Log odds of positive lymph nodes as a novel prognostic predictor for gastric cancer: a systematic review and meta-analysis.

BACKGROUND: We conducted a systematic review and meta-analysis to summarize the predictive and prognostic ability of the log odds of positive lymph nodes (LODDS) staging system and compare it with pathological N (pN) classification and the ratio-based lymph node system (rN) for the overall survival (OS) of gastric cancer (GC). METHODS: Through a systematic review till March 7, 2022, we identified population-based studies that reported the prognostic effects of LODDS in patients with GC. We compare the predictive effectiveness of the LODDS staging system with that of the rN and pN classification systems for the OS of GC. RESULTS: Twelve studies comprising 20,312 patients were included in this systematic review and meta-analysis. The results showed that LODDS1, LODDS2, LODDS3, and LODDS4 in GC patients were correlated with poor OS compared with LODDS0 (LODDS1 vs. LODDS0: HR = 1.62, 95% CI (1.42, 1.85); LODDS2 vs. LODDS0: HR = 2.47, 95% CI (2.02, 3.03); LODDS3 vs. LODDS0: HR = 3.15, 95% CI (2.50, 3.97); LODDS4 vs. LODDS0: HR = 4.55, 95% CI (3.29, 6.29)). Additionally, significant differences in survival were observed among patients with different LODDS classifications (all P-values were < 0.001) with the same rN and pN classifications. Meanwhile, for patients with different pN or rN classifications with the same LODDS classification, prognosis was highly similar. CONCLUSION: The findings show that LODDS is correlated with the prognosis of GC patients and is superior to the pN and rN classifications for prognostic assessment.

Development and validation of an RBP gene signature for prognosis prediction in colorectal cancer based on WGCNA.

BACKGROUND: RNA binding proteins (RBPs) have been implicated in oncogenesis and progression in various cancers. However, the potential value of RBPs as prognostic indicators and therapeutic targets in colorectal cancer (CRC) requires further investigation. METHODS: Four thousand eighty two RBPs were collected from literature. The weighted gene co-expression network analysis (WGCNA) was performed to identify prognosis-related RBP gene modules based on the data attained from the TCGA cohorts. LASSO algorithm was conducted to establish a prognostic risk model, and the validity of the proposed model was confirmed by an independent GEO dataset. Functional enrichment analysis was performed to reveal the potential biological functions and pathways of the signature and to estimate tumor immune infiltration. Potential therapeutic compounds were inferred utilizing CMap database. Expressions of hub genes were further verified through the Human Protein Atlas (HPA) database and RT-qPCR. RESULTS: One thousand seven hundred thirty four RBPs were differently expressed in CRC samples and 4 gene modules remarkably linked to the prognosis were identified, based on which a 12-gene signature was established for prognosis prediction. Multivariate Cox analysis suggested this signature was an independent predicting factor of overall survival (P < 0.001; HR:3.682; CI:2.377-5.705) and ROC curves indicated it has an effective predictive performance (1-year AUC: 0.653; 3-year AUC:0.673; 5-year AUC: 0.777). GSEA indicated that high risk score was correlated with several cancer-related pathways, including cytokine-cytokine receptor cross talk, ECM receptor cross talk, HEDGEHOG signaling cascade and JAK/STAT signaling cascade. ssGSEA analysis exhibited a significant correlation between immune status and the risk signature. Noscapine and clofazimine were screened as potential drugs for CRC patients with high-risk scores. TDRD5 and GPC1 were identified as hub genes and their expression were validated in 15 pairs of surgically resected CRC tissues. CONCLUSION: Our research provides a depth insight of RBPs' role in CRC and the proposed signature are helpful to the personalized treatment and prognostic judgement.

Log odds of positive lymph nodes as a novel prognostic predictor for colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer in the world, which remains one of the leading causes of cancer-related deaths. Accurate prognosis prediction of CRC is pivotal to reduce the mortality and disease burden. Lymph node (LN) metastasis is one of the most commonly used criteria to predict prognosis in CRC patients. However, inaccurate surgical dissection and pathological evaluation may lead to inaccurate nodal staging, affecting the effectiveness of pathological N (pN) classification in survival prediction among patients with CRC. In this meta-analysis, we aimed to estimate the prognostic value of the log odds of positive lymph nodes (LODDS) in patients with CRC. METHODS: PubMed, Medline, Embase, Web of Science and the Cochrane Library were systematically searched for relevant studies from inception to July 3, 2021. Statistical analyses were performed on Stata statistical software Version 16.0 software. To statistically assess the prognostic effects of LODDS, we extracted the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and disease-free survival (DFS) from the included studies. RESULTS: Ten eligible articles published in English involving 3523 cases were analyzed in this study. The results showed that LODDS1 and LODDS2 in CRC patients was correlated with poor OS compared with LODDS0 (LODDS1 vs. LODDS0: HR = 1.77, 95% CI (1.38, 2.28); LODDS2 vs. LODDS0: HR = 3.49, 95% CI (2.88, 4.23)). Meanwhile, LODDS1 and LODDS2 in CRC patients was correlated with poor DFS compared with LODDS0 (LODDS1 vs. LODDS0: HR = 1.82, 95% CI (1.23, 2.68); LODDS2 vs. LODDS0: HR =3.30, 95% CI (1.74, 6.27)). CONCLUSIONS: The results demonstrated that the LODDS stage was associated with prognosis of CRC patients and could accurately predict the prognosis of patients with CRC.

Development of a model to predict the prognosis of esophageal carcinoma based on autophagy-related genes.

Aim: To identify a potential prognostic signature of esophageal carcinoma based on autophagy-related genes (ARGs). Methods: RNA sequencing and clinical data were downloaded from the Cancer Genome Atlas. Significantly different ARGs were identified by Wilcoxon signed-rank test. A prognostic model was established employing Cox regression analysis. The model was evaluated by receiver operating characteristic and Kaplan-Meier curve. Results: A total of 28 significantly different ARGs were identified. Seven ARGs were screened to construct the prognostic model. The efficacy of the model was verified. A nomogram also validated the role of risk score in predicting prognosis. Enrichment analyses showed the possible underlying mechanisms. Conclusion: The seven-ARGs prognostic model was validated to be promising for predicting the prognosis of patients with esophageal carcinoma.

Plain language summary Autophagy is an important metabolic process in cells. Also known as type II cell death, it is a process in which cells degrade their damaged organelles and macromolecular substances by lysosomes. Autophagy is reported to be involved in the development of multiple tumor types, including esophageal carcinoma (ESCA). Autophagy-related genes (ARGs) are those genes proved to be closely related to, or in control of, autophagy. We aimed to identify a model for predicting prognosis based on ARGs, using gene expression profiles and clinical data of ESCA patients from an online database. We identified 28 ARGs as having significantly different activity in ESCA cells compared with normal cells. Among them, four genes were less active, and 24 genes were more active in cancer. Seven ARGs were screened to construct the prognostic model. The effectiveness of the model in predicting the prognosis of ESCA patients was confirmed by standard statistical methods. This study is valuable for finding possible therapeutic targets and predicting prognosis in ESCA patients based on ARGs.

Prognostic biomarkers and therapeutic targets in oral squamous cell carcinoma: a study based on cross-database analysis.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant cancer, the survival rate of patients is disappointing. Therefore, it is necessary to identify the driven-genes and prognostic biomarkers in OSCC. METHODS: Four Gene Expression Omnibus (GEO) datasets were integratedly analyzed using bioinformatics approaches, including identification of differentially expressed genes (DEGs), GO and KEGG analysis, construction of protein-protein interaction (PPI) network, selection of hub genes, analysis of prognostic information and genetic alterations of hub genes. ONCOMINE, The Cancer Genome Atlas (TCGA) and Human Protein Atlas databases were used to evaluate the expression and prognostic value of hub genes. Tumor immunity was assessed to investigate the functions of hub genes. Finally, Cox regression model was performed to construct a multiple-gene prognostic signature. RESULTS: Totally 261 genes were found to be dysregulated. 10 genes were considered to be the hub genes. The Kaplan-Meier analysis showed that upregulated SPP1, FN1, CXCL8, BIRC5, PLAUR, and AURKA were related to poor outcomes in OSCC patients. FOXM1 and TPX2 were considered as the potential immunotherapeutic targets with future clinical significance. Moreover, we constructed a nine-gene signature (TEX101, DSG2, SCG5, ADA, BOC, SCARA5, FST, SOCS1, and STC2), which can be utilized to predict prognosis of OSCC patients effectively. CONCLUSION: These findings may provide new clues for exploring the molecular mechanisms and targeted therapy in OSCC. The hub genes and risk gene signature are helpful to the personalized treatment and prognostic judgement.

Prognostic value of circulating tumor cells detected with the CellSearch system in esophageal cancer patients: a systematic review and meta-analysis.

BACKGROUND: Esophageal carcinoma (EC) is the seventh-most prevalent tumor in the world, which is still one of the primary causes of tumor-related death. Identifying noteworthy biomarkers for EC is particularly significant in guiding effective treatment. Recently, circulating tumor cells (CTCs) in peripheral blood (PB) were intensively discussed as prognostic markers in patients with EC. However, an ongoing controversy still exists regarding the prognostic significance of CTCs determined by the CellSearch system in EC sufferers. This meta-analysis was designed to approach this topic. METHODS: We systematically conducted searches using PubMed, Medline, Web of Science and the Cochrane Library for relevant studies, which were published through February 20, 2020. Using the random-effects model, our study was performed in Review Manager software, with odds ratios (ORs), risk ratios (RRs), hazard ratios (HRs) and 95% confidence intervals (CIs) as the effect values. RESULTS: Totally 7 articles were finally included in this study. For clinicopathological characteristics, the pooled results on TNM stage indicated that the III/IV group had higher rate of CTCs compared with the I/II group (OR = 1.36, 95% CI: 0.68-2.71, I2 = 0%). Incidence of CTCs was higher in patients with T3/T4 stage (OR = 2.92, 95% CI: 1.31-6.51, I2 = 0%) and distant metastasis group (OR = 5.18, 95% CI: 2.38-11.25, I2 = 0%) compared to patients with T1/T2 stage or non-metastatic group. The pooled analysis revealed that CTC positivity detected in EC patients was correlated with poor overall survival (OS) (HR = 2.83, 95% CI:1.99-4.03, I2 = 0%) and relapse-free survival (RFS) (HR = 4.71, 95% CI:2.73-8.13, I2 = 0%). When pooling the estimated RR, a poor therapeutic response to chemoradiotherapy was discovered in patients with CTC positivity (RR = 1.99, 95% CI:1.73-2.29, I2 = 60%). CONCLUSIONS: In summary, our meta-analysis demonstrated that CTCs positivity determined by the CellSearch system are correlated with the prognosis of EC patients and might indicate a poor therapeutic response to chemotherapy in EC patients.

Prognostic value of dynamic changes of pre- and post-operative tumor markers in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) prognosis assessment is vital for personalized treatment plans. This study investigates the prognostic value of dynamic changes of tumor markers CEA, CA19-9, CA125, and AFP before and after surgery and constructs prediction models based on these indicators. METHODS: A retrospective clinical study of 2599 CRC patients who underwent radical surgery was conducted. Patients were randomly divided into training (70%) and validation (30%) datasets. Univariate and multivariate Cox regression analyses identified independent prognostic factors, and nomograms were constructed. RESULTS: A total of 2599 CRC patients were included in the study. Patients were divided into training (70%, n = 1819) and validation (30%, n = 780) sets. Univariate and multivariate Cox regression analyses identified age, total number of resected lymph nodes, T stage, N stage, the preoperative and postoperative changes in the levels of CEA, CA19-9, and CA125 as independent prognostic factors. When their postoperative levels are normal, patients with elevated preoperative levels have significantly worse overall survival. However, when the postoperative levels of CEA/CA19-9/CA125 are elevated, whether their preoperative levels are elevated or not has no significance for prognosis. Two nomogram models were developed, and Model I, which included CEA, CA19-9, and CA125 groups, demonstrated the best performance in both training and validation sets. CONCLUSION: This study highlights the significant predictive value of dynamic changes in tumor markers CEA, CA19-9, and CA125 before and after CRC surgery. Incorporating these markers into a nomogram prediction model improves prognostic accuracy, enabling clinicians to better assess patients' conditions and develop personalized treatment plans.

Efficacy and safety of robotic vs. laparoscopic gastrectomy for patients with gastric cancer: systematic review and meta-analysis.

BACKGROUND: The emergence of robotic surgical systems compensated for the technological shortcomings of laparoscopic approaches. However, whether robotic gastrectomy (RG) has better perioperative outcomes and survival than laparoscopic gastrectomy (LG) for gastric cancer is still unclear but increasingly drawing attention. MATERIALS AND METHODS: In this systematic review and meta-analysis, we searched the PubMed, EMBASE, Web of Science, and Cochrane Library as of January 20, 2024 and referenced list of eligible articles for all published studies comparing RG and LG for patients with gastric cancer, Data on study characteristics, individual characteristics, and outcome parameters were extracted. The quality of studies was assessed using the Revised Cochrane risk-of-bias 2 tool and the risk of bias in non-randomized studies of interventions tool. The main outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS: We identified 3641 articles, of which 72 studies (30081 patients) were included in the meta-analysis. Compared with LG, RG was associated with higher OS [hazard ratio (HR)=0.89, 95% CI=0.83 to 0.96), lower rate of overall postoperative complications [odds ratio (OR)=0.77, 95% CI=0.71 to 0.84], longer operating time [mean difference (MD)=35.53, 95% CI=29.23 to 41.83], less estimated blood loss (MD=-37.45, 95% CI=-46.24 to -28.67), a higher number of retrieved lymph nodes (MD=1.88, 95% CI=0.77 to 3.00), faster postoperative recovery, and lower rate of conversion (OR=0.44, 95% CI=0.36 to 0.55). Mortality and DFS were not significantly different between the two groups. The subgroup of meta-analysis results also showed the advantages of robotic surgery over laparoscopic surgery in intracorporeal reconstruction, total gastrectomy, Ⅰ/Ⅱ stage, and BMI≥25, especially for patients with stage Ⅰ/Ⅱ, there is better overall survival and disease-free survival. CONCLUSION: Our findings point to robotic surgery having great benefits compared with laparoscopic surgery in gastric cancer. Our study may help inform decision-making in applying robotic surgical systems to clinical treatment.

3D-hUMSCs Exosomes Ameliorate Vitiligo by Simultaneously Potentiating Treg Cells-Mediated Immunosuppression and Suppressing Oxidative Stress-Induced Melanocyte Damage.

Vitiligo is an autoimmune disease characterized by epidermal melanocyte destruction, with abnormal autoimmune responses and excessive oxidative stress as two cardinal mechanisms. Human umbilical mesenchymal stem cells-derived exosomes (hUMSCs-Exos) are regarded as promising therapeutic choice for autoimmune diseases due to potent immunosuppressive and anti-oxidative properties, which can be potentiated under 3D cell culture condition. Nevertheless, whether exosomes derived from 3D spheroids of hUMSCs (3D-Exos) exhibit considerable therapeutic effect on vitiligo and the underlying mechanism remain elusive. In this study, systemic administration of 3D-Exos showed a remarkable effect in treating mice with vitiligo, as revealed by ameliorated skin depigmentation, less CD8+T cells infiltration, and expanded Treg cells in skin, and 3D-Exos exerted a better effect than 2D-Exos. Mechanistically, 3D-Exos can prominently facilitate the expansion of Treg cells in vitiligo lesion and suppress H2O2-induced melanocytes apoptosis. Forward miRNA profile analysis and molecular experiments have demonstrated that miR-132-3p and miR-125b-5p enriched in 3D-Exos greatly contributed to these biological effects by targeting Sirt1 and Bak1 respectively. In aggregate, 3D-Exos can efficiently ameliorate vitiligo by simultaneously potentiating Treg cells-mediated immunosuppression and suppressing oxidative stress-induced melanocyte damage via the delivery of miR-132-3p and miR-125b-5p. The employment of 3D-Exos will be a promising treament for vitiligo.

Small extracellular vesicles-mediated cellular interactions between tumor cells and tumor-associated macrophages: Implication for immunotherapy.

The tumor microenvironment consists of cancer cells and various stromal cells, including macrophages, which exhibit diverse phenotypes with either pro-inflammatory (M1) or anti-inflammatory (M2) effects. The interaction between cancer cells and macrophages plays a crucial role in tumor progression. Small extracellular vesicles (sEVs), which facilitate intercellular communication, are known to play a vital role in this process. This review provides a comprehensive summary of how sEVs derived from cancer cells, containing miRNAs, lncRNAs, proteins, and lipids, can influence macrophage polarization. Additionally, we discuss the impact of macrophage-secreted sEVs on tumor malignant transformation, including effects on proliferation, metastasis, angiogenesis, chemoresistance, and immune escape. Furthermore, we address the therapeutic advancements and current challenges associated with macrophage-associated sEVs, along with potential solutions.

Akkermansia muciniphila ameliorates colonic injury in mice with DSS-induced acute colitis by blocking macrophage pro-inflammatory phenotype switching via the HDAC5/DAB2 axis.

Akkermansia muciniphila (A. muciniphila), a probiotic, has been linked to macrophage phenotypic polarization in different diseases. However, the role and mechanisms of A. muciniphila in regulating macrophage during ulcerative colitis (UC) are not clear. This research aimed to examine the impact of A. muciniphila on dextran sulfate sodium (DSS)-induced acute colitis and elucidate the underlying mechanism related to macrophage phenotypic polarization. A. muciniphila inhibited weight loss, increased disease activity index, and ameliorated inflammatory injury in colonic tissues in mice induced with DSS. Furthermore, A. muciniphila reduced macrophage M1 polarization and ameliorated epithelial barrier damage in colonic tissues of DSS-induced mice through inhibition of histone deacetylase 5 (HDAC5). In contrast, the effect of A. muciniphila was compromised by HDAC5 overexpression. HDAC5 deacetylated H3K9ac modification of the disabled homolog 2 (DAB2) promoter, which led to repressed DAB2 expression. DAB2 overexpression blocked HDAC5-induced pro-inflammatory polarization of macrophages, whereas knockdown of DAB2 resulted in the loss of effects of A. muciniphila against colonic injury in DSS-induced mice. Taken together, A. muciniphila-induced loss of HDAC5 hampered the deacetylation of DAB2 and enhanced the expression of DAB2. Our findings propose that A. muciniphila may be a possible probiotic agent for alleviating DSS-induced acute colitis.

Effects of marital status on survival of retroperitoneal liposarcomas stratified by age and sex: A population-based study.

BACKGROUND: Previous studies have shown that marital status is associated with survival in patients with a variety of cancer types, including lung cancer, prostate cancer, and bladder cancer. However, to date, the impact of marital status on the survival of patients with retroperitoneal liposarcomas (RPLs) has not been established. METHODS: A total of 1211 eligible patients diagnosed with RPLs were identified in the Surveillance, Epidemiology, and End Results (SEER) database. The relationships between marital status and survival in patients with RPLs were assessed. Patients were stratified by age to determine whether an association exists between marital status and age. We also probed the association between marital status and survival in males and females. RESULTS: Our findings suggest that divorced, separated, or widowed patients have more advanced cancer stages, and more of these patients do not undergo surgery. Meanwhile, divorced, separated, or widowed patients have worse survival outcomes than married patients (overall survival (OS): HR = 1.66 (95% CI, 1.12, 2.46)); cancer-specific survival (CSS): HR = 1.90 (95% CI, 1.13, 3.19)). OS does not differ between single patients and married patients (HR = 1.21 [95% CI, 0.81, 1.81]) or CSS (HR = 1.36 [95% CI, 0.80, 2.29]). In addition, these results demonstrate that being divorced, separated, or widowed can play a significant detrimental role in mortality in older and female patients. CONCLUSION: Married patients have earlier disease stages at diagnosis and better survival outcomes than divorced, separated, or widowed patients with RPLs. In addition, this effect is especially pronounced in older people and females.

A nomogram was developed using clinicopathological features to predict postoperative liver metastasis in patients with colorectal cancer.

PURPOSE: The objective of this study is to examine the risk factors that contribute to the development of liver metastasis (LM) in patients who have suffered radical resection for colorectal cancer (CRC), and to establish a nomogram model that can be used to predict the occurrence of the LM. METHODS: The present study enrolled 1377 patients diagnosed with CRC between January 2010 and July 2021. The datasets were allocated to training (n = 965) and validation (n = 412) sets in a randomly stratified manner. The study utilized univariate and multivariate logistic regression analyses to establish a nomogram for predicting LM in patients with CRC. RESULTS: Multivariate analysis revealed that T stage, N stage, number of harvested lymph nodes (LNH), mismatch repair (MMR) status, neutrophil count, monocyte count, postoperative carcinoembryonic antigen (CEA) levels, postoperative cancer antigen 125 (CA125) levels, and postoperative carbohydrate antigen 19-9 (CA19-9) levels were independent predictive factors for LM after radical resection. These factors were then utilized to construct a comprehensive nomogram for predicting LM. The nomogram demonstrated great discrimination, with an area under the curve (AUC) of 0.782 for the training set and 0.768 for the validation set. Additionally, the nomogram exhibited excellent calibration and significant clinical benefit as confirmed by the calibration curves and the decision curve analysis, respectively. CONCLUSION: This nomogram has the potential to support clinicians in identifying high-risk patients who may develop LM post-surgery. Clinicians can devise personalized treatment and follow-up plans, ultimately leading to an improved prognosis for patients.

Development and validation of a ligand-receptor pairs signature to predict outcome and provide a therapeutic strategy in gastric cancer.

BACKGROUND: An important factor in tumor development and progression is the tumor microenvironment (TME), which is heterogeneous. Previous studies have mainly investigated the expression profile and prognostic values of genes in gastric cancer (GC) at the cell population level but neglected the interactions and heterogeneity between cells. METHODS: The pattern of ligand-receptor (LR) interactions was delineated on a scRNA-seq dataset containing 44,953 cells from nine GC patients and a fourth bulk RNA-seq dataset including data from 1159 GC patients. We then constructed an LR.Score scoring model to comprehensively evaluate the influence of LR-pairs on the TME, overall survival, and immunotherapy response in GC patients from several cohorts. RESULTS: Cell communication network among 13 cell types was constructed based on the LR-pairs. We proposed a new molecular subtyping model for GC based on the LR-pairs and revealed the differences in prognosis, pathophysiologic features, mutation characteristics, function enrichment, and immunological characteristics among the three subtypes. Finally, an LR.Score model based on LR-pairs was developed and validated on several datasets. CONCLUSIONS: Based on the selected LR-pairs, we successfully constructed a novel prediction model and observed its well performance on molecular subtyping, target and pathway screening, prognosis judging, and immunotherapy response predicting.

Prognostic role and immune infiltration characteristics of EI24 in multiple cancer types.

BACKGROUND: The autophagy-associated transmembrane protein EI24 is associated with cancer growth and patient survival. We aimed to explore the prognostic role and immune infiltration characteristics of EI24 at a pan-cancer level. METHODS: We collected data from multiple databases to explore the expression and prognostic role of EI24 in various cancers. Correlations between EI24 expression and DNA methylation, RNA modification, tumor mutation burden (TMB), microsatellite instability (MSI), immune moderator, immune checkpoint-related genes, the tumor immune microenvironment, and clinicopathological characteristics were analyzed. Finally, immunohistochemistry and western blotting were performed to validate the protein levels of EI24 in different tumors. RESULTS: Differential expression of EI24 was observed in most cancer types compared to non-cancerous tissues. EI24 showed a significant association with prognosis and may represent a new indicator of prognosis in patients with cancer. In most cancers, EI24 is closely associated with tumor immunity and interacts with various immune cells. Moreover, significant correlations were observed between EI24 expression and RNA modification, TMB, MSI, immune moderators, and immune checkpoint-related genes. CONCLUSION: This study provides new insights into the functions and clinical value of EI24 in different tumors and suggests that EI24 may serve as a promising biomarker or therapeutic target for cancer management.

Single-cell analysis unveils activation of mast cells in colorectal cancer microenvironment.

The role of mast cells (MCs) in colorectal cancer (CRC) remains unclear, and a comprehensive single-cell study on CRC MCs has not been conducted. This study used a multi-omics approach, integrating single-cell sequencing, spatial transcriptomics, and bulk tissue sequencing data to investigate the heterogeneity and impact of MCs in CRC. Five MC signature genes (TPSAB1, TPSB2, CPA3, HPGDS, and MS4A2) were identified, and their average expression was used as a marker of MCs. The MC density was found to be lower in CRC compared to normal tissue, but MCs in CRC demonstrated distinct activation features. Activated MCs were defined by high expression of receptors and MC mediators, while resting MCs had low expression. Most genes, including the five MC signature genes, were expressed at higher levels in activated MCs. The MC signature was linked to a better prognosis in both CRC and pan-cancer patient cohorts. Elevated KITLG expression was observed in fibroblasts and endothelial cells in CRC samples compared to normal tissue, and co-localization of MCs with these cell types was revealed by spatial transcriptome analysis. In conclusion, this study finds decreased MC density in CRC compared to normal tissue, but highlights a shift in MC phenotype from CMA1high resting cells to activated TPSAB1high, CPA3high, and KIThigh cells. The elevated KITLG expression in the tumor microenvironment's fibroblasts and endothelial cells may activate MCs through the KITLG-KIT axis, potentially suppressing tumor progression.

Prognostic value of normal levels of preoperative tumor markers in colorectal cancer.

Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), and alpha-fetoprotein (AFP) are widely used tumor markers for colorectal cancer (CRC), but their clinical significance is unknown when the levels of these tumor markers were within the normal range. This retrospective study included 2145 CRC patients. The entire cohort was randomly divided into training and validation datasets. The optimal cut-off values of tumor markers were calculated using X-tile software, and univariate and multivariate analyses were performed to assess its association with overall survival (OS). The nomogram model was constructed and validated. The entire cohort was randomly divided into a training dataset (1502 cases, 70%) and a validation dataset (643 cases,30%). Calculated from the training dataset, the optimal cut-off value was 2.9 ng/mL for CEA, 10.1 ng/mL for CA19-9, 13.4 U/mL for CA125, and 1.8 ng/mL for AFP, respectively. Multivariate analysis revealed that age, tumor location, T stage, N stage, preoperative CA19-9, and CA125 levels were independent prognostic predictors. Even within the normal range, CRC patients with relatively high levels of CA19-9 or CA125 worse OS compared to those with relatively low levels. Then, based on the independent prognostic predictors from multivariate analysis, two models with/without (model I/II) CA19-9 and CA125 were built, model I showed better prediction and reliability than model II. Within the normal range, relatively high levels of preoperative CA19-9 and CA125 were significantly associated with poor OS in CRC patients. The nomogram based on CA19-9 and CA125 levels showed improved predictive accuracy ability for CRC.

Pyroptosis impacts the prognosis and treatment response in gastric cancer via immune system modulation.

Pyroptosis plays a vital role in the development of cancers; however, its role in regulating immune cell infiltration in tumor microenvironment (TME) and pyroptosis-related molecular subtypes remain unclear. Herein, we comprehensively analyzed the molecular subtypes mediated by the pyroptosis-related genes (PRGs) in gastric cancer (GC). Three pyroptosis patterns were determined with distinct TME cell-infiltrating characteristics and prognosis. Principal component analysis was performed to establish the pyroptosis score. The high pyroptosis score group was featured by increased activated CD4+ T cell infiltration, better prognosis, elevated tumor mutation burden, higher immune and stromal scores, and enhanced response to immunotherapy. However, the low pyroptosis score group was characterized by poorer survival, decreased immune infiltration, and glycerolipid and histidine metabolism pathways. Additionally, high pyroptosis score was confirmed as an independent favorable prognostic factor for overall survival. Three cohorts designed to analyze the response to immunotherapy verified that patients with higher pyroptosis score showed treatment benefit. In summary, our study demonstrated that pyroptosis regulates the complex TME. Assessing the pyroptosis patterns will advance our understanding on TME features and tumor immunology and provide the rationale for designing personalized immunotherapy strategies.

Development and Validation of a Prognostic Model to Predict the Prognosis of Patients With Retroperitoneal Liposarcoma: A Large International Population-Based Cohort Study.

Background: Retroperitoneal liposarcomas (RPLs), sarcoma of mesenchymal origin, are the most common soft tissue sarcomas (STS) of the retroperitoneum. Given the rarity of RPLs, the prognostic values of clinicopathological features in the patients remain unclear. The nomogram can provide a visual interface to aid in calculating the predicted probability that a patient will achieve a particular clinical endpoint and communication with patients. Methods: We included a total of 1,392 RPLs patients diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. For nomogram construction and validation, patients in the SEER database were divided randomly into the training cohort and internal validation cohort at a ratio of 7:3, while 65 patients with RPLs from our center between 2010 and 2016 served as the external validation cohort. The OS curves were drawn using the Kaplan-Meier method and assessed using the log-rank test. Moreover, Fine and Gray's competing-risk regression models were conducted to assess CSS. Univariate and multivariate analyses were performed to select the prognostic factors for survival time. We constructed a predictive nomogram based on the results of the multivariate analyses. Results: Through univariate and multivariate analyses, it is found that age, histological grade, classification, SEER stage, surgery constitute significant risk factors for OS, and age, classification, SEER stage, AJCC M stage, surgery, and tumor size constitute risk factors for CSS. We found that the nomogram provided a good assessment of OS and CSS at 1, 3, and 5 years in patients with RPLs (1-year OS: (training cohort: AUC = 0.755 (95% CI, 0.714, 0.796); internal validation cohort: AUC = 0.754 (95% CI, 0.681, 0.827); external validation cohort: AUC = 0.793 (95% CI, 0.651, 0.935)); 3-year OS: (training cohort: AUC = 0.782 (95% CI, 0.752, 0.811); internal validation cohort: AUC = 0.788 (95% CI, 0.736, 0.841); external validation cohort: AUC = 0.863 (95% CI, 0.773, 0.954)); 5-year OS: (training cohort: AUC = 0.780 (95% CI, 0.752, 0.808); internal validation cohort: AUC = 0.783 (95% CI, 0.732, 0.834); external validation cohort: AUC = 0.854 (95% CI, 0.762, 0.945)); 1-year CSS: (training cohort: AUC = 0.769 (95% CI, 0.717, 0.821); internal validation cohort: AUC = 0.753 (95% CI, 0.668, 0.838); external validation cohort: AUC = 0.799 (95% CI, 0.616, 0.981)); 3-year CSS: (training cohort: AUC = 0.777 (95% CI, 0.742, 0.811); internal validation cohort: AUC = 0.787 (95% CI, 0.726, 0.849); external validation cohort: AUC = 0.808 (95% CI, 0.673, 0.943)); 5-year CSS: (training cohort: AUC = 0.773 (95% CI, 0.741, 0.805); internal validation cohort: AUC = 0.768 (95% CI, 0.709, 0.827); external validation cohort: AUC = 0.829 (95% CI, 0.712, 0.945))). The calibration plots for the training, internal validation, and external validation cohorts at 1-, 3-, and 5-year OS and CSS indicated that the predicted survival rates closely correspond to the actual survival rates. Conclusion: We constructed and externally validated an unprecedented nomogram prognostic model for patients with RPLs. The nomogram can be used as a potential, objective, and supplementary tool for clinicians to predict the prognosis of RPLs patients around the world.

The obesity paradox in patients with colorectal cancer: a systematic review and meta-analysis.

CONTEXT: Obesity is widely regarded as an established risk factor for colorectal cancer (CRC). However, recent studies have shown that lower mortality and better cancer-specific survival were observed in CRC patients with elevated body mass index (BMI), an example of the obesity paradox, which is the inverse correlation between obesity and mortality in some populations. OBJECTIVE: The aim of this systematic review and meta-analysis was to investigate the association between BMI and CRC outcomes. DATA SOURCES: PubMed, Web of Science, MEDLINE, the Cochrane Library, and Embase databases were searched for relevant articles published from inception to December 31, 2020. STUDY SELECTION: Studies comparing the prognosis of CRC patients with obesity or overweight with that of normal-weight CRC patients were eligible. DATA EXTRACTION: Data were extracted by 2 reviewers independently; differences were resolved by a third reviewer. BMI was classified according to WHO categories. DATA ANALYSIS: To assess the prognostic effects of different BMI categories in CRC patients, hazard ratios and 95%CIs of overall survival, disease-free survival, and cancer-specific survival were extracted from included articles. RESULTS: Sixteen studies (55 391 patients in total) were included. Higher BMI was significantly associated with more favorable CRC outcomes. Compared with normal-weight patients, underweight patients had worse overall survival (HR = 1.26; 95%CI, 1.15-1.37) and disease-free survival (HR = 1.19; 95%CI, 1.11-1.27, while patients with overweight had better overall survival (HR = 0.92; 95%CI, 0.86-0.99), disease-free survival (HR = 0.96; 95%CI, 0.93-1.00), and cancer-specific survival (HR = 0.86; 95%CI, 0.76-0.98). Patients with morbid obesity had worse overall survival (HR = 1.12; 95%CI, 1.02-1.22) and disease-free survival (HR = 1.15; 95%CI, 1.07-1.24) than normal-weight patients. There was no significant difference in cancer-specific survival between patients with obesity (HR = 0.94; 95%CI, 0.76-1.16) and patients with normal weight, nor between patients with underweight and patients with normal weight (HR = 1.14; 95%CI, 0.82-1.58). CONCLUSIONS: CRC patients with a higher BMI appear to have reduced mortality compared with normal-weight CRC patients, even though higher BMI/obesity is an established determinant for the development of CRC. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42020202320.