Search Results (128)

CAPOX and FOLFOX are widely used chemotherapy regimens for colorectal cancer (CRC). The superiority of one regimen over the other in a real-world setting (RWE) could have significant clinical implications given their common use, but such RWE is limited. This study analyzed provincial database records of 13,461 Canadian patients treated from 2005 to 2017. The primary outcomes were rates of Emergency Department visits and/or hospitalizations (ED/H) and overall survival (OS). CAPOX was used less frequently (8.4%) than FOLFOX (91.6%), often in older patients (p < 0.003 for Stage I–III; p < 0.001 for Stage IV). CAPOX recipients had shorter treatment durations (median 15 vs. 20 weeks, p = 0.002) and higher unadjusted ED/H rates (60.8% vs. 50.9%, p < 0.001), though this difference was nonsignificant on multivariate analysis (MVA) (HR 1.05 (0.92, 1.20), p = 0.466). Patients receiving CAPOX had worse OS than those on FOLFOX, (5-year OS 70.1% vs. 77.2% (p < 0.001) non-metastatic; 16.6% vs. 33.2% (p < 0.001) metastatic). MVA confirmed inferior OS with CAPOX (HR 1.42, p < 0.001). Other predictors of shorter OS included older age, male sex, comorbidities, rural residence, and lower income. This administrative data is at risk of bias but highlights the need for careful patient selection and informed treatment decision making. Full article

Stage IV colorectal cancer has a poor prognosis, and liver metastases are prone to recurrence, even after resection. This study aimed to identify common cancer antigens, using immunohistochemical staining, as promising targets for antigen-specific immunotherapies in colorectal cancer. We analyzed expression levels and intracellular localization of seven common cancer antigens, CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC, and human leukocyte antigen (HLA) class I via immunohistochemical staining of 85 surgical specimens from primaries and liver metastases. Staining intensity and positive staining were scored to evaluate antigen expression. In 25 primaries, seven cancer antigens were expressed in 88–96% of cases, while HLA class I was expressed on the cell membrane in 80.0% of cases. In 60 liver metastases, FOXM1 and SPARC expression were approximately half that observed in the primaries. Other antigens and HLA class I were highly expressed in both. Most of the primaries and liver metastases may benefit from chimeric antigen receptor-T cell therapy targeting CLDN1, EphB4, and LAT1. Cases with high HLA class I expression may be suitable for vaccine-based and T cell receptor-T cell therapy targeting CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC for primaries and targeting antigens, excluding FOXM1 and SPARC, for liver metastases. Full article

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. Full article

Background/Objectives: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway is a critical mediator of immune regulation, inflammation, and cancer progression. Although implicated in colorectal cancer (CRC) pathogenesis, its molecular heterogeneity and clinical significance remain insufficiently characterized—particularly within early-onset CRC (EOCRC) and across diverse treatment and demographic contexts. We present AI-HOPE-JAK-STAT, a novel conversational artificial intelligence platform built to enable the real-time, natural language-driven exploration of JAK/STAT pathway alterations in CRC. The platform integrates clinical, genomic, and treatment data to support dynamic, hypothesis-generating analyses for precision oncology. Methods: AI-HOPE-JAK-STAT combines large language models (LLMs), a natural language-to-code engine, and harmonized public CRC datasets from cBioPortal. Users define analytical queries in plain English, which are translated into executable code for cohort selection, survival analysis, odds ratio testing, and mutation profiling. To validate the platform, we replicated known associations involving JAK1, JAK3, and STAT3 mutations. Additional exploratory analyses examined age, treatment exposure, tumor stage, and anatomical site. Results: The platform recapitulated established trends, including improved survival among EOCRC patients with JAK/STAT pathway alterations. In FOLFOX-treated CRC cohorts, JAK/STAT-altered tumors were associated with significantly enhanced overall survival (p < 0.0001). Stratification by age revealed survival advantages in younger (age < 50) patients with JAK/STAT mutations (p = 0.0379). STAT5B mutations were enriched in colon adenocarcinoma and correlated with significantly more favorable trends (p = 0.0000). Conversely, JAK1 mutations in microsatellite-stable tumors did not affect survival, emphasizing the value of molecular context. Finally, JAK3-mutated tumors diagnosed at Stage I–III showed superior survival compared to Stage IV cases (p = 0.00001), reinforcing stage as a dominant clinical determinant. Conclusions: AI-HOPE-JAK-STAT establishes a new standard for pathway-level interrogation in CRC by empowering users to generate and test clinically meaningful hypotheses without coding expertise. This system enhances access to precision oncology analyses and supports the scalable, real-time discovery of survival trends, mutational associations, and treatment-response patterns across stratified patient cohorts. Full article

Identifying prognostic markers in colorectal cancer (CRC) is crucial for improving treatment outcomes. Although carcinoembryonic antigen (CEA) is recommended in the guidelines of the National Comprehensive Cancer Network, its sensitivity and specificity are inconsistent, limiting its utility in patients with normal CEA levels. Circulating tumor cells (CTCs), including those expressing CD133—a cancer stem cell marker involved in tumor progression and therapy resistance—are associated with metastasis and survival outcomes. This study evaluated the prognostic significance of CD133-positive CTCs, and their combined effect with CEA, in patients with CRC. Peripheral blood samples from 195 patients with CRC (stages I–IV) were analyzed. CTCs were isolated using OncoQuick tubes and CD133 mRNA expression was detected by reverse transcription polymerase chain reaction. In clinicopathological analysis, CD133-positive CTCs were detected in 27.2% of cases, correlating with serosal invasion (p = 0.016). Multivariate Cox analysis showed that CD133-positive CTCs were associated with worse disease-specific survival (p = 0.001). Patients with CD133-positive CTCs and CEA ≥ 5 ng/mL (high CEA) had a significantly poorer prognosis (p < 0.001), whereas those with CD133-negative CTCs and CEA < 5 ng/mL (low CEA) had a better prognosis (p = 0.039). CD133 expression in CTCs, especially in combination with CEA, may serve as a valuable prognostic marker in CRC. Full article

Background: The use of regorafenib and 5-fluorouracil in the management of refractory metastatic colorectal cancer has gained increasing attention due to their demonstrated efficacy in extending the survival of patients with colorectal cancer. This study aims to discuss the effect of using regorafenib and 5-fluorouracil combination therapy in refractory metastatic colorectal cancer patients. Case Presentation: We present a case report of a 68-year-old female patient with KRAS G12D and PIK3CA mutations who was diagnosed with stage IV-C colon cancer. She was referred to hospice care and subsequently received therapeutic intervention with 56 cycles of regorafenib and 5-fluorouracil for 31 months while maintaining stable disease (SD). The patient exhibited good tolerance with minimal adverse effects, including Grade I-II Hand–Foot Syndrome. Conclusions: Our case showed the feasibility of using Regorafenib and 5-fluorouracil combination therapy in stage IV refractory metastatic colorectal cancer treatment, which resulted in an improvement in the overall survival after she was referred to Hospice care. Utilizing this case report may provide valuable input in managing refractory metastatic colorectal cancer, given the prolonged survival and the clinical meaningfulness of this regimen in our patient. Full article

Peritoneal carcinomatosis is a common presentation found in advanced-stage gastrointestinal (GI) and gynecological cancers. Combined cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant survival benefits for select patients. CRS/HIPEC is not currently provided in Newfoundland and Labrador (NL). The Canadian HIPEC Collaborative Group recommends that centres complete a minimum of one case monthly to maintain competency and achieve good outcomes. Thus, we aimed to demonstrate that the annual patient volume in NL justifies the feasibility of implementing a combined surgical and gynecological oncology CRS/HIPEC program. Methods: A retrospective chart review of the NL Cancer Care Registry identified patients with stage IV colorectal, appendiceal, or gastric cancer and stage III to IV epithelial ovarian cancer over a 1-year period (1 January 2020–31 December 2020) to identify the number of patients meeting the criteria for CRS/HIPEC and/or those referred out of province to receive the treatment. The results are presented as proportions and percentages. Results: Thirty-one patients were eligible to receive CRS/HIPEC during the study period (11 GI, 20 gynecological). Of the GI patients, 63% were referred out of province for the procedure. Gynecological patients underwent CRS and systemic therapy +/− outpatient intraperitoneal chemotherapy in NL. Conclusions: Allowing patients to receive this standard of care treatment near home reduces financial, social, and emotional stressors. Our results confirm a sufficient patient volume to support a combined CRS/HIPEC program in NL. The implementation of this program will require multidisciplinary collaboration, specialized training, equipment, and protocol development. Full article

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality, influenced by both genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) such as GAS5 and CASC8 have been implicated in cancer susceptibility. This study aimed to assess the association of GAS5 rs145204276 ins/del and CASC8 rs10505477 A>G polymorphisms with CRC risk in a Romanian population. A case-control study was conducted, including 156 CRC patients and 195 healthy controls. Genotyping for GAS5 and CASC8 polymorphisms was performed using real-time PCR, and the association with CRC risk was evaluated using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). The carriers of GAS5 rs145204276 del allele was significantly associated with increased CRC risk (OR: 2.13, 95% CI: 1.24–3.63, p = 0.005) in a dominant model. In the subgroup analysis, the association of GAS5 rs145204276 ins/del polymorphism was restricted to distal colon cancer cases (OR: 2.98, 95% CI: 1.57–5.66, p = 0.001), advanced tumor stages (III + IV) (OR: 2.54, 95% CI: 1.31–4.91, p = 0.007), and poorly differentiated tumors (G3) (OR: 3.98, 95% CI: 1.49–10.59, p = 0.009). No significant correlation was found for the CASC8 rs10505477 A>G polymorphism. GAS5 rs145204276 polymorphism may influence CRC susceptibility, particularly in distal tumors and advanced stages. However, CASC8 rs10505477 polymorphism showed no association with CRC risk in this Romanian cohort. Full article

Background and Objectives: Mucinous adenocarcinoma (MAC) and mucinous components (MCP) in colorectal cancers (CRC) have shown conflicting results regarding their prognostic impact. This study aims to evaluate survival differences between MAC, MCP, and non-mucinous adenocarcinoma (nMAC) in stage II and III CRC patients. Materials and Methods: 224 CRC patients who underwent surgery between 2013 and 2021 were analyzed retrospectively. Patients were classified as nMAC, MCP, or MAC based on the percentage of extracellular mucin. Those who received neoadjuvant therapy, had stage I or IV TNM disease, and emergency cases were excluded. Survival analysis was performed using Kaplan–Meier curves and Cox regression models. Results: MAC patients showed worse survival outcomes compared to nMAC (p = 0.025). No difference in survival was found between MCP and nMAC (p = 0.055). Multivariate analysis identified MAC (OR: 2.814; p = 0.014) and perineural invasion (PNI) (OR: 2.283; p = 0.008) as independent factors associated with worse survival. Kaplan–Meier analysis revealed MAC’s worse prognosis than nMAC (p = 0.027). Conclusions: MAC was shown to have a worse prognosis than nMAC in stage II and III CRC patients, while MCP survival rates were similar with nMAC. These findings suggest that MAC requires more careful treatment approaches, while MCP and nMAC have better survival rates. Further studies focusing on molecular and genetic profiles are needed to better understand these outcomes. Full article

Background/Objectives: BRAF^V600E-mutant colorectal cancer (CRC) is associated with poor prognosis, and despite the introduction of BEACON therapy, significant treatment challenges remain. This study investigates the clinical utility of BRAF^V600E in cell-free DNA (cfDNA BRAF^V600E) as a biomarker for real-time treatment monitoring in metastatic cases and for evaluating minimal residual disease (MRD) after curative resection. Methods: This single-center, prospective observational study included 37 patients with BRAF^V600E-mutant CRC treated at Nippon Medical School Hospital between April 2017 and June 2024. Patients were divided into two cohorts: Cohort 1 (Stage IV cases): Evaluated cfDNA BRAF^V600E for treatment monitoring. Cohort 2 (Stage I–III curatively resected cases): Assessed cfDNA BRAF^V600E for recurrence risk prediction. Blood samples were collected before and during treatment and analyzed using droplet digital PCR (ddPCR) to measure cfDNA BRAF^V600E levels. Results: Cohort 1 (Stage IV, n = 14): Pre-treatment cfDNA BRAF^V600E was detected in 93% of cases. Patients with a decrease in cfDNA BRAF^V600E variant allele frequency (VAF) after chemotherapy had significantly longer overall survival (511 vs. 189 days, p = 0.03) than those without a decrease. Cohort 2 (curatively resected, n = 23): cfDNA BRAF^V600E was detected in 4/23 patients (17.4%) at 1 month post-surgery. cfDNA BRAF^V600E showed better recurrence prediction compared to CEA (100% vs. 18.8%, p = 0.004). Among the seven patients who experienced recurrence, those with postoperative cfDNA BRAF^V600E positivity had significantly shorter disease-free survival compared to cfDNA BRAF^V600E-negative patients (179 vs. 840 days, p = 0.04). Conclusions: These findings support cfDNA BRAF^V600E as a promising biomarker for monitoring treatment response and MRD detection in BRAF^V600E-mutant CRC, reinforcing its role in guiding personalized treatment strategies and postoperative surveillance. Full article

Background: Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Tertiary lymphoid structures (TLSs), organized immune cell aggregates in non-lymphoid tissues, are linked to chronic inflammation and tumorigenesis. However, the precise relationship between TLSs and CRC prognosis remains unclear. This study aimed to develop a TLS-associated genetic signature to predict CRC prognosis and support clinical applications. Methods: Utilizing the TCGA database, we analyzed TLS-related gene expression in CRC versus normal tissues. Prognostic models were constructed using Cox and Kaplan-Meier analyses. CRC samples were stratified into high and low TLS groups via ssGSEA, with validation in the GSE75500 dataset. We identified clinical characteristics associated with TLS scores, created prognostic nomograms, analyzed the top 50 differential genes, assessed tumor mutations, estimated immune infiltration using CIBERSORT, and examined correlations between TLS scores and immune checkpoints. Results: A 13-gene TLS-associated prognostic model for CRC was developed, emphasizing immune response genes. Survival analysis indicated significantly better outcomes for the TLS-high group. Cox regression identified stage IV and M1 as independent factors influencing TLS scores. Nomogram analysis demonstrated that combining TLS scores with clinical features enhances prognostic accuracy. TLS scores were closely associated with immune checkpoint genes, suggesting potential immunotherapy benefits for TLS-high patients. Conclusions: This study developed and validated a TLS-based prognostic model for CRC, exploring relevant immune cells. The model holds promise for predicting clinical prognosis and treatment responsiveness in CRC patients. Full article

Background/Objectives: Mutations in BRCA1 and/or BRCA2 (BRCAm) and other homologous recombination repair genes (HRRm) are associated with several cancers. We evaluated the prevalence and association with overall survival (OS) of somatic BRCAm and HRRm among patients with advanced solid tumors. Methods: We used deidentified data from the AACR GENIE Biopharma Collaborative dataset derived from patients with tumors genotyped using next-generation sequencing between 1 January 2014 and 31 December 2017. Eligible patients were aged ≥18 years diagnosed with non-small-cell lung, colorectal, breast, bladder, prostate, or pancreatic cancer, with documented BRCA/HRR somatic mutation status. The primary analysis was OS (censored at the start of poly[ADP ribose] polymerase inhibitors [PARPi]/immunotherapy) after initiation of second-line therapy since most patients had sequencing after first-line therapy. Results: Among eligible patients, 242/7022 (3.4%) had BRCAm and 477/5474 (8.7%) had HRRm. Adjusted OS HRs (95% CI) for the primary analysis (using the initiation of second-line therapy as index date) were 0.79 (0.61–1.03) with/without BRCAm (n = 116/n = 3394) and 0.83 (0.69–0.99) with/without HRRm (n = 247/n = 2656); in sensitivity analysis of patients with stage IV disease, HRs were 0.97 (0.68–1.38) with/without BRCAm (n = 58/n = 1847) and 0.92 (0.73–1.18) with/without HRRm (n = 132/n = 1488). Conclusions: Overall, BRCAm and HRRm did not show a strong association with OS, with a trend toward longer OS among patients receiving standard second-line therapies excluding PARPi/immunotherapy. Full article

Background/Objectives: Liquid biopsy methods have gained prominence as minimally invasive tools to improve cancer treatment outcomes. Circulating tumor cells (CTCs) offer valuable insights into both primary and metastatic lesions. However, validating the CTC test results requires confirmation that the detected cells originate from cancer tissue. While studies have identified CTCs in colorectal cancer (CRC) patients using molecular markers, simultaneous validation of their cancer tissue origin remains unexplored. Methods: This study introduces a simple approach to detect adenomatous polyposis coli (APC) gene abnormalities alongside established CTC markers using a molecular imaging flow cytometer (MI-FCM). Given that APC gene abnormalities occur in 60–70% of CRC patients, their detection serves as strong evidence of cancer origin. Results: Our method achieved 92% concordance with DNA sequence analysis of tumor-derived cells. In a proof-of-concept study using 5 mL of whole blood from CRC patients, we observed a high frequency of cells exhibiting APC abnormalities, cytokeratin (CK), and vimentin (Vim) expression. Extending the study to 80 CRC patients across pathological stages I–IV confirmed CK and Vim as valid CTC markers. Three distinct cell populations were identified in blood: CK+/Vim−, CK+/Vim+, and CK−/Vim+. CTC number and frequency increased progressively with cancer stage. Conclusions: This is the first report demonstrating CK and Vim as effective markers for direct CTC detection in CRC patients. Our findings provide evidence-based validation of CTC markers, offering new insights and advancing approaches for patient care. Full article

Background: As colorectal cancers are histopathologically and molecularly highly heterogeneous tumors, it is necessary to consider the tumor’s microenvironment as well as its cellular characteristics in order to determine the biological behavior of the tumor. This study included 100 patients who underwent resection for colorectal cancer. We aimed to investigate the relationships between the expression status of the HIF-1α, LOX and ITGA5 proteins and clinicopathologic parameters. Methods: HIF-1α, LOX and ITGA5 antibodies were applied immunohistochemically to tissue microarrays prepared from tumor samples. Expression status in the tumor microenvironment were evaluated using a combined scoring system based on staining intensity and the percentage of positively stained cells. Nuclear HIF-1α expression in tumor cells was quantified, with >1% considered positive. The staining of HIF-1α, ITGA5 and LOX was analyzed in relation to prognostic and molecular features. Results: The staining of HIF-1α, ITGA5 and LOX in the tumor microenvironment demonstrated a positive correlation with one another and with HIF-1α and LOX expression in tumor cells. In patients with KRAS, NRAS or BRAF mutation and the moderate to strong expression of all three of these proteins in the tumor microenvironment, the number of metastatic lymph nodes was higher than in other patients. Stage IV patients with the moderate to strong expression of HIF-1α, ITGA5 or LOX in the microenvironment had lower progression-free survival than those with weak expression (p < 0.05). In addition, female gender; moderate to strong HIF-1α, LOX and ITGA5 stromal expression; and metastatic first line chemotherapy only were found to be independently associated with an increased risk of progression. Conclusions: These markers may be useful in predicting treatment responses and may also guide the development of alternative or combined treatments that specifically target molecules such as HIF and LOX. Our study should be supported by more comprehensive studies addressing the tumor stroma and its prognostic importance. Full article

Background: Recent advancements in understanding plasma extracellular vesicles (EVs) and their role in disease biology have provided additional unique insights into the study of Colorectal Cancer (CRC). Methods: This study aimed to gain biological insights into disease progression from plasma-derived extracellular vesicle proteomic profiles of 80 patients (20 from each CRC stage I–IV) against 20 healthy age- and sex-matched controls using a high-resolution SWATH-MS proteomics with a reproducible centrifugation method to isolate plasma EVs. Results: We applied the High-Stringency Human Proteome Project (HPP) guidelines for SWATH-MS analysis, which refined our initial EV protein identification from 1362 proteins (10,993 peptides) to a more reliable and confident subset of 853 proteins (6231 peptides). In early-stage CRC, we identified 11 plasma EV proteins with differential expression between patients and healthy controls (three up-regulated and eight down-regulated), many of which are involved in key cancer hallmarks. Additionally, within the same cohort, we analysed EV proteins associated with tumour recurrence to identify potential prognostic indicators for CRC. A subset of up-regulated proteins associated with extracellular vesicle formation (GDI1, NSF, and TMED9) and the down-regulation of TSG101 suggest that micro-metastasis may have occurred earlier than previously anticipated. Discussion: By employing stringent proteomic analysis and a robust SWATH-MS approach, we identified dysregulated EV proteins that potentially indicate early-stage CRC and predict recurrence risk, including proteins involved in metabolism, cytoskeletal remodelling, and immune response. While our findings underline discrepancies with other studies due to differing isolation and stringency parameters, they provide valuable insights into the complexity of the EV proteome, emphasising the need for standardised protocols and larger, well-controlled studies to validate potential biomarkers. Full article