Prognostic Factor In Colorectal Cancer Research Articles

Prediction of Postoperative Survival Nomogram of Colorectal Cancer Patients based on Lymph Node Classification: a Study based on a SEER Population

Background: Lymph node metastases have a significant impact on the stage, treatment, and prognosis of patients with Colorectal cancer. Lymph node metastasis (LNM), log odds of positive lymph nodes (LODDS), and lymph node ratio (LNR) are independent prognostic factors for colon cancer. We are working to explore a more accurate prediction model and compare it with the staging predictions proposed by the American Joint Committee on Cancer (AJCC). Methods: A total of 15,957 patients with colorectal cancer who underwent surgical resection were included in the study, and they were randomly divided into training group (11,169 patients) and validation group (4,788 patients). Univariate Cox analysis, random forest regression analysis and Lasso analysis were performed on the training group. Based on the results of the analysis, the best independent prognostic factors were identified and integrated to construct a nomogram. The concordance index (C-index) and calibration curves were used to evaluate the nomograms of the training group and the validation group. Nomograms were compared to AJCC 8th edition TNM staging system using decision curve analysis (DCA) and area under curve (AUC). Results: N, LODDS, and LNR are independent prognostic factors for colorectal cancer. The C-index of nomogram predicting overall survival (OS) is higher than that of the AJCC 8th edition TNM staging system. Decision curve analysis (DCA) and ROC curve suggested that the nomogram was better than AJCC 8th TNM stage in terms of clinical practicability. Conclusions: We constructed a nomogram of the prognosis of patients with colorectal cancer, which may help clinicians provide individualized treatment.

Prognostic Significance of Desmoplastic Reaction After Neoadjuvant Chemoradiotherapy in Advanced Rectal Cancer.

Desmoplastic reaction is recognized as a prognostic factor in colorectal cancer. However, its significance in locally advanced rectal cancer following neoadjuvant chemoradiotherapy remains underexplored. To assess the prognostic value of desmoplastic reaction in specimens from patients with advanced rectal cancer after chemoradiotherapy. This is a retrospective study. This study was conducted at a single comprehensive cancer center. The study included 255 patients with advanced rectal cancer who underwent fluoropyrimidine-based chemoradiotherapy followed by total mesorectal excision from 2005 to 2014. Desmoplastic reaction was classified into mature, intermediate, and immature categories based on histological analysis. The primary outcomes were recurrence-free survival and overall survival. Desmoplastic reaction was classified as mature (69.0%), intermediate (5.5%), or immature (25.5%). The mature group had a higher percentage of good responders (34.1%) compared with the intermediate (0%) and immature (4.6%) groups (p < 0.0001). The mature group correlated with better outcomes, with a higher 5-year recurrence-free survival (85.4%) and overall survival (93.0%) as compared with intermediate (45.1% and 76.2%, respectively) and immature (65.8% and 88.8%, respectively) groups. In the multivariable analysis, intermediate/immature desmoplastic reaction was significantly associated with poorer recurrence-free survival (p = 0.03). Among poor responders, intermediate/immature desmoplastic reaction was associated with poorer recurrence-free survival (p = 0.03). Adjuvant chemotherapy did not significantly improve the 5-year recurrence-free survival rate for the mature group (adjuvant chemotherapy vs. no chemotherapy, 86.4% vs. 84.8%; p = 0.64), with worse trends observed in the intermediate/immature combined group (55.9% vs. 69.4%, respectively, p = 0.27). The limitations include the subjective nature of desmoplastic reaction assessment and the study's retrospective design. Desmoplastic reaction in surgical specimens post-chemoradiotherapy is associated with responses to chemoradiotherapy and serves as a significant prognostic factor in advanced rectal cancer, particularly for those responding poorly to chemoradiotherapy. See Video Abstract.

Global Distribution of Colorectal Cancer Staging at Diagnosis: An Evidence Synthesis.

Stage at diagnosis is a key prognostic factor for colorectal cancer (CRC) survival. We aimed to assess the global distribution of CRC staging at diagnosis using population-based or hospital-based registry data. We systematically searched in MEDLINE and Embase from their inception until 6 December 2023. Grey literature was searched through published cancer reports. Studies from population-based or hospital-based cancer registries reporting the stage distribution of diagnosed CRC were included. We extracted stage-specific proportions among patients with CRC based on TNM, SEER, or Dukes staging systems. Subgroup analyses by sex, age, tumor site, calendar period, and status of population-based screening were performed. Correlations between the Human Development Index (HDI), Socio-Demographic Index (SDI), and the distant metastatic CRC proportion were also evaluated. 84 eligible studies/reports from 46 countries were analyzed, covering 3.8 million patients. Among 36 countries included in the main analysis, the most recent distant metastatic CRC proportions varied from 16.2% in Puerto Rico to 28.2% in Oman and Latvia, with a median (interquartile range) of 23.7% (21.8%-26.3%). Higher metastatic proportions were observed in younger patients, those with colon cancer, and those without screening implementation, with no apparent difference between males and females. Over time, some countries/regions, such as Southern Portugal (36.5% in 2000 to 22.2% in 2016), showed declining proportions of metastatic CRC, while others remained stable (e.g., Austria, Belgium) or increased (e.g., United States, Slovenia, Spain). Higher HDI and SDI were correlated with lower proportions of distant metastatic CRC (HDI: ρ=-0.48; SDI: ρ=-0.26). Global disparities in CRC staging exist, indicating a need for targeted interventions to enhance early detection and management, especially in high-metastasis areas.

New Prognostic Factors in Colorectal Cancer

Введение. Колоректальный рак занимает лидирующие позиции в структуре онкологической заболеваемости. В результате онкоскрининга диагноз ставится на более ранних стадиях, и чаще пациентам стала проводиться адъювантная химиотерапия. В настоящее время имеются известные факторы прогноза, влияющие на включение в план лечения адъювантной химиотерапии, однако они не включают биологические и молекулярно-генетические особенности опухоли. Возможно, поиск новых прогностических факторов приведет к изменению парадигмы лечения больных с колоректальным раком. Цель. Ооптимизация выбора адъювантной химиотерапии путем оценки влияния совокупности имеющихся факторов прогноза и дополнительных (индекс пролиферации Ki67, KRAS мутация, экспрессия хемокиновых рецепторов) факторов на безрецидивную выживаемость у пациентов с РОК после радикального хирургического лечения. Материалы и методы. В исследование было включено 113 пациентов с диагнозом рак ободочной кишки II (группа А) или III стадии (группа В) после проведенного хирургического лечения. Всем пациентам было проведено лечение по имеющимся на тот момент стандартам, так пациентам в группе А было проведено только хирургическое лечение, а пациентам в группе В — комплексное лечение (хирургическое лечение + адъювантная химиотерапия). Все пациенты были под наблюдением в течение 60 мес. и, в зависимости от выявления отдаленных метастазов, были разделены на подгруппы. Далее были оценены клинические характеристики пациентов (возраст, пол, локализация первичной опухоли, характер выполненной операции) и морфологические характеристики опухоли (определение уровня экспрессии Ki-67; наличие и уровня экспрессии хемокинового рецептора CCRX4 и молекулярно-генетический анализ (определение мутации в 12,13 кодонах гена KRAS). Результаты. Выявлены дополнительные факторы прогноза, влияющие на показатель безрецидивной выживаемости: экспрессия хемокинового рецептора CXCR4, индекс пролиферации Ki-67 и локализация опухоли. Заключение. Дополнительные факторы прогноза, определенные в результате работы, целесообразно использовать для оптимизации комплексного лечения у пациентов с РОК.

The expression of keratin 17 and p27 predicts clinical outcomes in colorectal cancer.

Keratin 17 (K17) is frequently overexpressed, associated with poor prognosis in various cancers, and contributes to p27 degradation during cancer progression. Using immunohistochemistry, we evaluated K17 and p27 expression and assessed their biological behavior and prognostic significance in 326 colorectal cancers. High K17 expression was associated with poorly differentiated tumors, high pT classification, and lymph node metastases. Low p27 expression was associated with large tumors, high pT classification, lymphovascular invasion, and lymph node metastases. The overall survival of patients with high K17 expression was significantly worse than that of patients with low K17 expression [hazard ratio (HR) = 1.805, 95% confidence interval (CI) 1.169-2.787; p = 0.007]. Patients with low p27 expression showed significantly worse overall survival than those with high p27 expression (HR = 3.082, 95% CI 1.722-5.517; p < 0.001). When combining the results of K17 and p27 expression, the K17highp27low expression group showed the worst overall survival. On the contrary, the K17high/lowp27high group showed the best overall survival (p < 0.001). Therefore, K17highp27low expression is an independent poor prognostic factor in colorectal cancer. Thus, high K17 and low p27 expression correlate with aggressive clinicopathologic behavior and can be used as poor prognostic markers in colorectal cancer.

The Prognostic Significance of Tumor Deposits in Non-Metastatic Colorectal Cancer: Comparing Risk of Recurrence and Metastasis with High-Risk Features

Abstract Introduction/Objective Tumor deposit (TD) is a prognostic factor in colorectal cancer (CRC) patients. This study aims to determine if TD poses a similar risk of local recurrence and distant metastasis as known high-risk (HR) features in non-metastatic CRC. Methods/Case Report An analytical cross-sectional design was employed. Our hospital clinical and pathology databases were queried for stage I-III CRC patients from January 2016 to December 2018 and divided into two groups: TD only group defined by TD on histopathology and HR group defined by obstruction, perforation, or T4- stage. The following variables were collected from each case; biological factors (age, gender, race, and BMI), tumor features (tumor size, tumor grade, presence of LVI, PNI, lymph node status and TN staging) and postoperative follow up (development of recurrence, adjuvant chemotherapy, and overall survival (OS) duration). Data were analyzed using Kruskal-Wallis test for continuous variables and chi-square and Fisher’s exact test for categorical variables. Survival analysis was conducted using Kaplan-Meier estimate graphs. Results (if a Case Study enter NA) A total of 138 non-metastatic CRC patients who underwent surgery and chemotherapy were identified. The TD group consisted of 79 (57.2%) patients with a median age of 67 y (range 35 - 94 y), including 40 (50.6%) males and 39 (49.4%) females. The HR group comprised 59 (42.7%) patients with a median age of 70 y (range 28 - 103 y), including 25 (42.4%) males and 34 (57.6%) females. There were no significant demographic differences between the groups (P&amp;gt;0.05). However, tumor size, tumor grade, presence of lymphatic vessel invasion (LVI), perineural invasion (PNI), and tumor-node (TN) staging exhibited statistically significant differences between the groups (P&amp;lt;0.05). Local tumor recurrence and/ distant metastasis occurred in 29 patients (36.7%) in the TD group and 18 patients (30.5%) in the HR group, with median time for recurrence and/or metastasis 11 months and 12 months, respectively. There was no significant difference between the groups (P&amp;gt;0.05). TD patients had a median survival duration of 42 months, whereas HR group patients had a median survival of 51 months, although this difference was not statistically significant (P&amp;gt;0.05). Conclusion In non-metastatic CRC patients, TD poses a similar risk of local tumor recurrence and distant metastasis as HR factors. HR patients may have a longer survival than TD counterpart. Based on these findings both groups should be subjected to enhanced surveillance.

Contribution of Immunoscore to Survival Prediction in Pancreatic Ductal Adenocarcinoma.

The presence of tumor-infiltrating lymphocytes (TILs) has been demonstrated as a prognostic factor in colorectal cancer after surgical resection of malignancy, but knowledge on their role in pancreatic cancer is lacking. The Immunoscore (IS) assesses TILs at the core of the tumor (CT) and invasive margin (IM) and is being evaluated as a new concept in tumor immunity. The aim of this study was to evaluate the relationship between IS and prognosis in PDAC. The IS was analyzed by immunohistochemistry using surgical tissue blocks from 131 patients with pancreatic ductal adenocarcinoma (PDAC) who underwent surgery to investigate the relationship between immune cell infiltration into the tumor and prognosis in PDAC. A high IS in both CT and IM of the tumor was significantly associated with prolonged overall survival (OS) (p<0.01) and relapse-free survival (RFS) (p<0.01). In multivariate logistic regression models adjusted for clinical pathology data, IS predicted survival and recurrence (p<0.01 and p<0.01, respectively). Moreover, in patients who received preoperative chemotherapy, a high IS was statistically significantly associated with longer OS and RFS (p<0.01 and p<0.01, respectively). The immunohistochemically assessed IS might be a useful prognostic marker for patients with PDAC who underwent primary tumor resection.

Cathepsin V is a useful prognostic factor for colorectal cancer

Molecular studies have identified various treatment-related prognostic molecules to enhance the effectiveness of colorectal cancer (CRC) treatment and improve survival rates. The expression of cathepsin V in gastrointestinal cancer cells prompted an investigation into its potential as a prognostic indicator for CRC. The evaluation of cathepsin V expression and its clinicopathological significance was conducted through immunohistochemistry in a tissue microarray, encompassing 142 CRC and normal colorectal tissues. Overall and disease-free survival rates, based on cathepsin V expression levels, were assessed using the Kaplan–Meier method and compared utilizing the log-rank test. Univariate and multivariate analyses, employing a Cox proportional hazards model, were performed to identify prognostic factors. Cathepsin V expression exhibited no correlation with age, sex, tumor location, tumor size, or histological grade. However, it was significantly correlated with depth of tumor invasion, regional lymph node (LN) metastasis, distant metastasis, and lymphovascular involvement (all p<0.001). Overall and disease-free survival rates were significantly better with low cathepsin V expression than with high expression (p<0.001). Univariate analysis identified several prognostic factors, including histological grade (low vs. high), tumor size (≤ vs. >5 cm), tumor depth (T1 vs. ≥T2), regional LN metastasis, distant metastasis, tumor-node-metastasis (TNM) stage (Stage I vs ≥II), lymphovascular involvement, and cathepsin V expression. Multivariate analysis revealed that tumor depth, distant metastasis, and cathepsin V expression are independent predictors of poor survival. Cathepsin V is frequently expressed in CRC, and its high expression is associated with poor prognosis. Therefore, cathepsin V is a useful prognostic marker for CRC.

Multicenter Study on Tumor Budding in Lung Squamous Cell Carcinoma: Comparison Between Biopsy and Resection With Interobserver Variability Assessment

Grading lung squamous cell carcinoma (LUSC) is controversial and not universally accepted. The histomorphologic feature of tumor budding (TB) is an established independent prognostic factor in colorectal cancer, and its importance is growing in other solid cancers, making it a candidate for inclusion in tumor grading schemes. We aimed to compare TB between preoperative biopsies and resection specimens in pulmonary squamous cell carcinoma and assess interobserver variability. A retrospective cohort of 249 consecutive patients primarily resected with LUSC in Bern (2000-2013, n = 136) and Lausanne (2005-2020, n = 113) with available preoperative biopsies was analyzed for TB and additional histomorphologic parameters, such as spread through airspaces and desmoplasia, by 2 expert pathologists (M.M., C.N.). Results were correlated with clinicopathologic parameters and survival. In resection specimens, peritumoral budding (PTB) score was low (0-4 buds/0.785 mm2) in 47.6%, intermediate (5-9 buds/0.785 mm2) in 27.4%, and high (≥10 buds/0.785 mm2) in 25% of cases (median bud count, 5; IQR, 0-26). Both the absolute number of buds and TB score were similar when comparing tumor edge and intratumoral zone (P = .192) but significantly different from the score obtained in the biopsy (P < .001). Interobserver variability was moderate, regardless of score location (Cohen kappa, 0.59). The discrepant cases were reassessed, and consensus was reached in all cases with identification of causes of discordance. TB score was significantly associated with stage (P = .002), presence of lymph node (P = .033), and distant metastases (P = .020), without significant correlation with overall survival, tumor size, or pleural invasion. Desmoplasia was significantly associated with higher PTB (P < .001). Spread through airspaces was present in 34% and associated with lower PTB (P < .001). To conclude, despite confirming TB as a reproducible factor in LUSC, we disclose areas of scoring ambiguity. Preoperative biopsy evaluation was insufficient in establishing the final TB score of the resected tumor.

Establishing Criteria for Tumor Necrosis as Prognostic Indicator in Colorectal Cancer.

Tumor necrosis has been reported to represent an independent prognostic factor in colorectal cancer, but its evaluation methods have not been described in sufficient detail to introduce tumor necrosis evaluation into clinical use. To study the potential of tumor necrosis as a prognostic indicator in colorectal cancer, criteria for 3 methods for its evaluation were defined: the average percentage method (tumor necrosis percentage of the whole tumor), the hotspot method (tumor necrosis percentage in a single hotspot), and the linear method (the diameter of the single largest necrotic focus). Cox regression models were used to calculate cancer-specific mortality hazard ratios (HRs) for tumor necrosis categories in 2 colorectal cancer cohorts with more than 1800 cases. For reproducibility assessment, 30 cases were evaluated by 9 investigators, and Spearman's rank correlation coefficients and Cohen's kappa coefficients were calculated. We found that all 3 methods predicted colorectal cancer-specific survival independent of other prognostic parameters, including disease stage, lymphovascular invasion, and tumor budding. The greatest multivariable HRs were observed for the average percentage method (cohort 1: HR for ≥ 40% vs. <3% 3.03, 95% CI, 1.93-4.78; cohort 2: HR for ≥ 40% vs. < 3% 2.97; 95% CI, 1.63-5.40). All 3 methods had high reproducibility, with the linear method showing the highest mean Spearman's correlation coefficient (0.91) and Cohen's kappa (0.70). In conclusion, detailed criteria for tumor necrosis evaluation were established. All 3 methods showed good reproducibility and predictive ability. The findings pave the way for the use of tumor necrosis as a prognostic factor in colorectal cancer.

BMP Signaling Is a Prognostic Marker in Patients With Colorectal Cancer and Associates With Frailty.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β superfamily of ligands and have been shown to promote or suppress colorectal cancer (CRC) growth. Developing treatments that target BMPs is challenging due to their multiple roles, including involvement in the inflammatory response and nutritional status. The present study evaluated the prognostic value of BMP-4, which is believed to be highly expressed in CRC, and its correlation with inflammatory and nutrition statuses in patients with CRC. We analyzed BMP-4 expression in tumor tissues from 144 patients who underwent CRC surgery using immunohistochemistry and evaluated the relationship between BMP-4 levels and clinical outcomes. Kaplan-Meier analysis revealed that patients with high expression levels of BMP-4 exhibited a shorter overall survival rate than those with low levels of expression. Multivariate analysis revealed that BMP-4 expression was an independent prognostic factor for overall survival and death from other diseases in CRC patients. Furthermore, high BMP-4 expression was significantly correlated with high C-reactive protein/Albumin ratio, sarcopenia, and osteopenia. BMP-4 is a significant prognostic factor in CRC, particularly in predicting death from other diseases, while also showing associations with inflammatory and nutritional statuses.

NAT1 inhibits liver metastasis of colorectal cancer by regulating EMT and glycolysis.

Metastasis is the primary cause of cancer-related deaths, and colorectal cancer (CRC) liver metastasis is a major poor prognostic factor in CRC. NAT1 (N-acetyltransferase 1) plays a crucial role in the invasive and metastatic processes of colorectal cancer. The role and molecular mechanism of NAT1 on tumor cells were verified by establishing a cell model of overexpression and knockdown of NAT1, and further verified by establishing a liver metastasis model of colorectal cancer for animal experiments. In vivo and in vitro experiments have demonstrated that overexpression of NAT1 reduces the ability of metastasis and invasion of colorectal cancer cells. NAT1 overexpression inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing the EMT (epithelial-mesenchymal transition) process and glycolytic ability of tumor cells. Additionally, decreased glycolytic ability results in reduced VEGF (Vascular endothelial growth factor) expression in colorectal cancer cells. The decreased VEGF expression leads to decreased angiogenesis and vascular permeability in liver metastases, ultimately reducing the occurrence of liver metastasis. Our findings highlight that overexpression of NAT1 significantly inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing EMT, glycolytic ability, and VEGF expression in colorectal cancer cells, collectively preventing the development of liver metastasis.

Integrated analysis reveals a novel 5-fluorouracil resistance-based prognostic signature with promising implications for predicting the efficacy of chemotherapy and immunotherapy in patients with colorectal cancer.

5-Fluorouracil (5-FU) has been used as a standard first-line treatment for colorectal cancer (CRC) patients. Although 5-FU-based chemotherapy and immune checkpoint blockade (ICB) have achieved success in treating CRC, drug resistance and low response rates remain substantial limitations. Thus, it is necessary to construct a 5-FU resistance-related signature (5-FRSig) to predict patient prognosis and identify ideal patients for chemotherapy and immunotherapy. Using bulk and single-cell RNA sequencing data, we established and validated a novel 5-FRSig model using stepwise regression and multiple CRC cohorts and evaluated its associations with the prognosis, clinical features, immune status, immunotherapy, neoadjuvant therapy, and drug sensitivity of CRC patients through various bioinformatics algorithms. Unsupervised consensus clustering was performed to categorize the 5-FU resistance-related molecular subtypes of CRC. The expression levels of 5-FRSig, immune checkpoints, and immunoregulators were determined using quantitative real-time polymerase chain reaction (RT‒qPCR). Potential small-molecule agents were identified via Connectivity Map (CMap) and molecular docking. The 5-FRSig and cluster were confirmed as independent prognostic factors in CRC, as patients in the low-risk group and Cluster 1 had a better prognosis. Notably, 5-FRSig was significantly associated with 5-FU sensitivity, chemotherapy response, immune cell infiltration, immunoreactivity phenotype, immunotherapy efficiency, and drug selection. We predicted 10 potential compounds that bind to the core targets of 5-FRSig with the highest affinity. We developed a valid 5-FRSig to predict the prognosis, chemotherapeutic response, and immune status of CRC patients, thus optimizing the therapeutic benefits of chemotherapy combined with immunotherapy, which can facilitate the development of personalized treatments and novel molecular targeted therapies for patients with CRC.

CT-determined low skeletal muscle index predicts poor prognosis in patients with colorectal cancer.

Sarcopenia is highly prevalent among patients with colorectal cancer (CRC). Computed tomography (CT)-based assessment of low skeletal muscle index (SMI) is widely used for diagnosing sarcopenia. However, there are conflicting findings on the association between low SMI and overall survival (OS) in CRC patients. The objective of this study was to investigate whether CT-determined low SMI can serve as a valuable prognostic factor in CRC. We collected data from patients with CRC who underwent radical surgery at our institution between June 2020 and November 2021. The SMI at the third lumbar vertebra was calculated using CT scans, and the cutoff values for defining low SMI were determined using receiver operating characteristic curves. Univariate and multivariate analyses were performed to assess the associations between clinical characteristics and postoperative major complications. A total of 464 patients were included in the study, 229 patients (46.7%) were classified as having low SMI. Patients with low SMI were older and had a lower body mass index (BMI), a higher neutrophil to lymphocyte ratio (NLR), and higher nutritional risk screening 2002 (NRS2002) scores compared to those with normal SMI. Furthermore, patients with sarcopenia had a higher rate of major complications (10.9% vs. 1.3%; p < 0.001) and longer length of stay (9.09 ± 4.86 days vs. 8.25 ± 3.12 days; p = 0.03). Low SMI and coronary heart disease were identified as independent risk factors for postoperative major complications. Moreover, CRC patients with low SMI had significantly worse OS. Furthermore, the combination of low SMI with older age or TNM stage II + III resulted in the worst OS in each subgroup analysis. CT-determined low SMI is associated with poor prognosis in patients with CRC, especially when combined with older age or advanced TNM stage.

Clinical significance of combined tumour-infiltrating lymphocytes and microsatellite instability status in colorectal cancer: a systematic review and network meta-analysis

Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating the combination of TIL and MSI status identified distinct colorectal cancer subtypes with unique prognostic associations. However, these studies were often limited by sample size, particularly for MSI-high (MSI-H) tumours, and there is no comprehensive summary of the available evidence. We aimed to review the literature to compare the survival outcomes associated with the subtypes derived from the integrated MSI-TIL classification in patients with colorectal cancer. In this systematic review and network meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library without language restrictions, for articles published between Jan 1, 1990, and March 13, 2024. Patient cohorts comparing different combinations of TIL (high or low) and MSI status (MSI or microsatellite stable [MSS]) in patients with surgically resected colorectal cancer were included. Studies were excluded if they focused on neoadjuvant therapy or on other immune markers such as B cells or macrophages. Methodological quality assessment was done with the Newcastle-Ottawa scale; data appraisal and extraction was done independently by two reviewers. Summary estimates were extracted from published reports. The primary outcomes were overall survival, disease-free survival, and cancer-specific survival. A frequentist network meta-analysis was done to compare hazard ratios (HRs) and 95% CI for each outcome. The MSI-TIL subgroups were prognostically ranked based on P-score, bias, magnitude, and precision of associations with each outcome. The protocol is registered with PROSPERO (CRD42023461108). Of 302 studies initially identified, 21 studies (comprising 14 028 patients) were included in the systematic review and 19 (13 029 patients) in the meta-analysis. Nine studies were identified with a low risk of bias and the remaining ten had a moderate risk of bias. The MSI-TIL-high (MSI-TIL-H) subtype exhibited longer overall survival (HR 0·45, 95% CI 0·34-0·61; I2=77·7%), disease-free survival (0·43, 0·32-0·58; I2=61·6%), and cancer-specific survival (0·53, 0·43-0·66; I2=0%), followed by the MSS-TIL-H subtype for overall survival (HR 0·53, 0·41-0·69; I2=77·7%), disease-free survival (0·52, 0·41-0·64; I2=61·6%), and cancer-specific survival (0·55, 0·47-0·64; I2=0%) than did patients with MSS-TIL-low tumours (MSS-TIL-L). Patients with the MSI-TIL-L subtype had similar overall survival (0·88, 0·66-1·18; I2=77·7%) and disease-free survival (0·93, 0·69-1·26; I2=61·6%), but a modestly longer cancer-specific survival (0·72, 0·57-0·90; I2=0%) than did the MSS-TIL-L subtype. Results from the direct and indirect evidence were strongly congruous. The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer. German Research Council (HO 5117/2-2).

Association of the TRIM family protein with survival outcomes and clinicopathological features in colorectal cancer: a systematic review and meta-analysis

BackgroundThe tripartite motif (TRIM) proteins have been reported to play crucial roles in various malignancies. However, the clinical significance of TRIM proteins in colorectal cancer (CRC) remains controversial. This study aimed to evaluate the association between TRIM proteins and the clinicopathological features and survival outcomes in patients with CRC.MethodsWe performed a meta-analysis to investigate whether TRIM is a prognostic factor in CRC. PubMed, Embase, Web of Science, CNKI and Weipu databases were searched to identify eligible studies that evaluated the association between TRIM proteins and overall survival (OS), as well as the clinicopathological features of patients with CRC. Hazard ratios (HR) or odds ratios (OR) with 95% confidence interval (CI) were derived and pooled using a fixed-effects model.ResultsFrom inception to March 2023, we extracted study characteristics and prognostic data for each identified study. Twelve studies enrolling 1608 patients were eligible for inclusion. Data on OS and recurrence-free survival (RFS) were available for 12 and 2 studies, respectively. The pooled analysis results showed a significant correlation between the elevated TRIM proteins and shorter OS (HR = 2.42, 95% CI: 1.96–2.99) and worse RFS (HR = 2.51, 95% CI: 1.78–3.54) in patients with CRC. The combined ORs indicated that TRIM protein over-expression was significantly associated with advanced TNM stage (OR = 2.26, 95% CI: 1.25–4.10), deep tumor invasion (OR = 2.01, 95% CI: 1.04–3.88), lymph node metastasis (OR = 2.99, 95% CI: 2.19–4.09) and perineural invasion (OR = 1.95, 95% CI: 1.18–3.23).ConclusionsOur findings suggest that TRIM proteins can predict tumor progression and poor prognosis in CRC. Therefore, TRIM proteins may be promising therapeutic targets for patients with CRC.Graphical

Identification and validation of cuproptosis and disulfidptosis related genes in colorectal cancer

Colorectal cancer, the third most prevalent malignant cancer, is associated with poor prognosis. Recent studies have investigated the mechanisms underlying cuproptosis and disulfidptosis in colorectal cancer. However, whether genes linked to these processes impact the prognosis of colorectal cancer patients through analogous mechanisms remains unclear. In this study, we developed a model of cuproptosis and disulfidptosis in colorectal cancer and concurrently explored the role of the pivotal model gene HSPA8 in colorectal cancer cell lines. Our results revealed a positive correlation between cuproptosis and disulfidptosis, both of which are emerging as protective factors for the prognosis of CRC patients. Consequently, a prognostic model encompassing HSPA8, PDCL3, CBX3, ATP6V1G1, TAF1D, RPL4, and RPL14 was constructed. Notably, the key gene in our model, HSPA8, exhibited heightened expression and was validated as a protective prognostic factor in colorectal cancer, exerting inhibitory effects on colorectal cancer cell proliferation. This study offers novel insights into the interplay between cuproptosis and disulfidptosis. The application of the prognostic model holds promise for more effectively predicting the overall survival of colorectal cancer patients.

Enhancing Colorectal Cancer Tumor Bud Detection Using Deep Learning from Routine H&E-Stained Slides.

Tumor budding refers to a cluster of one to four tumor cells located at the tumor-invasive front. While tumor budding is a prognostic factor for colorectal cancer, counting and grading tumor budding are time consuming and not highly reproducible. There could be high inter- and intra-reader disagreement on H&E evaluation. This leads to the noisy training (imperfect ground truth) of deep learning algorithms, resulting in high variability and losing their ability to generalize on unseen datasets. Pan-cytokeratin staining is one of the potential solutions to enhance the agreement, but it is not routinely used to identify tumor buds and can lead to false positives. Therefore, we aim to develop a weakly-supervised deep learning method for tumor bud detection from routine H&E-stained images that does not require strict tissue-level annotations. We also propose Bayesian Multiple Instance Learning (BMIL) that combines multiple annotated regions during the training process to further enhance the generalizability and stability in tumor bud detection. Our dataset consists of 29 colorectal cancer H&E-stained images that contain 115 tumor buds per slide on average. In six-fold cross-validation, our method demonstrated an average precision and recall of 0.94, and 0.86 respectively. These results provide preliminary evidence of the feasibility of our approach in improving the generalizability in tumor budding detection using H&E images while avoiding the need for non-routine immunohistochemical staining methods.

The activation of HAMP promotes colorectal cancer cell proliferation through zinc-mediated upregulation of SMAD4 expression.

Colorectal cancer (CRC) poses a significant challenge in digestive system diseases, and emerging evidence underscores the critical role of zinc metabolism in its progression. This study aimed to investigate the clinical implications of genes at the intersection of zinc metabolism and CRC. We downloaded CRC prognosis-related genes and zinc metabolism-related genes from public databases. Then, the overlapping genes were screened out, and bioinformatics analysis was performed to obtain the hub gene associated with CRC prognosis. Subsequently, in vitro assays were carried out to investigate the expression of this hub gene and its exact mechanism between zinc metabolism and CRC. HAMP was identified as the hub CRC prognostic gene from overlapping zinc metabolism-related and CRC prognostic genes. In vitro analysis showed HAMP was over-expressed in CRC, and its knockdown inhibited RKO and HCT-116 cell invasion and migration significantly. ZnSO4 induced HAMP up-regulation to promote cell proliferation, while TPEN decreased HAMP expression to inhibit cell proliferation. Importantly, we further found that ZnSO4 enhanced SMAD4 expression to augment HAMP promoter activity and promote cell proliferation in CRC. HAMP stands out as an independent prognostic factor in CRC, representing a potential therapeutic target. Its intricate regulation by zinc, particularly through the modulation of SMAD4, unveils a novel avenue for understanding CRC biology. This study provides valuable insights into the interplay between zinc metabolism, HAMP, and CRC, offering promising clinical indicators for CRC patients. The findings present a compelling case for further exploration and development of targeted therapeutic strategies in CRC management.

Pathological image profiling identifies onco-microbial, tumor immune microenvironment, and prognostic subtypes of colorectal cancer.

Histology slide, tissue microbes, and the host gene expression can be independent prognostic factors of colorectal cancer (CRC), but the underlying associations and biological significance of these multimodal omics remain unknown. Here, we comprehensively profiled the matched pathological images, intratumoral microbes, and host gene expression characteristics in 527 patients with CRC. By clustering these patients based on histology slide features, we classified the patients into two histology slide subtypes (HSS). Onco-microbial community and tumor immune microenvironment (TIME) were also significantly different between the two subtypes (HSS1 and HSS2) of patients. Furthermore, variation in intratumoral microbes-host interaction was associated with the prognostic heterogeneity between HSS1 and HSS2. This study proposes a new CRC classification based on pathological image features and elucidates the process by which tumor microbes-host interactions are reflected in pathological images through the TIME.