Colon Tumor Research Articles

The effectiveness of endoscopic diagnostics of colon tumors using artificial intelligence: prospective tandem study

AIM: to estimate the effectiveness of a medical decision support system based on artificial intelligence in the endoscopic diagnosis of benign tumors during tandem study.PATIENTS AND METHODS: from October to December 2023, a single-center comparative tandem study of medical decision support system based on artificial intelligence “ArtInCol” was done. The first stage was a traditional colonoscopy under sedation, the second one — colonoscopy using AI. A pairwise comparison of the main indicators of the effectiveness was made.RESULTS: in the primary endpoint, the polyp detection rate (PDR) in the traditional colonoscopy group was 40.6% vs 56.4% in the AI group, p = 0.0001 (RR = 1.39; 95% CI: 1.04–1.87). The mean number of lesions detected (MPP) was 1.63 (± 1.2) vs 2.47 (± 1.8) in the AI group (mean difference = 0.84; (95% CI: 1.07–0.61).CONCLUSION: the study demonstrated the effectiveness of the original medical decision support system for benign colon tumors detection in real clinical practice. The further stage, a multicenter randomized trial is needed.

ATG16L1 in myeloid cells limits colorectal tumor growth in ApcMin/+ mice infected with colibactin-producing Escherichia coli via decreasing inflammasome activation

ABSTRACT Escherichia coli strains producing the genotoxin colibactin, designated as CoPEC (colibactin-producing E. coli), have emerged as an important player in the etiology of colorectal cancer (CRC). Here, we investigated the role of macroautophagy/autophagy in myeloid cells, an important component of the tumor microenvironment, in the tumorigenesis of a susceptible mouse model infected with CoPEC. For that, a preclinical mouse model of CRC, the Apc Min/+ mice, with Atg16l1 deficiency specifically in myeloid cells (Apc Min/+ /Atg16l1[∆MC]) and the corresponding control mice (Apc Min/+ ), were infected with a clinical CoPEC strain 11G5 or its isogenic mutant 11G5∆clbQ that does not produce colibactin. We showed that myeloid cell-specific Atg16l1 deficiency led to an increase in the volume of colonic tumors in Apc Min/+ mice under infection with 11G5, but not with 11G5∆clbQ. This was accompanied by increased colonocyte proliferation, enhanced inflammasome activation and IL1B/IL-1β secretion, increased neutrophil number and decreased total T cell and cytotoxic CD8+ T cell numbers in the colonic mucosa and tumors. In bone marrow-derived macrophages (BMDMs), compared to uninfected and 11G5∆clbQ-infected conditions, 11G5 infection increased inflammasome activation and IL1B secretion, and this was further enhanced by autophagy deficiency. These data indicate that ATG16L1 in myeloid cells was necessary to inhibit colonic tumor growth in CoPEC-infected Apc Min/+ mice via inhibiting colibactin-induced inflammasome activation and modulating immune cell response in the tumor microenvironment. Abbreviation: AOM, azoxymethane; APC, APC regulator of WNT signaling pathway; ATG, autophagy related; Atg16l1[∆MC] mice, mice deficient for Atg16l1 specifically in myeloid cells; CASP1, caspase 1; BMDM, bone marrow-derived macrophage; CFU, colony-forming unit; CoPEC, colibactin-producing Escherichia coli; CRC, colorectal cancer; CXCL1/KC, C-X-C motif chemokine ligand 1; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; MC, myeloid cell; MOI, multiplicity of infection; PBS, phosphate-buffered saline; pks, polyketide synthase; qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; siRNA, small interfering RNA; TME, tumor microenvironment; TNF/TNF-α, tumor necrosis factor.

The prevalence of sickle cell phenotype and its association with clinical outcomes in patients with solid malignancies.

10563 Background: Sickle cell disease (SCD) is the most common inherited blood disorder in the United States and is caused by a mutation of β-globin ( HBB-Mt). The risk of developing solid malignancies in this population remains controversial, with research showing increased rates of some solid tumors (colon, kidney, and thyroid) and decreased rates of others (breast and male genitourinary). We report the prevalence of HBB mutations across a cohort of solid tumors and clinical outcomes between HBB-Wild type (-Wt) v Mutant (-Mt) tumors. Methods: Non-small cell lung cancer (NSCLC, N = 3307), breast (BC, N = 1960), colorectal (CRC, N = 2161), prostate (N = 899), and gynecologic cancers (N = 2,805) in persons of African descentwere tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (whole exome) and RNA (whole transcriptome). Her2/Neu (+: ≥3+ and >10%) and HR (ER or PR+: ≥1+ and ≥1%) expression was tested by immunohistochemistry. Tumors were assessed for single nucleotide variations (SNVs) and insertions/deletions (indels) in HBB associated with a sickle cell phenotype. Mutation prevalence for all other genes was calculated for pathogenic SNVs/indels. Differentially regulated pathways were assessed by gene set enrichment analysis (GSEA). Fisher’s Exact/χ2 tests were applied as appropriate with p-values adjusted for multiple comparisons ( p < .05). Real-world overall survival (OS) and ethnicity data was obtained from insurance claims and log-rank estimates were calculated for molecularly defined subpopulations. Results: Amongst persons of African descent, uterine sarcoma had the highest prevalence of HBB-Mt (17.1%, 43/251) followed by uterine serous carcinoma (9.1, 70/768) and endometrial carcinoma (7.8, 55/708). Tumors with the highest absolute number of HBB-Mt tumors were NSCLC (7.0, 230/3307), CRC (8.1, 176/2161) and BC (6.7, 131/1960). In CRC, there was no significant difference in the prevalence of right-sided tumors between HBB-Wt v Mt (42% v 51, p = .06), nor in the prevalence of HBB-Mt by consensus molecular subtype ( p = .34). No significant enrichment of HBB-Mt across BC subtypes was observed (HR- HER2-: 7.8%, HR-HER2+: 9.7, HR+/HER2-:5.8, HR+/HER2+: 8.1, p = .34). No difference in the prevalence of pathogenic alterations was observed between HBB-Mt vs -Wt across NSCLC, CRC, and BC ( p > .05). HBB-Mt NSCLC were significantly enriched (GSEA) for genes related interferon /, inflammatory response and IL6/JAK/STAT3. No significant difference in OS was observed in CRC (median survival HBB-Wt: 957 days v -Mt: 1034, p = .43), NSCLC (-Wt: 591 v -Mt: 648, p = .59) or BC (-Wt: 924 v -Mt: 922, p = .61). Conclusions: No significant differences in the genomic landscape nor in OS of HBB-Mt vs HBB-Wt NSCLC, CRC or BC were observed. NSCLC HBB-Mt was enriched with inflammatory response genes. Future work should focus on potential role HBB-Mt plays in NSCLC.

Survival analysis and associated factors in metastatic early-onset colorectal cancer vs. metastatic average-onset colorectal cancer.

e15549 Background: Early-onset colorectal cancer (EO-CRC) is defined as colorectal cancer diagnosed before age 50 and its incidence has been increasing during the last decade. Average-onset colorectal cancer (AO-CRC) has presented a steady decline in incidence and related mortality over the past 20 years. There is controversy surrounding the disparities in outcomes and overall survival (OS) in EO-CRC vs. AO-CRC. Our study compared the OS and cause-specific survival (CSS) between metastatic EO-CRC (mEO-CRC) and metastatic AO-CRC (mAO-CRC) and identified associated factors. Methods: Data on patient characteristics, tumor characteristics, incidence and mortality were obtained from the SEER database from 2010 to 2020. We identified 23,278 individuals aged > 18 with confirmed diagnosis of all histologic subtypes of metastatic CRC (M1 on TNM stage) using ICD-O-3 site code C180, C182-9, C209 and histology codes: 8000, 8010, 8012, 8013, 8020-2, 8031-33, 8041, 8045, 8070-2, 8083, 8123-4, 8140, 8144-45, 8201, 8210-11, 8213, 8220-1, 8240, 8243-46, 8249, 8253, 8255, 8260-3, 8261-3, 8265, 8310, 8323, 8480-1, 8490, 8507, 8510, 8550, 8560, 8570, 8574, 8936, 8980. OS distributions and CCS were conducted using the Kaplan-Meier method and log-rank test was used to assess differences between mEO-CRC and mAO-CRC. Cox regression model used to assess associations between variables. Results: mEO-CRC constituted 17.79% of the cases, while 82.21% were mAO-CRC. Most patients with mEO-CRC were between 45-49 years old (47.66%), males (52.16%), white (72.57%), with histology of adenocarcinoma (87.30%). Left colon tumors were most prevalent in both groups (40.26%), but higher among mEO-CRC than in mAO-CRC (49.63% vs 38.23%, p < 0.001). mEO-CRC were more likely to receive chemotherapy (87.23% vs. 66.66%, p < 0.001) and radiotherapy (14.92% vs. 9.51%, p < 0.001), while surgery was similar in both groups (87.71% vs. 88.52%, p = 0.140). Patients with mEO-CRC had a higher OS (HR: 1.53, CI 95% 1.47-1.59, p < 0.001), as well as a higher CSS (HR: 1.33, 95% CI: 1.27-1.39, p < 0.001) when compared to mAO-CRC. mEO-CRC also had a significantly better median overall survival (30 months vs. 18 months p < 0.001). Factors associated with worse OS include mAO-CRC (p < 0.001), mucinous adenocarcinoma (p < 0.001), male sex (p 0.003) and no surgical intervention (p < 0.001). Conclusions: Patients with mEO-CRC had better OS and CSS when compared to patients with mAO-CRC and were more likely to receive cancer-directed therapy which could be explained by the mEO-CRC cohort having a higher performance status, less comorbidities, and better tolerance to cancer-related therapy. Factors associated with worse OS and CSS are mAO-CRC, mucinous adenocarcinoma, male sex and lack of surgical intervention. Furthermore, it is crucial to continue studying potential candidates who would benefit from early CRC screening.

Neoadjuvant chemotherapy versus surgery plus adjuvant chemotherapy for locally advanced colon cancer: A meta-analysis of randomized controlled trials.

e15631 Background: The primary treatment for colon tumors is surgical resection, but the use of neoadjuvant chemotherapy (NAC) in managing locally advanced cases remains a subject of ongoing debate. We conducted a thorough meta-analysis, including randomized clinical trials (RCTs), to assess the oncological safety of neoadjuvant chemotherapy (NAC) in colorectal tumor patients. Methods: We systematically searched in PubMed, Scopus, Google Academic and Cochrane Library in January 2024 for studies that directly compared NAC versus surgery in patients with T3-4, N0-2, M0 colorectal cancer. We assessed overall survival (OS) and disease-free survival (DFS). We calculated odds ratios (ORs) and hazard ratios (HRs) using generic inverse variance in Review Manger 5.4. Heterogeneity was assessed using I² statistics. Results: We included seven RCTs, involving 4,391 patients. Among them, 53.5% underwent NAC, with a median age of 61.41 years and an average follow-up of 62.35 months. The comprehensive analysis revealed no statistically significant differences in 3-year OS (OR: 1.20, 95% CI: 0.91 to 1.59, p = 0.20), more than 2 years DFS (OR: 0.88, 95% CI: 0.37 to 2.13, p = 0.78) and five-year DFS (OR: 1.09, 95% CI: 0.83 to 1.43, p = 0.55). Employing a time-to-effect modeling approach, there was no significant difference in OS (HR: 1.04, 95% CI: 0.63 to 1.70, p = 0.88) or DFS (HR: 0.86, 95% CI: 0.7 to 1.06, p = 0.16); (Table 1). Conclusions: Our systematic review and meta-analysis of seven RCTs showed that neoadjuvant chemotherapy compared with surgery followed by adjuvant chemotherapy had similar overall survival and disease-free-survival in patients with locally advanced colon cancer. [Table: see text]

Correlation between metastatic site and immunotherapy efficacy in patients with advanced dMMR/MSI colorectal cancer: Real-World Italian multicentric retrospective study (Colon-MSI).

e15544 Background: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in metastatic colorectal cancer (mCRC) patients (pts) with microsatellite instability (MSI). The Colon-MSI study aimed to describe a cohort of MSI mCRC pts treated with ICIs before Italian pembrolizumab approval and to evaluate the efficacy, safety, and possible predictive factors of response in a real-world setting. Methods: We retrospectively collected data of pts with MSI mCRC treated with ICIs before June 30, 2023, in 16 Italian Cancer Centers. The OS was calculated from the diagnosis of metastatic disease, and the PFS from the beginning of ICIs. We explored the correlation between clinicopathological factors, survival outcomes, and treatment response. Results: Between January 2021 and June 2023, we reported 83 consecutive pts with data available. Among all, the median age was 61 years (23-86), 42 (51%) were female, and 45 (54%) had a ECOG PS 0; 35 (42%) pts were at stage IV at diagnosis, and 61 (74%) had right colon tumor site. The most common metastatic sites were liver (35%), lymph nodes (43%), peritoneum (31%), and lung (15%); 48 (58%) pts had a single metastatic site. 33 (39%) pts had a mucinous adenocarcinoma, 32 (39%) BRAF mutated, 32 (39%) RAS mutated, and 26% presented a Lynch syndrome. The majority of pts (69%) were pre-treated, and 26 pts (31%) received ICIs in first line. Nivolumab alone or plus Ipilimumab, and Pembrolizumab, were administered in 23 (28%), 3 (4%), and 57 (68%) pts, respectively. The median follow-up was 23 (1-65) months (m) and the median duration of treatment was 23 m (0-65) with 27 pts still ongoing. Treatment-related severe toxicities (G3 or G4) were observed only in 5.6% of pts. The median OS and PFS were not reached; the mean OS was 45.6 m (IC 95% 39.6-51.6) and the mean PFS was 38.8 m (IC 95% 32.5-45.1). Complete response (CR) was observed in 20 pts (24%), partial response (PR) in 28 (34%), stable disease (SD) in 19 (23%) and progression disease (PD) in 16 (19%). Overall response (ORR) was observed in 48 pts (57.8%; 95 %IC 0.31- 0.53), and disease control rate in 67 pts (80.7%; 95% IC 0.11– 0.29). Lung metastatic site was associated with poorer outcome in terms of OS (p = 0.001, HR 3.88 IC 95% 1.7-8.9), PFS (p = 0.045 HR = 2.31 IC95% 1-5.2), and ORR (p = 0.015 OR = 6.19 IC95% 1.4-26.9). Significantly worse PFS was also observed in pts with liver metastasis (p = 0.009 HR = 2.5 IC 95% 1.3-4.9). Conclusions: Our data confirm that ICIs are effective and well-tolerated treatment in MSI mCRC pts, with long-term clinical outcomes reported. These results suggest an unfavorable correlation between lung and liver metastasis and the ICI response. Further biomolecular analysis will be provided in the future.

Single-Cell Profiling Reveals the Impact of Genetic Alterations on the Differentiation of Inflammation-Induced Murine Colon Tumors.

Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (MinApcΔ716/+) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAFV600E mutation (BRAFF-V600ELgr5tm1(Cre/ERT2)CleMinApcΔ716/+, BLM) or knocking out Msh2 (Msh2LoxP/LoxPVil1-creMinApcΔ716/+, MSH2KO) in the Min model altered colon tumor differentiation. Using single-cell RNA sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single-cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the tumor stem cell population. Interestingly, the tumor stem cell population of BLM tumors had revival colon stem cell characteristics with low WNT signaling and an increase in RevCSC marker gene expression. In contrast, MSH2KO tumors were characterized by an increased tumor stem cell population that had higher WNT signaling activity compared to Min tumors. Furthermore, overall BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we identified additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer.

RAS/RAF mutations and microsatellite instability status in primary colorectal cancers according to HER2 amplification.

HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established. In this study, we assessed the prevalence of HER2 amplification and microsatellite instability (MSI) status of 992 patients with primary CRC. In addition, molecular alterations of HER2 amplified and unamplified CRCs were examined and compared by next-generation sequencing. HER2 amplifications were found in 41 (4.1%) of 992 primary CRCs. HER2 amplification was identified in 1.0% of the right colonic tumors, 5.1% of the left colonic tumors, and 4.8% of the rectal tumors. Approximately 95% of HER2 amplification was observed in the left colon and rectum. Seven (87.5%) of eight metastatic tumors showed HER2 amplification. Most clinicopathologic features were unrelated to HER2 amplification except tumor size and MSI status. All 41 HER2 amplified CRCs were microsatellite stable. In a molecular analysis of frequently identified somatic mutations in CRCs, HER2 amplified CRCs showed a lower rate of KRAS mutations (24.4%) but a higher rate of TP53 mutations (83%) than unamplified CRCs. No BRAF and NRAS mutations were identified in HER2 amplified CRCs. Our study suggests that HER2 amplified CRCs are mutually exclusive of MSI and harbor less frequent KRAS/NRAS/BRAF mutations but frequent T53 mutations.

Risk factor analysis and nomogram development and verification for medullary carcinoma of the colon using SEER database

Medullary Carcinoma of the Colon (MCC) is a rare histological subtype of colon cancer, and there is currently no recognized optimal treatment plan for it, with its prognosis remaining unclear. The aim of this study is to analyze the independent prognostic factors for MCC patients and develop and validate nomograms to predict overall survival (OS). A total of 760 patients newly diagnosed with MCC from 2004 to 2020 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. All patients were randomly allocated to a training group and a validation group in a 7:3 ratio. Univariate and multivariable Cox regression analyses were conducted to identify prognostic factors and construct nomograms. The nomogram prediction model was evaluated and validated using receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). The study found that elderly women are more susceptible to MCC, and the ascending colon and cecum are the most common sites of involvement. MCC is poorly differentiated, with stages II and III being the most common. Surgery is the primary treatment for MCC. The prognosis for patients with stage IV MCC is poor, with a median survival time of only 10 months. Independent prognostic factors for MCC include age, N stage, M stage, surgery, chemotherapy, and tumor size. Among them, age < 75 years and completion of chemotherapy were protective factors for colon medullary carcinoma, while N2 (HR = 2.18, 95%CI 1.40–3.38), M1 (HR = 3.31, 95%CI 2.01–5.46), no surgery (HR = 27.94, 95%CI 3.69–211.75), and tumor diameter > 7 cm (HR = 1.66, 95%CI 1.20–2.30) were risk factors for colon medullary carcinoma. The results of ROC, AUC, calibration curves, and DCA demonstrate that the nomogram prediction model exhibits good predictive performance. We have updated the demographic characteristics of colon medullary carcinoma and identified age, N staging, M staging, surgery, chemotherapy and tumor size as independent prognostic factors for colon medullary carcinoma. Additionally, we have established nomograms for prognostic prediction. These nomograms can provide personalized predictions and serve as valuable references for clinical decision-making.

Early-Onset Colorectal Cancer-A Retrospective Study from a Tertiary Referral Hospital in Romania.

Early-onset colorectal cancer emerges as a distinctive clinical and biological entity and is generally defined as the onset of colon or rectal neoplasia before the age of 50. Several reports describe an increasing incidence worldwide of colorectal cancers occurring in individuals younger than 50 years, along with particular histologic and molecular features. Although heredity may be an explanation in some cases with young-onset colorectal cancer, other driving factors remain partially unknown. The present study explores demographic, clinical, and pathological features within a group of patients diagnosed with colorectal cancer before the age of 50. It is a retrospective survey based on data collected between 2017 and 2023 within three surgical departments from a tertiary Romanian hospital. The clinical and pathological features we identified (later-stage disease, distal colon tumor localization, mucinous histology) are mainly superimposed with the existing data in the literature regarding this pathology. In order to lower the burden that colorectal neoplasia diagnosed in the young implies, a change of paradigm should be made in terms of establishing effective and targeted screening programs but also in the direction of enhancing complex clinical, pathological, and molecular diagnosis.

Gain-Type Aneuploidies Influence the Burden of Selective Long Non-Coding Transcripts in Colorectal Cancer.

Chromosomal instability is a hallmark of colorectal carcinogenesis and produces an accumulation of different forms of aneuploidies or broad copy number aberrations. Colorectal cancer is characterized by gain-type broad copy number aberrations, specifically in Chr20, Chr8q, Chr13 and Chr7, but their roles and mechanisms in cancer progression are not fully understood. It has been suggested that broad copy number gains might contribute to tumor development through the so-called caricature transcriptomic effect. We intend to investigate the impact of broad copy number gains on long non-coding RNAs' expression in colorectal cancer, given their well-known role in oncogenesis. The influence of such chromosomal aberrations on lncRNAs' transcriptome profile was investigated by SNP and transcriptome arrays in our series of colorectal cancer samples and cell lines. The correlation between aneuploidies and transcriptomic profiles led us to obtain a class of Over-UpT lncRNAs, which are transcripts upregulated in CRC and further overexpressed in colon tumors bearing specific chromosomal aberrations. The identified lncRNAs can contribute to a wide interaction network to establish the cancer driving effect of gain-type aneuploidies.

SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer.

Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether-linked phosphatidylethanolamine (ePE) and a marked increase in ether-linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate-15-lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI-knockdown cells, while SELENOI overexpression can partially rescue GPX4-knockdown-induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.

Evaluation of the Immunohistochemical Scoring System of CDX2 Expression as a Prognostic Biomarker in Colon Cancer.

Encoded by the CDX2 homeobox gene, the CDX2 protein assumes the role of a pivotal transcription factor localized within the nucleus of intestinal epithelial cells, orchestrating the delicate equilibrium of intestinal physiology while intricately guiding the precise development and differentiation of epithelial tissue. Emerging research has unveiled that positive immunohistochemical expression of this protein shows that the CDX2 gene exerts a potent suppressive impact on tumor advancement in colorectal cancer, impeding the proliferation and distant dissemination of tumor cells, while the inhibition or suppression of CDX2 frequently correlates with aggressive behavior in colorectal cancer. In this study, we conducted an immunohistochemical assessment of CDX2 expression on a cohort of 43 intraoperatively obtained tumor specimens from patients diagnosed with colon cancer at Colțea Clinical Hospital in Bucharest, between April 2019 and December 2023. Additionally, we shed light on the morphological diversity within colon tumors, uncovering varying differentiation grades within the same tumor, reflecting the variations in CDX2 expression as well as the genetic complexity underlying these tumors. Based on the findings, we developed an innovative immunohistochemical scoring system that addresses the heterogeneous nature of colon tumors. Comprehensive statistical analysis of CDX2 immunohistochemical expression unveiled significant correlations with known histopathological parameters such as tumor differentiation grades (p-value = 0.011) and tumor budding score (p-value = 0.002), providing intriguing insights into the complex involvement of the CDX2 gene in orchestrating tumor progression through modulation of differentiation processes, and highlighting its role in metastatic predisposition. The compelling correlation identified between CDX2 expression and conventional histopathological parameters emphasizes the prognostic significance of the CDX2 biomarker in colon cancer. Moreover, our novel immunohistochemical scoring system reveals a distinct subset of colon tumors exhibiting reserved prognostic outcomes, distinguished by their "mosaic" CDX2 expression pattern.

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Colonic Cancer in Occlusion: A Case Report of 70 Patients Experience of the Visceral Surgery Department at the Moulay Ismail Military Hospital in Meknes, Sidi Mohamed Ben Abdallah University in Fez

Occlusive colon cancer is a serious condition, as it combines two very serious pathologies: cancer and acute intestinal obstruction. Colon cancer is a malignant proliferative neoformation developed at the expense of the colonic wall. Colonic obstruction is defined as the interruption of normal intestinal transit, and represents the mode of revelation in 8 to 29% of colon cancers. Occlusion is the most common complication of colonic cancer, either as a result of the disease or as it progresses, accounting for 15-30% of cases. Occluded colon cancer poses a twofold problem:  On the one hand, occlusion and its potential repercussions, particularly of a general or upstream intestinal nature.  On the other hand, it reveals a late diagnosis most often associated with a locally advanced or metastatic tumour. Our study concerns 70 cases of colonic cancer in occlusion diagnosed and treated in the visceral surgery department of the Moulay Ismail Military Hospital in Meknes, over 5 years from 01 January 2019 to 31 December 2023. The aims of our retrospective study are:  Evaluate the proportion of this complication that is indicative of colonic tumour pathology.  To review the range of surgical and non-surgical techniques available.  To establish guidelines for dealing with this type of complication in order to minimise morbidity and mortality. Our series includes 46 men and 24 women with a sex ratio of 1.9 aged between 35 and 86 years, who presented to the emergency department after an average delay of 07 days with extremes of 03 days and 08 days, with an occlusive syndrome (78.6%), sub-occlusive syndrome (21.4%), abdominal pain (95.7%), transit disorders (82.9%), vomiting (75.7%) and rectal bleeding (72.9%). The clinical examination revealed weight loss in 49 patients (70%); abdominal distension in all our patients (100%); and an empty rectal ampulla in all our patients (100%). All our patients underwent PSA, which revealed colonic NHA in 81.4% of cases, .......

Examining variations in body composition among patients with colorectal cancer according to site and disease stage

Patients with colorectal cancer (CRC) often exhibit changes in body composition (BC) which are associated with poorer clinical outcomes. Many studies group colon and rectal cancers together, irrespective of staging, potentially affecting assessment and treatment strategies. Our study aimed to compare BC in patients with CRC focusing on tumor location and metastasis presence. A total of 635 individuals were evaluated, with a mean age of 61.8 ± 12.4 years and 50.2% female. The majority had rectal cancer as the primary cancer site (51.0%), and 23.6% had metastatic disease. The first regression model showed tumor site and metastasis as independent factors influencing skeletal muscle (SM), skeletal muscle index (SMI), and visceral adipose tissue variability (all p values < 0.05). The second model, adjusted for BMI, indicated tumor site as the primary factor affecting SMI variations (adjusted R2 = 0.50 p < 0.001), with colon tumors inversely associated with SM (standardized β − 2.15(− 3.3; − 0.9) p < 0.001). A third model, considering all the confounders from the directed acyclic graphs, was constructed and the found association remained independent. Our findings highlight significant BC variations in patients with CRC, influenced by tumor location and metastases presence, underscoring the need for location-specific assessment in CRC management.

A Tumor Environment-Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer.

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG2000-SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.

The role of endoluminal surgery in a colorectal surgical practice. A global view

Patients with large colorectal polyps or mucosal neoplasms not amenable to standard polypectomy have traditionally undergone colon resection. However, minimally invasive surgical techniques have gained popularity over the past two decades. Transanal approaches such as transanal endoscopic microsurgery and transanal minimally invasive surgery have enabled surgeons to treat mucosal neoplasms located in the rectum. Later on, robotic surgery was incorporated into the transanal approach. Meanwhile, there was no such treatment option for more proximal colonic neoplasms then, and endoscopic mucosal resection and endoscopic submucosal dissection emerged in Japan to provide resection in treating such proximal lesions. Nowadays, all procedures performed in a hollow organ integrating standard surgical (dissection, resection, suturing, homeostasis) and oncological principles (en-bloc resection, clean surgical margins) are merged under endoluminal surgery. Within the scope of this review, we aimed to elaborate an overview of the role of endoluminal surgery in daily colorectal surgery practice while focusing on endoscopic procedures.

Cytotoxic prenylated phenols of false indigo-bush (Amorpha fruticosa L.)

This study employed the MTT assay to assess the cytotoxicity of one flavan and two stilbene derivatives isolated from the false indigo-bush (Amorpha fruticosa L.) fruits: 5,7-dihydroxy-8-geranylflavanone (1), 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl (2), and 2-carboxy-3-hydroxy-4-prenyl-5-methoxybibenzyl (3). The examined compounds reduced the survival of human cervical and colon tumour cells (HeLa, HT-29, HCT-116, and LS174) with IC50 values ranging from 10.55 to 147.09 μg/mL, except for 1, which did not affect LS174 cells within the tested concentrations. The highest activity was observed for 1 against HeLa cells, and 1 also exhibited the weakest effect against normal foetal lung fibroblasts (IC50 = 166.11 μg/mL), demonstrating good potency and selectivity. Stilbenes 2 and 3 proved efficacious, but lacked selectivity compared to 1. Our findings revealed the cytotoxicity of false indigo-bush constituents, justifying further mechanistic and in vivo investigations, particularly on 5,7-dihydroxy-8-geranylflavanone, which displayed considerable in vitro anticancer capacity and a potentially favourable safety profile.

Norepinephrine may promote the progression of Fusobacterium nucleatum related colorectal cancer via quorum sensing signalling

ABSTRACT Fusobacterium nucleatum (F. nucleatum) is closely correlated with tumorigenesis in colorectal cancer (CRC). We aimed to investigate the effects of host norepinephrine on the carcinogenicity of F. nucleatum in CRC and reveal the underlying mechanism. The results revealed that both norepinephrine and bacterial quorum sensing (QS) molecule auto-inducer-2 (AI-2) were positively associated with the progression of F. nucleatum related CRC (p < 0.01). In vitro studies, norepinephrine induced upregulation of QS-associated genes and promoted the virulence and proliferation of F. nucleatum. Moreover, chronic stress significantly increased the colon tumour burden of ApcMin/+ mice infected with F. nucleatum (p < 0.01), which was decreased by a catecholamine inhibitor (p < 0.001). Our findings suggest that stress-induced norepinephrine may promote the progression of F. nucleatum related CRC via bacterial QS signalling. These preliminary data provide a novel strategy for the management of pathogenic bacteria by targeting host hormones-bacterial QS inter-kingdom signalling.