revealed their excellent predictive performance. The LNR demonstrated a more powerful performance than other LN staging methods in LOGC patients after surgery. Our novel nomogram exhibited superior clinical feasibility and may assist in patient clinical decision-making.

Mechanisms of immune checkpoint inhibitors: insights into the regulation of circular RNAS involved in cancer hallmarks.

Current treatment strategies for cancer, especially advanced cancer, are limited and unsatisfactory. One of the most substantial advances in cancer therapy, in the last decades, was the discovery of a new layer of immunotherapy approach, immune checkpoint inhibitors (ICIs), which can specifically activate immune cells by targeting immune checkpoints. Immune checkpoints are a type of immunosuppressive molecules expressed on immune cells, which can regulate the degree of immune activation and avoid autoimmune responses. ICIs, such as anti-PD-1/PD-L1 drugs, has shown inspiring efficacy and broad applicability across various cancers. Unfortunately, not all cancer patients benefit remarkably from ICIs, and the overall response rates to ICIs remain relatively low for most cancer types. Moreover, the primary and acquired resistance to ICIs pose serious challenges to the clinical application of cancer immunotherapy. Thus, a deeper understanding of the molecular biological properties and regulatory mechanisms of immune checkpoints is urgently needed to improve clinical options for current therapies. Recently, circular RNAs (circRNAs) have attracted increasing attention, not only due to their involvement in various aspects of cancer hallmarks, but also for their impact on immune checkpoints in shaping the tumor immune microenvironment. In this review, we systematically summarize the current status of immune checkpoints in cancer and the existing regulatory roles of circRNAs on immune checkpoints. Meanwhile, we also aim to settle the issue in an evidence-oriented manner that circRNAs involved in cancer hallmarks regulate the effects and resistance of ICIs by targeting immune checkpoints.

Clinical calculator based on CT and clinicopathologic characteristics predicts short-term prognosis following resection of microsatellite-stabilized diffuse gastric cancer.

PURPOSE: Although microsatellite stability/Epithelial-mesenchymal transition (MSS/EMT) subtypes have been reported in multiple cancer prognosis studies, strong confounding factors between MSS/EMT (usually with Lauren's diffuse phenotype) and diffuse gastric cancer (GC) may obscure the independent prognostic value of diffuse GC. Additionally, recent studies suggest a strong correlation between mural stratification based on CT and diffuse GC. This study aims to investigate potential prognostic factors of MSS diffuse GC using mural stratification and to develop a risk assessment model. METHODS: This retrospective study included 131 patients with MSS diffuse GC who underwent radical surgery. Univariate and multivariate Cox proportional hazards regression analysis was used to identify model predictors and construct a nomogram for overall survival (OS) and recurrence-free survival (RFS) risks. The model's performance was evaluated using ROC, accuracy, and C-index. Internal validation of the model was conducted using the bootstrap resampling method. RESULTS: Among 131 cases, 60 cases (45.8%) exhibited grade 2 mural stratification, which correlated with a poorer tumor prognosis and a more invasive phenotype. Furthermore, a nomogram for predicting OS and RFS prognosis was established based on multivariate results (age, extranodal invasion, mural stratification, and/or P53). The nomogram demonstrated excellent performance, with an AUC of 0.859 (95% CI 0.794-0.924) for OS and 0.859 (95% CI 0.789-0.929) for RFS. Internal validation using 1000 bootstrap samples yielded AUC values of 0.845 and 0.846 for OS and RFS, respectively. CONCLUSION: Grade 2 mural stratification based on CT imaging revealed a more aggressive invasive phenotype, characterized by increased LN metastasis, higher rates of peritoneal metastasis, and a poorer short-term prognosis. Furthermore, the CT phenotype-based nomogram demonstrates favorable discrimination and calibration, enabling convenient individual short-term prognostic evaluation following resection of MSS diffuse GC.

CALD1 facilitates epithelial-mesenchymal transition progression in gastric cancer cells by modulating the PI3K-Akt pathway.

BACKGROUND: CALD1 has been discovered to be abnormally expressed in a variety of malignant tumors, including gastric cancer (GC), and is associated with tumor progression and immune infiltration; however, the roles and mechanisms of CALD1 in epithelial-mesenchymal transition (EMT) in GC are unknown. AIM: To investigate the role and mechanism of CALD1 in GC progression, invasion, and migration. METHODS: In this study, the relationship between CALD1 and GC, as well as the possible network regulatory mechanisms of CALD1, was investigated by bioinformatics and validated by experiments. CALD1-siRNA was synthesized and used to transfect GC cells. Cell activity was measured using the CCK-8 method, cell migration and invasive ability were measured using wound healing assay and Transwell assay, and the expression levels of relevant genes and proteins in each group of cells were measured using qRT-PCR and Western blot. A GC cell xenograft model was established to verify the results of in vitro experiments. RESULTS: Bioinformatics results showed that CALD1 was highly expressed in GC tissues, and CALD1 was significantly higher in EMT-type GC tissues than in tissues of other types of GC. The prognosis of patients with high expression of CALD1 was worse than that of patients with low expression, and a prognostic model was constructed and evaluated. The experimental results were consistent with the results of the bioinformatics analysis. The expression level of CALD1 in GC cell lines was all higher than that in gastric epithelial cell line GES-1, with the strongest expression found in AGS and MKN45 cells. Cell activity was significantly reduced after CALD1-siRNA transfection of AGS and MKN45 cells. The ability of AGS and MKN45 cells to migrate and invade was reduced after CALD1-siRNA transfection, and the related mRNA and protein expression was altered. According to bioinformatics findings in GC samples, the CALD1 gene was significantly associated with the expression of members of the PI3K-AKT-mTOR signaling pathway as well as the EMT signaling pathway, and was closely related to the PI3K-Akt signaling pathway. Experimental validation revealed that upregulation of CALD1 increased the expression of PI3K, p-AKT, and p-mTOR, members of the PI3K-Akt pathway,while decreasing the expression of PTEN; PI3K-Akt inhibitor treatment decreased the expression of PI3K, p-AKT, and p-mTOR in cells overexpressing CALD1 (still higher than that in the normal group), but increased the expression of PTEN (still lower than that in the normal group). CCK-8 results revealed that the effect of CALD1 on tumor cell activity was decreased by the addition of the inhibitor. Scratch and Transwell experiments showed that the effect of CALD1 on tumor cell migration and invasion was weakened by the addition of the PI3K-Akt inhibitor. The mRNA and protein levels of EMT-related genes in AGS and MKN45 cells were greatly altered by the overexpression of CALD1, whereas the effect of overexpression of CALD1 was significantly weakened by the addition of the PI3K-Akt inhibitor. Animal experiments showed that tumour growth was slow after inhibition of CALD1, and the expression of some PI3K-Akt and EMT pathway proteins was altered. CONCLUSION: Increased expression of CALD1 is a key factor in the progression, invasion, and metastasis of GC, which may be associated with regulating the PI3K-Akt pathway to promote EMT.

Impact of preoperative sarcopenia on postoperative complications and prognosis in patients undergoing robotic gastric cancer surgery: A propensity score matching study.

BACKGROUND: Sarcopenia, defined as decreased muscle mass and function, correlates with postoperative morbidity and mortality in cancer surgery. However, sarcopenia's impact specifically following robotic gastrectomy for gastric cancer has not been clearly defined. This study aimed to determine the influence of sarcopenia on short- and long-term clinical outcomes after robotic gastrectomy for gastric cancer. METHODS: This retrospective study analyzed 381 gastric cancer patients undergoing robotic gastrectomy. Sarcopenia was diagnosed by preoperative computed tomography (CT) body composition analysis. Propensity score matching created 147 pairs of sarcopenia and nonsarcopenia patients for comparison. Outcomes included postoperative complications, survival, inflammatory markers, length of stay, intensive care unit (ICU) transfer, and readmissions. RESULTS: Sarcopenia patients exhibited significantly higher rates of overall (53.7% versus 21.1%, P < 0.001), serious (12.9% versus 4.1%, P = 0.007), and grade III-IV complications compared to nonsarcopenia pairs after matching. Sarcopenia independently predicted reduced 3-years overall (HR = 2.53, 95% CI: 1.19-5.40, P = 0.016) and disease-free survival (HR = 1.99, 95% CI: 1.09-3.66, P = 0.026). Sarcopenia patients also showed heightened postoperative leukocyte, neutrophil, platelet, platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and monocyte to lymphocyte ratio (MLR) levels alongside suppressed lymphocytes, monocytes, and neutrophil to lymphocyte ratio (NLR). CONCLUSION: Preoperative sarcopenia is correlated with increased postoperative complications and poorer long-term survival in gastric cancer patients undergoing robotic gastrectomy. Sarcopenia assessment can optimize preoperative risk stratification and perioperative management in this population.

Recurrent metastatic patterns and prognosis after radical surgery in patients with alpha-fetoprotein-producing gastric cancer: a retrospective cohort study.

Alpha-fetoprotein-producing gastric cancer (AFPGC) is a rare and aggressive subtype of gastric cancer associated with poor prognosis. This study aimed to investigate the recurrent metastatic patterns and prognostic factors in AFPGC patients undergoing radical surgical resection. Data from 241 AFPGC patients diagnosed between January 2017 and January 2020 who underwent surgical resection were analyzed across multiple centers. Recurrence patterns, metastatic sites, and survival outcomes were evaluated. Univariate and multivariate analyses were performed to identify risk factors for recurrent metastasis, overall survival (OS), and disease-free survival (DFS). There is an annual increase in the proportion of AFPGC cases, rising from 3.45% in 2017 to 7.88% in 2023. Higher serum AFP level was associated with increased likelihood of lymph node metastasis (P=0.006), deeper invasion depth (P=0.000) and greater tumor diameter (P=0.036). Independent predictors of recurrent metastasis included T4 infiltration, lymph node metastasis, tumor diameter >5 cm, poorly differentiated-undifferentiated pathology, preoperative AFP>1000 ng/mL, and postoperative increasing trend in AFP levels. The 5-year OS and DFS rates were 36.5% and 34.2%, respectively, with poorer survival linked to higher preoperative AFP levels and postoperative increasing trend in AFP level. Independent risk factors for poor OS and DFS included T4 infiltration, lymph node metastasis, poorly differentiated-undifferentiated pathology, preoperative AFP>1000 ng/mL, and postoperative increasing trend in AFP. Serum AFP level can serve as a potential predictive and prognostic biomarker. Identifying independent risk factors informs risk stratification and personalized treatment for AFPGC patients.

Development and validation of nomogram models for predicting overall survival and cancer-specific survival in gastric cancer patients with liver metastases: a cohort study based on the SEER database.

OBJECTIVE: To establish nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of gastric cancer liver metastasis (GCLM) patients. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) database for 5,451 GCLM patients diagnosed between 2010 and 2015 were analyzed. The cohort was divided into a training set (3,815 cases) and an internal validation set (1,636 cases). External validation included 193 patients from the Fourth Hospital of Hebei Medical University and 171 patients from the People's Hospital of Shijiazhuang City, spanning 2016-2018. Multivariable Cox regression analysis identified eight independent prognostic factors for OS and CSS in GCLM patients, including age, histological type, grade, tumor size, surgery, chemotherapy, bone metastasis, and lung metastasis. Two nomogram models were developed based on these factors and evaluated using time-dependent receiver operating characteristic curve analysis, calibration curves, and decision curve analysis. RESULTS: Internal validation showed that the nomogram models outperformed the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system in predicting 1-year, 2-year, and 3-year OS and CSS in GCLM patients (1-year OS: 0.801 vs. 0.593, P < 0.001; 1-year CSS: 0.807 vs. 0.598, P < 0.001; 2-year OS: 0.803 vs. 0.630, P < 0.001; 2-year CSS: 0.802 vs. 0.633, P < 0.001; 3-year OS: 0.824 vs. 0.691, P < 0.001; 3-year CSS: 0.839 vs. 0.692, P < 0.001). CONCLUSION: This study developed and validated nomogram models using SEER database data to predict OS and CSS in GCLM patients. These models offer improved prognostic accuracy over traditional staging systems, aiding in clinical decision-making.

N6-methyladenosine modified circPAK2 promotes lymph node metastasis via targeting IGF2BPs/VEGFA signaling in gastric cancer.

Circular RNAs (circRNAs) have emerged as key regulators of cancer occurrence and progression, as well as promising biomarkers for cancer diagnosis and prognosis. However, the potential mechanisms of circRNAs implicated in lymph node (LN) metastasis of gastric cancer remain unclear. Herein, we identify a novel N6-methyladenosine (m6A) modified circRNA, circPAK2, which is significantly upregulated in gastric cancer tissues and metastatic LN tissues. Functionally, circPAK2 enhances the migration, invasion, lymphangiogenesis, angiogenesis, epithelial-mesenchymal transition (EMT), and metastasis of gastric cancer in vitro and in vivo. Mechanistically, circPAK2 is exported by YTH domain-containing protein 1 (YTHDC1) from the nucleus to the cytoplasm in an m6A methylation-dependent manner. Moreover, increased cytoplasmic circPAK2 interacts with Insulin-Like Growth Factor 2 mRNA-Binding Proteins (IGF2BPs) and forms a circPAK2/IGF2BPs/VEGFA complex to stabilize VEGFA mRNA, which contributes to gastric cancer vasculature formation and aggressiveness. Clinically, high circPAK2 expression is positively associated with LN metastasis and poor prognosis in gastric cancer. This study highlights m6A-modified circPAK2 as a key regulator of LN metastasis of gastric cancer, thus supporting circPAK2 as a promising therapeutic target and prognostic biomarker for gastric cancer.

Nomogram models for predicting overall and cancer-specific survival in early-onset gastric cancer patients: a population-based cohort study.

To develop nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of early-onset gastric cancer (EOGC) patients. A total of 1077 EOGC patients from the Surveillance, Epidemiology, and End Results (SEER) database were included, and an additional 512 EOGC patients were recruited from the Fourth Hospital of Hebei Medical University, serving as an external test set. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors. Based on these factors, two nomogram models were established, and web-based calculators were developed. These models were validated using receiver operating characteristics (ROC) curve analysis, calibration curves, and decision curve analysis (DCA). Multivariate analysis identified gender, histological type, stage, N stage, tumor size, surgery, primary site, and lung metastasis as independent prognostic factors for OS and CSS in EOGC patients. Calibration curves and DCA curves demonstrated that the two constructed nomogram models exhibited good performance. These nomogram models demonstrated superior performance compared to the 7th edition of the AJCC tumor-node-metastasis (TNM) classification (internal validation set: 1-year OS: 0.831 vs 0.793, P = 0.072; 1-year CSS: 0.842 vs 0.816, P = 0.190; 3-year OS: 0.892 vs 0.857, P = 0.039; 3-year CSS: 0.887 vs 0.848, P = 0.018; 5-year OS: 0.906 vs 0.880, P = 0.133; 5-year CSS: 0.900 vs 0.876, P = 0.109). In conclusion, this study developed two nomogram models: one for predicting OS and the other for CSS of EOGC patients, offering valuable assistance to clinicians.

Safety, tolerability, and pharmacokinetics of mitoxantrone hydrochloride injection for tracing in patients with gastric cancer: a single-blind, single-center, phase I clinical trial.

Mitoxantrone Hydrochloride Injection for Tracing (MHI), a modified new drug marketed in China, has been approved by the National Medical Products Administration for lymph node tracing in thyroid cancer and sentinel lymph node biopsy in breast cancer. This single-center, single-blind, dose-escalation phase I clinical trial aimed to investigate the safety of MHI on lymph node tracing in gastric cancer. In this study, four dose groups (1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL) with 3 gastric cancer patients in each group were set. The safety, tolerability, pharmacokinetics and preliminary efficacy of different doses were investigated. Results showed that none of the patients experienced dose-limiting toxicity or developed serious adverse events or adverse drug reactions. Pharmacokinetic analyses revealed minimal absorption of the tracer, resulting in low and transient blood drug concentrations across all participants. The mean time to peak concentration was (0.561 ± 0.3728) h (with mean peak concentration (Cmax) of 10.300 ng/mL), (0.500 ± 0.0167) h (mean Cmax of 13.687 ng/mL), (0.494 ± 0.0096) h (mean Cmax of 30.933 ng/mL), and (0.661 ± 0.2791) h (mean Cmax of 21.067 ng/mL) in the 1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL dose groups, respectively. The mean lymph node staining rates were 21.0%, 24.7%, 32.5%, and 44.5%, and the mean metastatic lymph node staining rates were 20.6%, 36.1%, 42.4%, and 21.0% in each group. This study confirmed that MHI was safe, well-tolerated, and had low systemic effects when used for lymphatic tracing of gastric cancer, and the tracing effect was better in the 3 mL dose group. This trail was registered on the website of Centre for Drug Evaluation State Drug and Food Administration (http://www.chinadrugtrials.org.cn/index.html) with the name of clinical study of lymphatic tracer in lymph node tracing of gastric cancer, the code was CTR20201906.

Comparative analysis of two digestive tract reconstruction methods in total laparoscopic radical total gastrectomy.

BACKGROUND: The incidence of gastric cancer has significantly increased in recent years. Surgical resection is the main treatment, but the method of digestive tract reconstruction after gastric cancer surgery remains controversial. In the current study, we sought to explore a reasonable method of digestive tract reconstruction and improve the quality of life and nutritional status of patients after surgery. To this end, we statistically analyzed the clinical results of patients with gastric cancer who underwent jejunal interposition double-tract reconstruction (DTR) and esophageal jejunum Roux-en-Y reconstruction (RY). AIM: To explore the application effect of DTR in total laparoscopic radical total gastrectomy (TLTG) and evaluate its safety and efficacy. METHODS: We collected the relevant data of 77 patients who underwent TLTG at the Fourth Hospital of Hebei Medical University from October 2021 to January 2023. Among them, 35 cases were treated with DTR, and the remaining 42 cases were treated with traditional RY. After 1:1 propensity score matching, the cases were grouped into 31 cases per group, with evenly distributed data. The clinical characteristics and short- and long-term clinical outcomes of the two groups were statistically analyzed. RESULTS: The two groups showed no significant differences in basic data, intraoperative blood loss, number of lymph node dissections, first defecation time after operation, postoperative hospital stay, postoperative complications, and laboratory examination results on the 1st, 3rd, and 5th days after operation. The operation time of the DTR group was longer than that of the RY group [(307.58 ± 65.14) min vs (272.45 ± 62.09) min, P = 0.016], but the first intake of liquid food in the DTR group was shorter than that in the RY group [(4.45 ± 1.18) d vs (6.0 ± 5.18) d, P = 0.028]. The incidence of reflux heartburn (Visick grade) and postoperative gallbladder disease in the DTR group was lower than that in the RY group (P = 0.033 and P = 0.038). Although there was no significant difference in body weight, hemoglobin, prealbumin, and albumin between the two groups at 1,3 and 6 months after surgery, the diet of patients in the DTR group was better than that in the RY group (P = 0.031). CONCLUSION: The clinical effect of DTR in TLTG is better than that of RY, indicating that it is a more valuable digestive tract reconstruction method in laparoscopic gastric cancer surgery.

Transcriptomics-based liquid biopsy panel for early non-invasive identification of peritoneal recurrence and micrometastasis in locally advanced gastric cancer.

BACKGROUND: This study aimed to develop a novel six-gene expression biomarker panel to enhance the early detection and risk stratification of peritoneal recurrence and micrometastasis in locally advanced gastric cancer (LAGC). METHODS: We used genome-wide transcriptome profiling and rigorous bioinformatics to identify a six-gene expression biomarker panel. This panel was validated across multiple clinical cohorts using both tissue and liquid biopsy samples to predict peritoneal recurrence and micrometastasis in patients with LAGC. RESULTS: Through genome-wide expression profiling, we identified six mRNAs and developed a risk prediction model using 196 samples from a surgical specimen training cohort. This model, incorporating a 6-mRNA panel with clinical features, demonstrated high predictive accuracy for peritoneal recurrence in gastric cancer patients, with an AUC of 0.966 (95% CI: 0.944-0.988). Transitioning from invasive surgical or endoscopic biopsy to noninvasive liquid biopsy, the model retained its predictive efficacy (AUC = 0.963; 95% CI: 0.926-1.000). Additionally, the 6-mRNA panel effectively differentiated patients with or without peritoneal metastasis in 95 peripheral blood specimens (AUC = 0.970; 95% CI: 0.936-1.000) and identified peritoneal micrometastases with a high efficiency (AUC = 0.941; 95% CI: 0.874-1.000). CONCLUSIONS: Our study provides a novel gene expression biomarker panel that significantly enhances early detection of peritoneal recurrence and micrometastasis in patients with LAGC. The RSA model's predictive capability offers a promising tool for tailored treatment strategies, underscoring the importance of integrating molecular biomarkers with clinical parameters in precision oncology.

Mechanisms and biomarkers of immune-related adverse events in gastric cancer.

Immune-checkpoint inhibitors (ICIs), different from traditional cancer treatment models, have shown unprecedented anti-tumor effects in the past decade, greatly improving the prognosis of many malignant tumors in clinical practice. At present, the most widely used ICIs in clinical immunotherapy for a variety of solid tumors are monoclonal antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and their ligand PD-L1. However, tumor patients may induce immune-related adverse events (irAEs) while performing immunotherapy, and irAE is an obstacle to the prospect of ICI treatment. IrAE is a non-specific disease caused by immune system imbalance, which can occur in many tissues and organs. For example, skin, gastrointestinal tract, endocrine system and lung. Although the exact mechanism is not completely clear, related studies have shown that irAE may develop through many ways. Such as excessive activation of autoreactive T cells, excessive release of inflammatory cytokines, elevated levels of autoantibodies, and common antigens between tumors and normal tissues. Considering that the occurrence of severe IrAE not only causes irreversible damage to the patient's body, but also terminates immunotherapy due to immune intolerance. Therefore, accurate identification and screening of sensitive markers of irAE are the main beneficiaries of ICI treatment. Additionally, irAEs usually require specific management, the most common of which are steroids and immunomodulatory therapies. This review aims to summarize the current biomarkers for predicting irAE in gastric cancer and their possible mechanisms.