Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Tubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. AIM OF THE STUDY: To elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. MATERIALS AND METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. RESULTS: The synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. CONCLUSIONS: Combined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

Laparoscopic colectomy for patients with poor American Society of Anesthesiology classifications.

INTRODUCTION: The American Society of Anesthesiologists (ASA) classification is used to assess the fitness of a patient for surgery. Whether laparoscopic surgery is appropriate for colorectal cancer patients with poor ASA performance status (PS) remains unclear. METHODS: Among 4585 patients who underwent colorectal surgery between 2016 and 2023, this study retrospectively reviewed all 458 patients with ASA-PS ≥3. Patients were divided into two groups: patients treated by open surgery (O group, n = 80); and patients treated by laparoscopic surgery (L group, n = 378). We investigated the impact of surgical approach on postoperative complications in patients with colorectal cancer and ASA-PS ≥3. RESULTS: Operation time was longer (170 min vs. 233 min, p < .001), blood loss was less (156 mL vs. 23 mL, p < .001), postoperative complications were less frequent (40.0% vs. 25.1%, p = .008), and hospital stay was shorter (23 days vs. 14 days, p < .001) in L group. Univariate analysis revealed rectal cancer, open surgery, longer operation time, and blood loss as factors significantly associated with postoperative complications. Multivariate analysis revealed open surgery (odds ratio [OR] 2.100, 95% confidence interval [CI] 1.164-3.788; p = .013) and longer operation time (OR 1.747, 95% CI 1.098-2.778; p = .018) as independent predictors of postoperative complications. CONCLUSION: Laparoscopic surgery provides favorable outcomes for colorectal cancer patients with poor ASA-PS.

Copy number amplification-induced overexpression of lncRNA LOC101927668 facilitates colorectal cancer progression by recruiting hnRNPD to disrupt RBM47/p53/p21 signaling.

BACKGROUND: Somatic copy number alterations (SCNAs) are pivotal in cancer progression and patient prognosis. Dysregulated long non-coding RNAs (lncRNAs), modulated by SCNAs, significantly impact tumorigenesis, including colorectal cancer (CRC). Nonetheless, the functional significance of lncRNAs induced by SCNAs in CRC remains largely unexplored. METHODS: The dysregulated lncRNA LOC101927668, induced by copy number amplification, was identified through comprehensive bioinformatic analyses utilizing multidimensional data. Subsequent in situ hybridization was employed to ascertain the subcellular localization of LOC101927668, and gain- and loss-of-function experiments were conducted to elucidate its role in CRC progression. The downstream targets and signaling pathway influenced by LOC101927668 were identified and validated through a comprehensive approach, encompassing RNA sequencing, RT-qPCR, Western blot analysis, dual-luciferase reporter assay, evaluation of mRNA and protein degradation, and rescue experiments. Analysis of AU-rich elements (AREs) within the mRNA 3' untranslated region (UTR) of the downstream target, along with exploration of putative ARE-binding proteins, was conducted. RNA pull-down, mass spectrometry, RNA immunoprecipitation, and dual-luciferase reporter assays were employed to elucidate potential interacting proteins of LOC101927668 and further delineate the regulatory mechanism between LOC101927668 and its downstream target. Moreover, subcutaneous xenograft and orthotopic liver xenograft tumor models were utilized to evaluate the in vivo impact of LOC101927668 on CRC cells and investigate its correlation with downstream targets. RESULTS: Significantly overexpressed LOC101927668, driven by chr7p22.3-p14.3 amplification, was markedly correlated with unfavorable clinical outcomes in our CRC patient cohort, as well as in TCGA and GEO datasets. Moreover, we demonstrated that enforced expression of LOC101927668 significantly enhanced cell proliferation, migration, and invasion, while its depletion impeded these processes in a p53-dependent manner. Mechanistically, nucleus-localized LOC101927668 recruited hnRNPD and translocated to the cytoplasm, accelerating the destabilization of RBM47 mRNA, a transcription factor of p53. As a nucleocytoplasmic shuttling protein, hnRNPD mediated RBM47 destabilization by binding to the ARE motif within RBM47 3'UTR, thereby suppressing the p53 signaling pathway and facilitating CRC progression. CONCLUSIONS: The overexpression of LOC101927668, driven by SCNAs, facilitates CRC proliferation and metastasis by recruiting hnRNPD, thus perturbing the RBM47/p53/p21 signaling pathway. These findings underscore the pivotal roles of LOC101927668 and highlight its therapeutic potential in anti-CRC interventions.

Beyond bacteria: Role of non-bacterial gut microbiota species in inflammatory bowel disease and colorectal cancer progression.

This letter emphasizes the need to expand discussions on gut microbiome's role in inflammatory bowel disease (IBD) and colorectal cancer (CRC) by including the often-overlooked non-bacterial components of the human gut flora. It highlights how viral, fungal and archaeal inhabitants of the gut respond towards gut dys-biosis and contribute to disease progression. Viruses such as bacteriophages target certain bacterial species and modulate the immune system. Other viruses found associated include Epstein-Barr virus, human papillomavirus, John Cunningham virus, cytomegalovirus, and human herpes simplex virus type 6. Fungi such as Candida albicans and Malassezia contribute by forming tissue-invasive filaments and producing inflammatory cytokines, respectively. Archaea, mainly metha-nogens are also found altering the microbial fermentation pathways. This corres-pondence, thus underscores the significance of considering the pathological and physiological mechanisms of the entire spectrum of the gut microbiota to develop effective therapeutic interventions for both IBD and CRC.

A lighter hybrid feature fusion framework for polyp segmentation.

Colonoscopy is widely recognized as the most effective method for the detection of colon polyps, which is crucial for early screening of colorectal cancer. Polyp identification and segmentation in colonoscopy images require specialized medical knowledge and are often labor-intensive and expensive. Deep learning provides an intelligent and efficient approach for polyp segmentation. However, the variability in polyp size and the heterogeneity of polyp boundaries and interiors pose challenges for accurate segmentation. Currently, Transformer-based methods have become a mainstream trend for polyp segmentation. However, these methods tend to overlook local details due to the inherent characteristics of Transformer, leading to inferior results. Moreover, the computational burden brought by self-attention mechanisms hinders the practical application of these models. To address these issues, we propose a novel CNN-Transformer hybrid model for polyp segmentation (CTHP). CTHP combines the strengths of CNN, which excels at modeling local information, and Transformer, which excels at modeling global semantics, to enhance segmentation accuracy. We transform the self-attention computation over the entire feature map into the width and height directions, significantly improving computational efficiency. Additionally, we design a new information propagation module and introduce additional positional bias coefficients during the attention computation process, which reduces the dispersal of information introduced by deep and mixed feature fusion in the Transformer. Extensive experimental results demonstrate that our proposed model achieves state-of-the-art performance on multiple benchmark datasets for polyp segmentation. Furthermore, cross-domain generalization experiments show that our model exhibits excellent generalization performance.

Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.

Increased neutrophil counts are associated with poor overall survival in patients with colorectal cancer: a five-year retrospective analysis.

Background: Colorectal cancer (CRC) continues to be a major health concern in today's world. Despite conflictive findings, evidence supports systemic inflammation's impact on CRC patients' survival rates. Therefore, this study aims to assess the prognostic role of the innate immune system in patients with CRC. Method: A total of 449 patients were included, with a 5-year follow-up period, and absolute neutrophil counts and their related ratios were measured. Results: The non-survival group had increased levels of white blood cells, neutrophils (both p<0.001), and monocytes (p=0.038), compared to the survival group, along with other neutrophil-related ratios. We observed increased mortality risk in patients in the highest tertile of white blood cells [HR=1.85 (1.09-3.13), p<0.05], neutrophils [HR=1.78 (95% CI: 1.07-2.96), p<0.05], and monocytes [HR=2.11 (95% CI: 1.22-3.63)], compared to the lowest tertile, after adjusting for all clinicopathological variables. Random forest analysis identified neutrophils as the most crucial variable in predicting survival rates, having an AUC of 0.712, considering all clinicopathological variables. A positive relationship between neutrophil counts and metastasis was observed when neutrophil counts are considered continuous (ß=0.92 (0.41), p<0.05) and tumor size (width) when neutrophils were considered as logistic variable (T1 vs T3) [OR=1.42, (95% CI: 1.05-1.98), p<0.05]. Conclusion: This study offers comprehensive insights into the immune factors that impact the prognosis of CRC, emphasizing the need for personalized prognostic tools.

Long-term outcomes for Advanced Colorectal Polyps in the BowelScreen Programme.

Aims: Colonoscopies performed as part of a colorectal cancer screening programmes regularly identify large non-pedunculated colorectal polyps (LNPCPs). Endoscopic Mucosal Resection (EMR) is a minimally invasive endoscopic resection strategy, for effective management of LNPCPs. There is limited published data on clinical outcomes for EMR carried out within screening programmes. Methods: A retrospective analysis of a prospectively-maintained EMR database of BowelScreen patients in a single centre over a 5 year period. Results: Fifty-two polyps in 50 patients underwent EMR in the study period. Median polyp size was 25mm (range 20-70mm). Adenocarcinoma was identified in 7.8% of resection specimens (n 4/51). Complications were recorded in 5.7% of EMRs (n 3/52). Surveillance was completed for 87.8% (n=36/41) of eligible patients with a site-check recurrence rate of 8.3% (n 3/36). Recurrence was successfully managed endoscopically through the surveillance programme with an 18 month recurrence rate of 2.7% (n 1/36). Surgery was avoided in 92% (n 46/50) of patients undergoing EMR. Discussion: Complex polyps identified in the colorectal cancer screening programme are effectively and definitively managed by minimally invasive endoscopic resection.. Low recurrence and complication rates underscore the value of EMR as part of a screening programme. Post-EMR surveillance identifies a small number of endoscopically manageable recurrences, with encouragingly high levels of compliance.

Clinicopathological characteristics of SMAD4 gene expressions in colorectal cancer patients.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths globally. SMAD4 gene acts as the central mediator of the signaling pathway for transforming growth factor-ß (TGFß) with a significant effect on colorectal cancer. Previous research has confirmed a relationship between the presence of the SMAD4 gene and the survival and progression of colorectal cancer in patients. In this study, our goal was to analyze the presence of SMAD4 in both colorectal cancer and nearby normal tissues. The expression levels of SMAD4 were evaluated in 45 colorectal tumor tissues and 45 adjacent control tissues using the Quantitative Real-Time PCR (qRT-PCR) method. Additionally, we assessed the diagnostic effectiveness of SMAD4 by creating a receiver operating characteristic (ROC) curve. Our findings showed that the expression of SMAD4 was significantly reduced in colorectal cancer patients compared to the adjacent control group sample. Examination of clinicopathological characteristics of patients revealed varied correlations between SMAD4 gene expressions and TMN stage (p<0.0001). These findings suggest that SMAD4 levels could be used as possible diagnostic indicators for colorectal cancer.

Artificial intelligence in predicting recurrence after first-line treatment of liver cancer: a systematic review and meta-analysis.

BACKGROUND: The aim of this study was to conduct a systematic review and meta-analysis to comprehensively evaluate the performance and methodological quality of artificial intelligence (AI) in predicting recurrence after single first-line treatment for liver cancer. METHODS: A rigorous and systematic evaluation was conducted on the AI studies related to recurrence after single first-line treatment for liver cancer, retrieved from the PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The area under the curve (AUC), sensitivity (SENC), and specificity (SPEC) of each study were extracted for meta-analysis. RESULTS: Six percutaneous ablation (PA) studies, 16 surgical resection (SR) studies, and 5 transarterial chemoembolization (TACE) studies were included in the meta-analysis for predicting recurrence after hepatocellular carcinoma (HCC) treatment, respectively. Four SR studies and 2 PA studies were included in the meta-analysis for recurrence after intrahepatic cholangiocarcinoma (ICC) and colorectal cancer liver metastasis (CRLM) treatment. The pooled SENC, SEPC, and AUC of AI in predicting recurrence after primary HCC treatment via PA, SR, and TACE were 0.78, 0.90, and 0.92; 0.81, 0.77, and 0.86; and 0.73, 0.79, and 0.79, respectively. The values for ICC treated with SR and CRLM treated with PA were 0.85, 0.71, 0.86 and 0.69, 0.63,0.74, respectively. CONCLUSION: This systematic review and meta-analysis demonstrates the comprehensive application value of AI in predicting recurrence after a single first-line treatment of liver cancer, with satisfactory results, indicating the clinical translation potential of AI in predicting recurrence after liver cancer treatment.

Engineered microparticles modulate arginine metabolism to repolarize tumor-associated macrophages for refractory colorectal cancer treatment.

BACKGROUND: Arginase is abundantly expressed in colorectal cancer and disrupts arginine metabolism, promoting the formation of an immunosuppressive tumor microenvironment. This significant factor contributes to the insensitivity of colorectal cancer to immunotherapy. Tumor-associated macrophages (TAMs) are major immune cells in this environment, and aberrant arginine metabolism in tumor tissues induces TAM polarization toward M2-like macrophages. The natural compound piceatannol 3'-O-glucoside inhibits arginase activity and activates nitric oxide synthase, thereby reducing M2-like macrophages while promoting M1-like macrophage polarization. METHODS: The natural compounds piceatannol 3'-O-glucoside and indocyanine green were encapsulated within microparticles derived from tumor cells, termed PG/ICG@MPs. The enhanced cancer therapeutic effect of PG/ICG@MP was assessed both in vitro and in vivo. RESULTS: PG/ICG@MP precisely targets the tumor site, with piceatannol 3'-O-glucoside concurrently inhibiting arginase activity and activating nitric oxide synthase. This process promotes increased endogenous nitric oxide production through arginine metabolism. The combined actions of nitric oxide and piceatannol 3'-O-glucoside facilitate the repolarization of tumor-associated macrophages toward the M1 phenotype. Furthermore, the increase in endogenous nitric oxide levels, in conjunction with the photodynamic effect induced by indocyanine green, increases the quantity of reactive oxygen species. This dual effect not only enhances tumor immunity but also exerts remarkable inhibitory effects on tumors. CONCLUSION: Our research results demonstrate the excellent tumor-targeting effect of PG/ICG@MPs. By modulating arginine metabolism to improve the tumor immune microenvironment, we provide an effective approach with clinical translational significance for combined cancer therapy.

Colitis cystica profunda associated with diverticulosis and calcification mimicking colorectal carcinoma: a case report and a brief literature review.

Colitis cystica profunda (CCP) is a rare, uncommon and nonneoplastic condition that can occur anywhere in gastrointestinal tract, but its main occurrence is in the rectum and sigmoid colon. It is characterized by the presence of mucin filled cysts, lined by benign epithelium, beneath the muscularis mucosae, usually confined to the submucosa, and it can clinically and radiologically mimic a neoplasm. Here we report a rare case of CCP in a patient with a 2-months history of abdominal pain and severe anemia, associated with diverticulosis. The knowledge of this entity and its differential diagnosis, in particular with the intestinal mucinous adenocarcinoma, is necessary, as it can be a clinically and histological mimic of a malignant neoplasm.

Association of various RAS codon mutations and prognostic outcomes of patients with colorectal liver metastases after hepatectomy.

PURPOSE: The prognostic and predictive value of RAS mutations in patients with colorectal liver metastases (CRLM) who have undergone hepatectomy holds substantial importance. The present study aimed to investigate the impact of different RAS codon mutations on long-term survival in CRLM patients. METHODS: A retrospective analysis was conducted on clinicopathological data from 399 CRLM patients with RAS mutations who underwent hepatectomy between January 2000 and December 2020. The RAS mutation gene status was assessed in KRAS codons (G12, G13, Q61, and A146) and NRAS codons (G12, G13, and Q61). Survival curves were generated using the Kaplan-Meier plotter and compared using the log-rank test. Univariate and multivariate analyses were performed to analyze the clinicopathological data. RESULTS: In the entire cohort, patients with KRAS G12 mutations exhibited the most favorable prognosis (p = 0.018). Comparatively, patients harboring KRAS Q61 mutations experienced poorer overall survival (OS) with a median of 15 months versus 33 months (p = 0.011) when compared to those with KRAS G12 mutations. Moreover, patients with NRAS Q61 mutations also showed decreased OS with a median of 26 months versus 33 months (p = 0.020) in comparison to KRAS G12 mutation patients. The results of multivariate analysis showed that both KRAS Q61 mutation (HR 2.130; 95% CI 1.088-4.168; p = 0.027) and NRAS Q61 mutation (HR 2.877; 95% CI 1.398-5.922; p = 0.004) were independent influencing factors of OS. Based on all identified risk factors, patients with RAS mutation were divided into high-risk and low-risk groups. Notably, in the high-risk group, the incorporation of postoperative chemotherapy was associated with longer OS, while it did not improve the survival of patients in the low-risk group. CONCLUSIONS: KRAS Q61 and NRAS Q61 mutations are promising predictors for OS in CRLM patients after hepatectomy. Postoperative chemotherapy may significantly benefit CRLM patients with RAS mutations, particularly those identified as high-risk.

The combination of transarterial chemoembolization and microwave ablation is superior to microwave ablation alone for liver metastases from colorectal cancer.

OBJECTIVES: This study aimed to compare the combination therapy of transarterial chemoembolization (TACE) and microwave ablation (MWA) with MWA alone in treating liver metastases from colorectal cancer (LMCRC). MATERIALS AND METHODS: In this retrospective study, a total of 251 patients with unresectable and not to chemotherapy responding LMCRC were included. Group A consisted of 184 patients (104 male and 80 females; mean age: 64 ± 11.4 years) with 442 metastases who received a combination of TACE and MWA. A total of 67 patients (49 male and 18 females; mean age: 63.2 ± 11.8 years) with 173 metastases patients were included in group B, who received only MWA. Parameters assessed were local tumor progression (LTP), hepatic distant tumor progression (hDTP), hepatic progression-free survival (hPFS), and overall survival (OS). RESULTS: The rate of LTP was 4.9% in group A and 4.5% in group B (p-value: 0.062). The rate of hDTP was 71.7% and 83.6% for groups A and B (p-value: 0.81), respectively. The mean hPFS was 13.8 months (95% CI 10.9-16.8) for group A and 8.1 months (95% CI 6.1-10.1) for group B (p-value: 0.03). The median OS time for group A was 30 months (95% CI 26-34), with 1-, 2-, 3-, and 4-year OS rates of 84.2%, 61.1%, 40.8% and 31.3%, respectively. In group B however, the median OS time was 26 months (95% CI 18-34) with 1-, 2-, 3-, and 4-year OS rates of 82.3%, 53.2%, 34.6% and 28.2%, respectively (p-value: 0.67). CONCLUSION: The combination therapy of TACE and MWA is superior to the monotherapy of MWA for LMCRC, especially regarding hDTP, hPFS and OS.

Inflammatory bowel disease, colitis, and cancer: unmasking the chronic inflammation link.

BACKGROUND: Chronic inflammation is a significant driver in the development of various diseases, including cancer. Colitis-associated colorectal cancer (CA-CRC) refers to the increased risk of colorectal cancer in individuals with chronic inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. METHODS: This narrative review examines the link between chronic inflammation and CA-CRC. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, focusing on studies published between 2000 and 2024. Studies were selected based on relevance to the role of inflammation in CA-CRC, specifically targeting molecular pathways and clinical implications. Both clinical and mechanistic studies were reviewed. CONCLUSION: Sustained inflammation in the colon fosters a pro-tumorigenic environment, leading to the initiation and progression of CA-CRC. Prevention strategies must focus on controlling chronic inflammation, optimizing IBD management, and implementing regular screenings. Emerging therapies targeting key inflammatory pathways and immune responses, along with microbiome modulation, hold promise for reducing CA-CRC risk. Understanding these molecular mechanisms provides a path toward personalized treatment and better outcomes for patients with IBD at risk of colorectal cancer.

Preoperative prediction of early recurrence in patients with BRAF mutant colorectal cancer using a intergrated nomogram.

Objective To explore the predictive value of radiomics nomogram combining with CT radiomics features and clinical features for postoperative early recurrence in patients with BRAF-mutant colorectal cancer. Methods A total of 220 patients with surgically and pathologically confirmed BRAF-mutant colorectal cancer from 2 institutions were retrospectively included. All patients from institution 1 were randomized at a 7:3 ratio into a training cohort (n = 108) and an internal validation cohort (n = 45), and patients from institution 2 were used as an external validation cohort (n = 67). The association between the radiomics features and early recurrence was assessed in the training cohort and verified in the validation cohort. Furthermore, the performance of the radiomics nomogram was evaluated by combining the rad-score and clinical risk factors. The predictive performance was evaluated by receiver operating characteristic curve analysis, calibration curve analysis, and decision curve analysis. Results The dierenees in the Lymphocyte/monocyte ratio (LMR) and Peripheral nerve infiltration (PNI) were statistically significant between the early recurrence in BRAF-mutant colorectal cancer groups and the early non-recurrence in BRAF-mutant colorectal cancer groups (P < 0.05); The two groups showed no significant differenee in clinical parameters including age, sex, and biochemistry serum markers (P > 0.05). Comparing with the pure radiomics or clinical data, combined models can be seen that the addition of LMR and PNI further improveed the predictive efficiency of the model. The rad-score based on LR, generated by 4 selected radiomics features, demonstrated a favorable ability to predict early recurrence in both the training (AUC 0.81), internal validation (AUC 0.73), external validation (AUC 0.63) cohorts. Subsequently, integrating two independent predictors into a nomogram exhibited more favorable discriminatory performance, with the AUC improved to 0.88 and 0.81 in both cohorts. Conclusions The proposed CT-based radiomics signature is associated with early recurrence among the patients with BRAF-mutant colorectal cancer. The present study also proposes a combined model can potentially be applied in the individual preoperative prediction of early recurrence in patients with BRAF-mutant colorectal cancer. Advances in knowledge CT-based radiomics showed satisfactory diagnostic significance for early recurrence in patients with BRAF-mutant colorectal cancer. Key baseline clinical characteristics were associated with early recurrence in patients with BRAF-mutant colorectal cancer. The combined model may be applied in the individual preoperative prediction of early recurrence in patients with BRAF-mutant colorectal cancer.

Persistent Activation of the P2X7 Receptor Underlies Chronic Inflammation and Carcinogenic Changes in the Intestine.

Aberrant signaling through damage-associated molecular patterns (DAMPs) has been linked to several health disorders, attracting considerable research interest over the last decade. Adenosine triphosphate (ATP), a key extracellular DAMP, activates the purinergic receptor P2X7, which acts as a danger sensor in immune cells and is implicated in distinct biological functions, including cell death, production of pro-inflammatory cytokines, and defense against microorganisms. In addition to driving inflammation mediated by immune and non-immune cells, the persistent release of endogenous DAMPs, including ATP, has been shown to result in epigenetic modifications. In intestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), consequent amplification of the inflammatory response and the resulting epigenetic reprogramming may impact the development of pathological changes associated with specific disease phenotypes. P2X7 is overexpressed in the gut mucosa of patients with IBD, whereas the P2X7 blockade prevents the development of chemically induced experimental colitis. Recent data suggest a role for P2X7 in determining gut microbiota composition. Regulatory mechanisms downstream of the P2X7 receptor, combined with signals from dysbiotic microbiota, trigger intracellular signaling pathways and inflammasomes, intensify inflammation, and foster colitis-associated CRC development. Preliminary studies targeting the ATP-P2X7 pathway have shown favorable therapeutic effects in human IBD and experimental colitis.

Single-Cell Transcriptomics Reveals Cellular Heterogeneity and Drivers in Serrated Pathway-Driven Colorectal Cancer Progression.

Serrated lesions are common precancerous pathways in colorectal cancer (CRC), but the process by which they progress to malignancy remains unclear. We aimed to elucidate this progression through a single-cell RNA landscape. We conducted single-cell RNA sequencing on three normal colonic tissues and fifteen SLs (including HPs, SSLs, SSLD, and TSAs) and integrated these data with datasets containing tumor samples. We identified three invasive malignant epithelial cell subtypes related to CRC progression: SLC1, SLC2, and tumor cell. SLC1, specific to SSLs, is involved in cell proliferation and shows a continuum of malignancy in gene expression. TSA-specific SLC2 exhibited FOXQ1 upregulation and active EMT, indicating invasiveness. The trajectory analysis showed that HPs do not progress to cancer, and different SL types are linked to the MSI status of advanced CRCs. We validated molecular drivers in premalignant lesions and later carcinogenesis. In the tumor microenvironment, CAF and pre-CAF fibroblast subtypes associated with progression were identified. During the premalignant stage, SLC1 triggered CD8+ T cell responses, while at the advanced stage, CAFs promoted tumor invasion and metastasis via FN1-CD44, influencing tumor progression and the treatment response. Our findings highlight transcriptional changes across serrated pathway stages, aiding in early CRC diagnosis and treatment.

Trp53 Deletion Promotes Exacerbated Colitis, Facilitates Lgr5+ Cancer Stem Cell Expansion, and Fuels Tumorigenesis in AOM/DSS-Induced Colorectal Cancer.

Colorectal cancer CRC remains one of the leading causes of cancer-related deaths worldwide, with chronic intestinal inflammation identified as a major risk factor. Notably, the tumor suppressor TP53 undergoes mutation at higher rates and earlier stages during human inflammation-driven colon tumorigenesis than in sporadic cases. We investigated whether deleting Trp53 affects inflammation-induced tumor growth and the expression of Lgr5+ cancer stem cells in mice. We examined azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis in wild-type Trp53 (+/+), heterozygous (+/-), and knockout (-/-) mice. Trp53-/- mice showed increased sensitivity to DSS colitis and earlier accelerated tumorigenesis with 100% incidence. All groups could develop invasive tumors, but knockouts displayed the most aggressive features. Unlike wild-type CRC, knockouts selectively showed increased populations of Lgr5+ colon cancer stem-like cells. Trp53 loss also boosted laminin, possibly facilitating the disruption of the tumor border. This study highlights how Trp53 deletion promotes the perfect storm of inflammation and stemness, driving colon cancer progression. Trp53 deletion dramatically shortened AOM/DSS latency and improved tumor induction efficiency, offering an excellent inflammation-driven CRC model.

Multigene Panel Next-Generation Sequencing Techniques in the Management of Patients with Metastatic Colorectal Carcinoma: The Way Forward for Personalized Treatment? A Single-Center Experience.

The efficacy and cost-effectiveness of Multigene Panel Next-Generation Sequencing (NGS) in directing patients towards genomically matched therapies remain uncertain. This study investigated metastatic colorectal cancer (mCRC) patients who underwent NGS analysis on formalin-fixed paraffin-embedded tumor samples. Data from 179 patients were analyzed, revealing no mutations in 39 patients (21.8%), one mutation in 83 patients (46.4%), and two or more mutations in 57 patients (31.8%). KRAS mutations were found in 87 patients (48.6%), including KRAS G12C mutations in 5 patients (2.8%), PIK3CA mutations in 40 patients (22.4%), and BRAF mutations in 26 patients (14.5%). Less common mutations were identified: ERBB2 in five patients (2.8%) and SMO in four patients (2.2%). Additionally, MAP2K1, CTNNB1, and MYC were mutated in three patients (2.4%). Two mutations (1.1%) were observed in ERBB3, RAF1, MTOR, JAK1, and FGFR2. No significant survival differences were observed based on number of mutations. In total, 40% of patients had druggable molecular alterations, but only 1.1% received genomically guided treatment, suggesting limited application in standard practice. Despite this, expanded gene panel testing can identify actionable mutations, aiding personalized treatment strategies in metastatic CRC, although current eligibility for biomarker-guided trials remains limited.