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BACKGROUND: The present study aimed to validate the accuracy of a tumor-specific antibody to target liver metastases of colorectal cancer. METHODS: A humanized anti-CEA antibody conjugated to a fluorescent dye (M5A-IR800) was tested for targeting human colorectal cancer liver metastases (CRLMs) expressing luciferase in an orthotopic mouse model. Orthotopic mouse models of CRLMs were established by implanting fragments of a luciferase-expressing human colorectal cancer cell line, LS174T, in the liver of nude mice. Mice received 50 µg M5A-IR800 72 h prior to imaging. To test co-localization, bioluminescence imaging was performed using D-luciferin, which was given via intraperitoneal injection just prior to imaging. RESULTS: Tumors were able to be visualized non-invasively through the skin with the luciferase-luciferin signal. Intra-abdominal imaging showed accurate labeling of CRLMs with M5A-IR800, which co-localized with the luciferase-luciferin signal. CONCLUSIONS: The present results validate the accuracy of a tumor-specific anti-CEA antibody in targeting liver metastases of colorectal cancer.

Simple Summary: This study focused on the identification of rare variants that are associated with high-risk colorectal cancer (CRC) from the Middle Eastern region. This study analyzed DNA samples from 146 patients with CRC and from 1395 healthy individuals. We identified rare inactivating variants in the APC gene that are strongly linked to CRC, increasing the risk approximately 60-fold. Other significant genes harboring rare damaging variants were also identified. These results may have implications for genetic counseling and the early detection of CRC in the Middle Eastern population. Background: Colorectal cancer (CRC) displays a complex pattern of inheritance. It is postulated that much of the missing heritability of CRC is enriched in high-impact rare alleles, which might play a crucial role in the etiology and susceptibility of CRC. Methods: In this study, an exome-wide association analysis was performed in 146 patients with high-risk CRC in the Middle East and 1395 healthy controls. The aim was to identify rare germline variants in coding regions and their splicing sites associated with high-risk CRC in the Middle Eastern population. Results: Rare inactivating variants (RIVs) in APC had the strongest association with high-risk CRC (6/146 in cases vs. 1/1395 in controls, OR = 59.7, p = 5.13 × 10−12), whereas RIVs in RIMS1, an RAS superfamily member, were significantly associated with high-risk CRC (5/146 case vs. 2/1395 controls, OR = 24.7, p = 2.03 × 10−8). Rare damaging variants in 17 genes were associated with high-risk CRC at the exome-wide threshold (p < 2.5 × 10−6). Based on the sequence kernel association test, nonsynonymous variants in six genes (TNXB, TAP2, GPSM3, ADGRG4, TMEM229A, and ANKRD33B) had a significant association with high-risk CRC. RIVs in APC—the most common high-penetrance genetic factor—were associated with patients with high-risk CRC in the Middle East. Individuals who inherited APC RIVs had an approximate 60-fold increased risk of developing CRC and were likely to develop the disease earlier. Conclusions: We identified new potential CRC predisposition variants in other genes that could play a role in CRC inheritance. However, large collaborative studies are needed to confirm the association of these variants with high-risk CRC. These results provide information for counseling patients with high-risk CRC and their families in our population. [ABSTRACT FROM AUTHOR]

Simple Summary: Various cancer therapies are often ineffective for advanced metastatic liver disease. While immunotherapy can be effective in some cases, it does not provide significant benefits for metastatic cancer in the liver. CBL0137 is an experimental drug that helps form a special type of DNA called Z-DNA, which may help boost the body's immune response against tumors. We investigated how CBL0137 affects metastatic liver tumor models from colon (CT26) and breast (4T1) cancers focusing on how it triggers immune responses. The results showed that CBL0137 hepatic arterial infusion (HAI) enhanced anti-tumor effects by depleting immune-suppressing cells while preserving effector T cells. Combining CBL0137 HAI with conventional immunotherapy improved survival in 4T1 tumors but not in CT26 tumors, highlighting the importance of targeting specific immune cell populations for effective treatment. Background: Surgery, chemotherapy, and radiation often have limited utility for advanced metastatic disease in the liver, and despite its promising activity in select cancers, PD-1 blockade therapy similarly has minimal benefit in this setting. Curaxin, CBL0137, is an experimental anti-cancer drug that disrupts the binding of DNA to histones, destabilizes chromatin, and induces Z-DNA formation which may stimulate anti-tumor immune responses. Methods: Murine cell lines of colon (CT26) and breast (4T1) cancer were interrogated for survival and CBL0137-associated DNA changes in vitro. Immunocompetent models of liver metastases followed by CBL0137 hepatic arterial infusion (HAI) were used to examine in vivo tumor cell DNA alterations, treatment responses, and the immune contexture associated with CBL0137, both alone and in combination with anti-PD-1 therapy. Results: CBL0137 induced immediate changes to favor tumor cell death in vitro and in vivo with an efficient tumor uptake via the HAI route. Toxicity to CBL0137 was minimal and anti-tumor treatment effects were more efficient with HAI compared to intravenous delivery. Immune effects were pronounced with CBL0137 HAI with concurrent depletion of a specific population of myeloid-derived suppressor cells and maintenance of effector T cell populations. Conclusions: Combination of CBL0137 HAI with PD-1 blockade improved survival in 4T1 tumors but not in CT26 tumors, and therapeutic efficacy relies on the finding of simultaneous and targeted depletion of myeloid-derived suppressor cells and skewing of T cell populations to produce synergy with PD-1 blockade therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Copper is a vital trace mineral supporting many body functions by acting as a cofactor for essential enzymes in energy production and antioxidant defense. It is mainly absorbed in the small intestine, and both its deficiency and excess can lead to serious health issues like neurological disorders and organ damage. In colorectal cancer (CRC), disruptions in copper metabolism play a significant role in tumor development and spread. A high copper concentration may facilitate cancer cell proliferation, angiogenesis, and metastasis. A newly discovered form of cell death called "cuproptosis" refers to a mitochondrial pathway of cell death triggered by excessive copper exposure and subsequent proteotoxic stress. Cuproplasia describes copper-dependent cell growth and proliferation, including hyperplasia, metaplasia, and neoplasia. Targeting copper concentration in the body is emerging as a promising strategy for CRC treatment. Therapies that reduce copper concentration using chelators or increase copper-induced cell death using ionophores have shown potential to inhibit tumor growth and enhance the effectiveness of existing treatments. Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30–40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome (LS) is an autosomal dominant disorder linked to increased risks of colorectal and endometrial cancers, caused by pathogenic variants in MMR genes (MLH1, MSH2, MSH6). In a cohort of 42,828 participants from the Taiwan Precision Medicine Initiative (TPMI), 89 individuals carried MMR gene variants: 25% MLH1, 53% MSH2, and 22% MSH6, with a prevalence of 1 in 481. Cancer incidence rates were 40.9% for MLH1, 29.8% for MSH2, and 40% for MSH6 carriers. Colonoscopy screening revealed no significant differences in polyp prevalence compared to controls. The study underscores the need for improved LS diagnosis and surveillance in the Taiwanese population. Lynch syndrome (LS) is an autosomal dominant disorder characterized by increased risks of colorectal and endometrial cancers. LS is defined by pathogenic variants in mismatch repair (MMR) genes, including MLH1, MSH2, and MSH6. Data on the prevalence and associated cancer risks of LS in the Han Chinese population remain limited. In this study, using a broad biobank approach through the Taiwan Precision Medicine Initiative (TPMI), we identified LS-associated MMR gene variants within a cohort of 42,828 participants from a Taiwanese medical center. A total of 89 individuals were found to carry pathogenic MMR variants: MLH1 (n = 22, 25%), MSH2 (n = 47, 53%), and MSH6 (n = 20, 22%). The overall prevalence of MMR variants was calculated, and cancer incidence rates among carriers were determined. The prevalence of MMR variants in the study population was 1 in 481. The distribution of MLH1, MSH2, and MSH6 variants were 24.7%, 52.8%, and 22.5%, respectively. Cumulative cancer incidence rates of carriers were 40.9% for MLH1 carriers, 29.8% for MSH2, and 40% for MSH6. Among the 19 individuals who underwent colonoscopy screening, the prevalence of polyps was similar to that of the control group (adenoma detection rate: 32% vs 26%, p = 0.585). A meticulous analysis of the detected polyps in seven participants, considering factors such as location, size, morphology, and pathological features, showed no significant differences from controls. A significant cancer risk is associated with LS-related MMR variants in the Taiwanese population. The apparent under diagnosis of LS highlights the urgent need for enhanced surveillance and genetic counseling in this demographic. Our findings suggest that adjustments in the current screening protocols may be warranted to better identify and manage at-risk individuals. [ABSTRACT FROM AUTHOR]

Simple Summary: The tyrosine kinase TYK2 was assessed in this study using digital image analysis of archived formalin-fixed paraffin-embedded blocks. The immunohistochemical expression of TYK2 was significantly weaker in cancer than in normal control tissues, and its high predictive value allowed its use as a biomarker in the diagnosis of CRC. The obtained results were additionally verified by other molecular methods, which confirmed the presence of a higher protein level of the kinase TYK2 and a higher TYK2 fluorescence intensity in normal colonic mucosa than in CRC tissue. Independently assessed TYK2 immunoreactivity in fresh colonic biopsies from CRC and ulcerative colitis (UC) patients showed that the kinase distribution was greater in UC than in cancer. Background/Objectives: The aim of this study was to examine the expression of TYK2 in colorectal cancer (CRC) and to determine the potential diagnostic and prognostic significance of this kinase. Methods: Digital image analysis was performed to assess immunohistochemical TYK2 reactivity. Results: There were significant differences for all positive pixels between CRC and normal colonic mucosa, with higher TYK2 expression levels observed in surgical margins than in adenocarcinomas (p = 0.0004). Paired t tests showed elevated immunoreactivity for overall TYK2 expression in matched pairs of CRC with adjacent surgical margins (p < 0.0001). Higher percentages of weak (p < 0.0001) and strong pixels (p = 0.0260) were detected in normal colonic mucosa than in cancer tissues. To distinguish cancer from normal intestinal mucosa, the following cutoffs for the TYK2 immune score were found: 29.5% for all cases and 31% for matched pairs. Tumor budding (Bd) was negatively correlated with the percentage of strong pixels for TYK2 (ρ = −0.270, p = 0.0096). The percentage of strong pixels was significantly elevated for the T parameter (p = 0.0428). There was a positive correlation between the number of involved lymph nodes and weak pixels (ρ = 0.239, p = 0.0242). Immunofluorescence staining showed significantly higher signal intensities in colonic mucosa than in CRC. The protein level of TYK2 was significantly higher in controls than in cancer tissues. TEM imaging showed lower levels of TYK2 in cancer than in ulcerative colitis. Conclusions: TYK2 protein expression may bring diagnostic value in patients diagnosed with CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the most commonly diagnosed cancers worldwide and is the second leading cause of cancer-related deaths. In the last decade, significant advances have been made in the development of cell-based models of disease, including for culturing and expanding cells derived from patient biopsy tissue. These advances have led to the development of intestinal organoids, 3D cellular models of the colon, that more accurately represent the disease state and hold the potential to improve our understanding of disease processes. Furthermore, increasing the complexity of these models to include important components, such as the gut microbiome and the stromal compartment with immune cells and vasculature, will provide deeper insight into individual drug responses and lead to better patient outcomes in the future. Despite improvements in participation in population-based screening programme, colorectal cancer remains a major cause of cancer-related mortality worldwide. Targeted interventions are desirable to reduce the health and economic burden of this disease. Two-dimensional monolayers of colorectal cancer cell lines represent the traditional in vitro models for disease and are often used for diverse purposes, including the delineation of molecular pathways associated with disease aetiology or the gauging of drug efficacy. The lack of complexity in such models, chiefly the limited epithelial cell diversity and differentiation, attenuated mucus production, lack of microbial interactions and mechanical stresses, has driven interest in the development of more holistic and physiologically relevant in vitro model systems. In particular, established ex vivo patient-derived explant and patient-derived tumour xenograft models have been supplemented by progress in organoid and microfluidic organ-on-a-chip cultures. Here, we discuss the applicability of advanced culturing technologies, such as organoid systems, as models for colorectal cancer and for testing chemotherapeutic drug sensitivity and efficacy. We highlight current challenges associated with organoid technologies and discuss their future for more accurate disease modelling and personalized medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: This article stems from my research project on the role of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in the treatment of peritoneal carcinoma originating from colorectal cancer. Our aim was to assess the existing literature regarding the impact, benefits, and risks associated with PIPAC for patients. The results are encouraging and suggest that PIPAC is a safe option for patients. However, monitoring the progression of peritoneal carcinomatosis and evaluating the effects of PIPAC can be challenging. These findings reinforce the need for a randomized study to better define the role of PIPAC in treating colorectal peritoneal carcinomatosis. By clarifying the implications of this innovative therapy, this research aims to provide valuable insights for clinicians, patients, and policymakers, ultimately enhancing patient care and treatment outcomes. Introduction: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) consists of the administration of aerosolized chemotherapy into the abdominal cavity of patients suffering from peritoneal carcinomatosis. Our aim was to review the evidence supporting PIPAC in patients with peritoneal carcinomatosis from colorectal cancer. Methods: A systematic review was performed in accordance with the 2020 PRISMA guideline. MEDLINE and CENTRAL were searched using combinations of terms including "Peritoneal carcinomatosis", "Peritoneal metastasis", "PIPAC", "Pressurized intraperitoneal aerosol chemotherapy" and "Colorectal cancer". Original studies, in English, including patients treated with PIPAC for colorectal peritoneal carcinomatosis, were considered eligible. Case reports, non-English or French language articles and secondary analyses were excluded. Results: A total of 385 articles were screened and 374 articles were excluded, leaving 11 publications for inclusion in the qualitative analysis. The included studies totalized 949 patients who received PIPAC for peritoneal carcinomatosis due to colorectal cancer. The median peritoneal carcinomatosis index (PCI) ranged from 10 to 31. In all studies, the complete PIPAC protocol was achieved with an average of two to three 3 PIPAC sessions per patient. Oxaliplatin (OX) was used as a chemotherapeutic agent in all studies and could be associated with intravenous 5-FU and leucovorin. Most post-operative adverse events were recorded as mild to moderate with no intraoperative complications. Only four studies reported a decrease in the average PCI score for 50% of the patients. Median overall survival ranged from 8 to 37.8 months. Quality of life indicators were stable between PIPAC-OX cycles with a small but not statistically significant trend of improvement of most functional scales. Conclusions: PIPAC for peritoneal carcinomatosis from colorectal origin is feasible, safe and tolerable. Its impact on survival outcomes or quality of life remains to be demonstrated by randomized trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Molecular biomarkers have gained a significant role not only in determining the prognosis but also the diagnosis of CRC in high-risk populations. Translational studies that evaluate the utility of molecular markers are fundamental to timely detection and prognosis stratification for treatment decisions in CRC. This study included a cohort of forty-nine CRC patients from the National Cancer Institute, Mexico, to evaluate the clinical utility of miRNA expression levels in CRC. We found that miR-3065-5p and miR-26a-5p levels discerned between CRC and non-tumoral tissues, and that high levels of miR-3065-5p were associated with better outcomes in CRC patients. Overall, miR-3065-5p expression levels and clinical stage remained as predictor factors of OS. Finally, the algorithm PROMIR-C (which included clinical and miR-3065-5p expression levels) was developed as a website to improve treatment decision-making and prognosis assessment. Altogether, these findings support the clinical utility of miR-26a-5p and miR-3065-5p in the diagnosis and prognosis of CRC. Background/Objectives: The prognosis of colorectal cancer (CRC) is mainly based on the clinical stage; however, CRC is considered a complex disease due to its molecular heterogeneity. The development of novel biomarkers to improve patients' diagnosis and prognosis remains fundamental. Methods: A cohort of forty-nine CRC patients from the National Cancer Institute of Mexico was included to collect clinical and miRNA expression data. The expression of a group of miRNAs was compared between CRC and non-tumoral adjacent tissues. Prognosis assessment considering each miRNA expression was tested using Kaplan–Meier survival curves and Cox regressions. Statistical significance was defined as p ≤ 0.05. Trial registration: Retrospective study No.2021/046. Results: miR-3065-5p and miR-26a-5p expression differed between non-tumoral adjacent and tumoral tissues (p = 0.02). In terms of overall survival (OS), patients with low expression of miR-3065-5p had a median OS of 70 months, while patients with high levels did not reach the median OS (p = 0.041). Male patients with low expression of this miRNA had an OS of 70 months, whereas patients with high levels did not reach the median OS (p = 0.050). Under uni-multivariate analysis, clinical stage (HR: 1.30, CI 1.23–2.30; p: 0.001) and low levels of miR-3065-5p (HR: 1.30, CI 1.23–2.30; p: 0.001) were determined as predictor factors of OS. To this end, we designed the "Prognosis miRNAs assessment in cancer" (PROMIR-C) algorithm, which integrated clinical features with miR-3065-5p expression levels. Conclusions: These findings support the clinical utility of miR-26a-5p and miR-3065-5p in the diagnosis and prognosis of CRC. PROMIR-C is a fundamental tool for clinicians in treatment decision-making, prognosis assessment, and outcome of CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the benefits of stool-based tests for colorectal cancer screening, the return rate is low. In this study, we tested if adding a tailored, one-page educational flyer to the mailed stool kits targeted at rural Midwestern residents in the USA improved the kit return rates. Overall, there was no significant difference in return rate between the groups that did and did not receive the flyer. However, females and older participants were more likely to return the kits compared to males and younger participants. To improve the kit return rates of male and younger participants, future programs should consider how the content and design of the flyer can be more closely tailored to the audience's needs and preferences as well as how the flyer can be combined with other approaches (e.g., reminders). Background/Objectives: Stool-based tests, such as the fecal immunochemical test (FIT), have been widely used for increasing colorectal cancer (CRC) screening. Small media, such as printed materials or flyers, are known to be an effective intervention to increase CRC screening by fecal tests. However, more evidence is needed to determine whether such small media are effective in improving screening uptake of a mailed FIT intervention targeted at rural populations in the USA. Methods: In this randomized study, 1230 FIT kits were mailed from July to December 2022 to rural Nebraskans aged 45–74 who were not up to date on CRC screening. Half of the participants (n = 608) also received a tailored, one-page, gender-specific educational flyer created based on focus groups with rural residents. Logistic regression was used to determine predictors of returning the FIT. Results: Study participants were predominantly female (76%), non-Hispanic White (83%), and within the age group of 55–64 (43%). Overall, 192 (15.6%) kits were returned (16.1% from the flyer group; 15.1% from the no-flyer group). However, we found no significant differences between the flyer and no-flyer groups (Adjusted Odds Ratio [AOR]: 1.21; 95% CI: 0.88–1.66). Females (AOR: 1.78; 95% CI: 1.19–6.14) and the oldest (65–74) age group (AOR: 5.03; 95% CI: 2.78–8.47) were more likely to return FIT kits than males and the youngest (45–54) age group. Conclusions: A tailored educational flyer was not effective in improving the CRC-screening-rate-by-mailed-FIT approach for rural populations. Future research should explore the content, timing, and mode of delivery of educational interventions as well as other multi-component strategies to improve screening rates. Public health officials might also consider developing strategies targeted at males and younger (45–54) age groups. [ABSTRACT FROM AUTHOR]

Simple Summary: This study reports the results of genetic testing to identify germline variants in the main genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, STK11) associated with hereditary polyposis syndromes in 75 index cases with colorectal polyps and a personal/family history of cancer that had been referred to genetic counseling at the Medical Genetics Unit of the National Institute of Gastroenterology "Saverio de Bellis", Castellana Grotte, Bari, Italy. In the screened patients, some of which did not meet the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, we identified 14 pathogenic variants and 6 variants of uncertain significance. Of note, by combining the results of multigene panel tests with the evaluation of patients' clinical phenotype and family history, we were able to confirm the diagnosis of hereditary polyposis syndrome for pathogenic variant carriers and assign them to specific clinical surveillance and management programs. Background: Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. Methods: A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, and STK11) in order to identify germline genetic variants. Results: In the screened index cases, we found 14 pathogenic variants involving APC, MUTYH, SMAD4, and STK11 and 6 variants of uncertain significance involving APC, BMPR1A, and SMAD4. In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. Conclusions: Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients' clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Somatostatin, a growth hormone-release-inhibiting peptide (SST/SRIF), is a widely distributed multifunctional cyclic peptide that acts by activating G protein-coupled receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. The current study showed significant differences in the expression of SST and all SSTRs in the tissue material of sporadic CRC, control colorectal mucosa, and in lymph node metastases from the same patients. A significant dependence of the immunoexpression of SST1-5 on the cellular localization pattern was proved. Differences and/or significant correlations of SRIF system components with clinicopathological data (age, histological subtype of CRC, TNM parameters, Ki-67 antigen, and laboratory tests) were found. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. Background/Objectives: Colorectal cancer (CRC) is one of the most common human malignancies worldwide. The somatotropin-releasing inhibitory factor/somatostatin (SRIF/SST) acts through activation of five membrane receptors (SSTRs, SST1-5). The diagnostic and prognostic role of these peptides in sporadic CRC remains unclear. This study aimed to determine the role of tissue expression of SST and all SSTRs in the pathogenesis, diagnosis, and prognosis of sporadic CRC. Methods: The expression of SST and all SSTRs was assessed in the tissues of CRC patients, control colorectal mucosa and lymph node metastasis from the same patients using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Results: Decreased SST (mRNA and peptide) and higher SST2 and SST5 (mRNA and peptide) expression in CRC vs. control was noted. A negative correlation between SST mRNA expression and patient's age in CRC and control groups were observed. IHC study confirmed the coexpression of SSTRs in all tissue groups and significant dependence on the cellular localization. Immunoexpression of SST2 and SST3 showed the most correlations with clinicopathological data in CRC patients. Interestingly, only control tissue showed differences in SST1-5 expression depending on the colon segment. Conclusions: Reduced SST expression in CRC indicates a weakening in its antitumor effect in this cancer in vivo. Overexpression of SST2 and SST5 in CRC suggests that these receptors play an important role in the pathogenesis of this cancer. Analysis of SST1-5 tissue expression allows for differentiation between the mucinous and nonmucinous CRC subtypes. The coexpression of all SST1-5 and overexpression of not only SST2 and SST5 in CRC may have applications for future therapy based on the SRIF system in sporadic CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is a major global health burden, with surgical resection being the standard treatment aimed at curative tumor removal. Oxidative stress is crucial in colorectal cancer progression and prognosis. This study hypothesizes that the physical removal of colorectal cancer, a primary source of oxidative stress, would reduce blood levels of reactive oxygen metabolite derivatives (d-ROMs), a marker of oxidative stress. This study included 123 patients who underwent radical resection for colorectal cancer. d-ROM levels were measured before and after surgery. The clinicopathological analysis showed a correlation between preoperative d-ROM levels and tumor size. This study confirmed a significant reduction in d-ROM levels following tumor resection. The d-ROM ratio before and after tumor resection was significantly higher in cases with positive lymph node metastasis and larger tumor size. These results suggest that d-ROM levels could serve as a valuable biomarker for monitoring tumor burden in patients with colorectal cancer. Background: Colorectal cancer is a major global health burden, with surgical resection being the standard treatment aimed at curative tumor removal. Oxidative stress plays a crucial role in colorectal cancer progression and prognosis. This study hypothesized that physical removal of colorectal cancer, a primary source of oxidative stress, would reduce blood levels of reactive oxygen metabolite derivatives (d-ROMs), a marker of oxidative stress, and biologic antioxidant potential (BAP) levels, a marker of antioxidant potential. Methods: This study included 123 patients who underwent radical resection for colorectal cancer. d-ROM and BAP levels were measured before and one month after surgery. Results: The clinicopathological analysis showed a correlation between preoperative d-ROM levels and tumor size (p < 0.001). This study confirmed a significant reduction in d-ROM levels following tumor resection, indicating reduced systemic oxidative stress. The reduction was significant in stages II and III, but not in stage I. The d-ROM ratio before and after tumor resection was significantly higher in cases with positive lymph node metastasis and larger tumor size. BAP levels showed no significant changes post-surgery. Conclusions: These results suggest that d-ROMs could serve as a valuable biomarker for monitoring tumor burden and surgical efficacy in patients with colorectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: RNA-binding proteins (RBPs) are crucial in regulating gene expression in the intestine, and their abnormal activity can lead to colorectal cancer (CRC). This review explores how specific RBPs, such as LIN28, IGF2BPs, Musashi, HuR, and CELF1, contribute to CRC by affecting the stability and translation of key cancer-related genes. These proteins can promote tumor growth, spread, and resistance to treatments. Although targeting RBPs is challenging, recently discovered small molecules can disrupt the harmful interactions, showing promise for new CRC therapies. Further research and development of RBP-targeting agents should lead to better treatment options for CRC patients. RNA-binding proteins (RBPs) play critical roles in regulating post-transcriptional gene expression, managing processes such as mRNA splicing, stability, and translation. In normal intestine, RBPs maintain the tissue homeostasis, but when dysregulated, they can drive colorectal cancer (CRC) development and progression. Understanding the molecular mechanisms behind CRC is vital for developing novel therapeutic strategies, and RBPs are emerging as key players in this area. This review highlights the roles of several RBPs, including LIN28, IGF2BP1–3, Musashi, HuR, and CELF1, in CRC. These RBPs regulate key oncogenes and tumor suppressor genes by influencing mRNA stability and translation. While targeting RBPs poses challenges due to their complex interactions with mRNAs, recent advances in drug discovery have identified small molecule inhibitors that disrupt these interactions. These inhibitors, which target LIN28, IGF2BPs, Musashi, CELF1, and HuR, have shown promising results in preclinical studies. Their ability to modulate RBP activity presents a new therapeutic avenue for treating CRC. In conclusion, RBPs offer significant potential as therapeutic targets in CRC. Although technical challenges remain, ongoing research into the molecular mechanisms of RBPs and the development of selective, potent, and bioavailable inhibitors should lead to more effective treatments and improved outcomes in CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with colorectal cancer (CRC) have a high prevalence of malnutrition, which is associated with a decrease in overall survival. In this study, we analyzed body composition using techniques such as BIVA, NU, HGS, and CT in a population with CRC and overweight and found that there is a high prevalence of sarcopenia in these patients. Early detection and treatment of sarcopenia will be essential to improving the prognosis of these patients. (1) Background: Accurate body composition assessment in CCR patients is crucial due to the high prevalence of malnutrition, sarcopenia, and cachexia affecting survival. This study evaluates the correlation between body composition assessed by CT imaging as a reference technique, BIVA, nutritional ultrasound, and handgrip strength in CCR patients. (2) Methods: This retrospective study included CCR patients assessed by the Endocrinology and Nutrition Services of Virgen de la Victoria in Malaga and Vall d'Hebron in Barcelona from October 2018 to July 2023. Assessments included anthropometry, BIVA, NU, HGS, and AI-assisted CT analysis at the L3 level for body composition. Pearson's analysis determined the correlation of CT-derived variables with BIVA, NU, and HGS. (3) Results: A total of 267 CCR patients (mean age 68.2 ± 10.9 years, 61.8% men) were studied. Significant gender differences were found in body composition and strength. CT-SMI showed strong correlations with body cell mass (r = 0.65), rectus femoris cross-sectional area (r = 0.56), and handgrip strength (r = 0.55), with a Cronbach's alpha of 0.789. CT-based adipose tissue measurements showed significant correlations with fat mass (r = 0.56), BMI (r = 0.78), A-SAT (r = 0.49), and L-SAT (r = 0.66). Regression analysis indicated a high predictive power for CT-SMI, explaining approximately 80% of its variance (R2 = 0.796). (4) Conclusions: Comprehensive screening of colorectal cancer patients through BIVA, NU, HGS, and CT optimizes the results of the evaluation. These methods complement each other in assessing muscle mass, fat distribution, and nutritional status in CCR. When CT is unavailable or bedside assessment is needed, HGS, BIVA, and NU provide an accurate assessment of body composition. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatments for colorectal cancer (CRC) largely rely on chemotherapeutics. For CRC treatment, irinotecan is widely used in various combinations with other drugs. Despite being an effective drug, irinotecan treatment often leads to drug resistance and tumor relapse. Mechanistically, it inhibits topoisomerase I and induces double-strand DNA breaks, which result in p53-dependent apoptosis. In the current study, we explored irinotecan-mediated, p53-independent pro- and anti-apoptotic effects. Our data show that irinotecan induces cyclin-dependent kinase inhibitors as well as anti-apoptotic proteins [osteopontin (OPN), survivin, and ISG15], the immunomodulatory molecule PD-L1, immune modulation mediated by proliferative NF-κB signaling, and metastatic markers (CD44, Sox2, Oct4, Snail, and Slug). Inhibition of OPN and/or NF-κB signaling potentiates irinotecan efficacy. The combination of OPN and/or an NF-κB inhibitor with irinotecan may lead to increased efficacy with reduced drug resistance. Among the most popular chemotherapeutic agents, irinotecan, regarded as a prodrug belonging to the camptothecin family that inhibits topoisomerase I, is widely used to treat metastatic colorectal cancer (CRC). Although immunotherapy is promising for several cancer types, only microsatellite-instable (~7%) and not microsatellite-stable CRCs are responsive to it. Therefore, it is important to investigate the mechanism of irinotecan function to identify cellular proteins and/or pathways that could be targeted for combination therapy. Here, we have determined the effect of irinotecan treatment on the expression/activation of tumor suppressor genes (including p15Ink4b, p21Cip1, p27Kip1, and p53) and oncogenes (including OPN, IL8, PD-L1, NF-κB, ISG15, Cyclin D1, and c-Myc) using qRT-PCR, Western blotting, immunofluorescence (IF), and RNA sequencing of tumor specimens. We employed stable knockdown, neutralizing antibodies (Abs), and inhibitors of OPN, p53, and NF-κB to establish downstream signaling and sensitivity/resistance to the cytotoxic activities of irinotecan. Suppression of secretory OPN and NF-κB sensitized colon cancer cells to irinotecan. p53 inhibition or knockdown was not sufficient to block or potentiate SN38-regulated signaling, suggesting p53-independent effects. Irinotecan treatment inhibited tumor growth in syngeneic mice. Analyses of allograft tumors from irinotecan-treated mice validated the cell culture results. RNA-seq data suggested that irinotecan-mediated activation of NF-κB signaling modulated immune and inflammatory genes in mice, which may compromise drug efficacy and promote resistance. In sum, these results suggest that, for CRCs, targeting OPN, NF-κB, PD-L1, and/or ISG15 signaling may provide a potential strategy to overcome resistance to irinotecan-based chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is a deadly disease in which KRAS mutations are prevalent and are associated with poor prognosis. The emergence of KRAS inhibitors is a promising treatment option. This review discusses various classes of KRAS inhibitors, that can be used alone or combined to overcome resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of various strategies to target KRAS in CRC. Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, with significant public health concerns. This review examines the landscape of KRAS inhibition in colorectal cancer (CRC), focusing on recent advances in therapeutic strategies targeting this oncogene. Historically deemed undruggable due to its complex structure and essential role in tumorigenesis, KRAS mutations are prevalent in CRC and are associated with poor prognosis. However, breakthroughs in drug development have led to the emergence of KRAS inhibitors as promising treatment options. This review discusses various classes of KRAS inhibitors, including covalent and non-covalent inhibitors, as well as combination therapies aimed at enhancing efficacy and overcoming resistance mechanisms. It highlights recent clinical trials evaluating the efficacy of KRAS inhibitors either as monotherapy or in combination with other agents, such as anti-EGFR antibodies. Despite challenges such as resistance mechanisms and tumor heterogeneity, the development of KRAS inhibitors represents a significant advance in CRC treatment and holds promise for improving patient outcomes in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Inhibition of the DNA repair protein PARP-1 is a promising concept in cancer therapy. More recently, PARP-1 has been revealed as a possible target in colorectal cancer, which is the second leading cause of cancer-related death worldwide. In this work, we screened a compound library to identify novel PARP inhibitors with low cytotoxicity and tested their efficacy in colorectal cancer cell models with and without defects in the DNA damage response. Furthermore, we evaluated whether the putative PARP inhibitors synergize with chemotherapeutic drugs used in the clinics to treat colorectal cancer patients. Using various experimental approaches, we were able to identify two promising molecules with potent PARP inhibition in colorectal cancer cells without causing cytotoxicity on their own. Moreover, the novel PARP inhibitors sensitized colorectal cancer cells to the anticancer drug irinotecan dependent on homologous recombination deficiency. Remarkably, the clinically approved PARP inhibitor olaparib displayed the strongest synergistic effects, but it was also cytotoxic as a single agent in wildtype colorectal cancer cells. The novel PARP inhibitors might, therefore, be useful for a combination therapy with irinotecan to avoid overlapping toxicity on healthy tissue such as bone marrow, which warrants further preclinical studies. The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies of BRCA1/2, such as breast cancer. More recently, the application of PARP inhibitors (PARPi) such as olaparib has been expanded to other cancer entities including colorectal cancer (CRC). We previously demonstrated that PARP-1 is overexpressed in human CRC and promotes CRC progression in a mouse model. However, acquired resistance to PARPi and cytotoxicity-mediated adverse effects limit their clinical applicability. Here, we detailed the role of PARP-1 as a therapeutic target in CRC and studied the efficacy of novel PARPi compounds in wildtype (WT) and DNA repair-deficient CRC cell lines together with the chemotherapeutics irinotecan (IT), 5-fluorouracil (5-FU), and oxaliplatin (OXA). Based on the ComPlat molecule archive, we identified novel PARPi candidates by molecular docking experiments in silico, which were then confirmed by in vitro PARP activity measurements. Two promising candidates (X17613 and X17618) also showed potent PARP-1 inhibition in a CRC cell-based assay. In contrast to olaparib, the PARPi candidates caused no PARP-1 trapping and, consistently, were not or only weakly cytotoxic in WT CRC cells and their BRCA2- or ATR-deficient counterparts. Importantly, both PARPi candidates did not affect the viability of nonmalignant human colonic epithelial cells. While both olaparib and veliparib increased the sensitivity of WT CRC cells towards IT, no synergism was observed for X17613 and X17618. Finally, we provided evidence that all PARPi (olaparib > veliparib > X17613 > X17618) synergize with chemotherapeutic drugs (IT > OXA) in a BRCA2-dependent manner in CRC cells, whereas ATR deficiency had only a minor impact. Collectively, our study identified novel lead structures with potent PARP-1 inhibitory activity in CRC cells but low cytotoxicity due to the lack of PARP-1 trapping, which synergized with IT in homologous recombination deficiency. [ABSTRACT FROM AUTHOR]

Simple Summary: This study assessed the prognostic impact of sarcopenic obesity (SO) in colorectal cancer patients. Among 211 sarcopenic patients, those with obesity (SO group) demonstrated significantly shorter cancer-related relapse-free survival (CRRFS) compared to their non-obese counterparts (non-SO group). While cancer-specific survival (CSS) was also poorer in the SO group, this difference did not reach statistical significance. Additionally, there was no significant difference in overall survival (OS) between the two groups. Multivariate analysis identified sarcopenic obesity, elevated CEA levels, and unfavorable histological types as independent predictors of poor CRRFS. These findings underscore the importance of routine assessment of both sarcopenia and obesity in clinical practice. Moreover, they highlight the potential benefits of interventions aimed at increasing muscle mass and reducing visceral fat to enhance patient outcomes. Background: Sarcopenia, the age-related loss of muscle mass, is a negative prognostic factor in gastrointestinal cancer. Sarcopenia combined with visceral obesity (sarcopenic obesity) is associated with poor outcomes. We explored the influence of obesity and other factors on the prognosis of patients with colorectal cancer diagnosed with sarcopenia. Methods: We enrolled 211 patients with colorectal cancer diagnosed with preoperative sarcopenic obesity who underwent radical resection at Osaka University Hospital between January 2009 and January 2012. Muscle mass was assessed using the psoas muscle mass index. Obesity was evaluated by measuring the visceral fat area in the umbilical region. Patients were categorized into two groups: sarcopenia with obesity (SO) and sarcopenia without obesity (non-SO). Overall survival, cancer-specific survival, and cancer-related relapse-free survival (CRRFS) were compared between the two groups. Patient characteristics, including age, sex, body mass index, serum albumin, C-reactive protein, tumor markers, prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and geriatric nutritional risk index (GNRI), were also analyzed. Results: CRRFS was significantly shorter in the SO group than in the non-SO group (p = 0.028). PNI, mGPS, and GNRI were not identified as significant prognostic factors for CRRFS. Multivariate analysis highlighted sarcopenic obesity, elevated carcinoembryonic antigen levels, and unfavorable histological types as significant predictors of poor CRRFS outcomes. Conclusions: Sarcopenic obesity is an independent predictor of poor prognosis in patients with CRC. Thus, interventions aimed at increasing muscle mass and reducing visceral fat could potentially improve the prognosis of these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we developed an mRNA cancer vaccine by encapsulating melanoma-associated antigen A3 (MAGE-A3) mRNA in lipid nanoparticles made of O,O′-dimyristyl-N-lysyl aspartate (DMKD) and phosphatidylserine (PS). These nanoparticles demonstrated stability, preserving mRNA integrity even after extended refrigeration. Immunization with this vaccine significantly inhibited tumor growth in mice and activated strong immune responses. This suggests that the MAGE-A3 mRNA vaccine using DMKD-PS nanoparticles could provide both therapeutic and preventive benefits for tumors associated with this antigen. Cancer causes over 10 million deaths annually worldwide and remains a significant global health challenge. This study investigated advanced immunotherapy strategies, focusing on mRNA vaccines that target tumor-specific antigens to activate the immune system. We developed a novel mRNA vaccine using O,O′-dimyristyl-N-lysyl aspartate (DMKD) to improve stability and phosphatidylserine (PS) to enhance antigen presentation to immune cells. This vaccine, containing melanoma-associated antigen A3 (MAGE-A3) mRNA encapsulated within lipid nanoparticles (LNPs), was evaluated for its therapeutic potential against colorectal cancer. Our findings demonstrated that MAGE-A3 mRNA-containing DMKD-PS LNPs significantly reduced tumor size and weight, effectively combating metastatic cancer. The vaccine elicited a robust immune response, increasing specific immunoglobulin and cytokine levels without causing histotoxicity in major organs. These results confirm that the DMKD-PS-based MAGE-A3 mRNA vaccine holds promise for cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Robotic surgery is increasingly being adopted in the field of minimally invasive colorectal surgery and has the ability to overcome the inherent drawbacks of conventional laparoscopic surgery. The adoption of new technology comes with the need to first overcome its learning curve in a safe manner without compromising on patient care. Understanding the learning curve and the factors that affect it can help institutions develop strategies to shorten it and acquire this new skill safely and efficiently. Prior experience in laparoscopic colorectal surgery, robotic surgical simulation, spending time as a bedside first assistant, along with a structured training program with proctorship were found to accelerate the process of skill acquisition. Aspiring robotic surgeons would require as little as 12 cases to attain operative efficiency and 15 cases to reduce complications. With the increasing adoption of robotic surgery in clinical practice, institutions intending to adopt this technology should understand the learning curve in order to develop strategies to help its surgeons and operating theater teams overcome it in a safe manner without compromising on patient care. Various statistical methods exist for the analysis of learning curves, of which a cumulative sum (CUSUM) analysis is more commonly described in the literature. Variables used for analysis can be classified into measures of the surgical process (e.g., operative time and pathological quality) and measures of patient outcome (e.g., postoperative complications). Heterogeneity exists in how performance thresholds are defined during the interpretation of learning curves. Factors that influence the learning curve include prior surgical experience in colorectal surgery, being in a mature robotic surgical unit, case mix and case complexity, robotic surgical simulation, spending time as a bedside first assistant, and being in a structured training program with proctorship. [ABSTRACT FROM AUTHOR]

Simple Summary: Irinotecan is a widely used chemotherapy drug for colorectal cancer, but overcoming resistance to irinotecan remains a significant challenge. FL118, a drug similar to irinotecan, has shown promise as a new treatment option. FL118 functions by reducing the levels of a protein called survivin, which, in turn, decreases the expression of RAD51, a key protein involved in DNA repair. FL118 has been demonstrated to reduce cancer cell viability and overcome irinotecan resistance in colorectal cancer cells, suggesting it could serve as an effective treatment following irinotecan. Background/Objectives: Irinotecan, a camptothecin (CPT) derivative, is commonly used as a first-line therapy for colorectal cancer (CRC), but resistance remains a significant challenge. This study aims to explore the therapeutic potential of FL118, another CPT derivative, with a focus on overcoming resistance to irinotecan. Methods: The effects of FL118 on CRC cells were evaluated, and bioinformatics analysis was performed on RNA-seq data. Transfection was conducted to observe the knockdown effect of survivin, and the in vivo efficacy of FL118 was assessed using a xenograft model. Results: FL118 induces apoptosis, G2/M arrest, and DNA damage. A notable mechanism of action of FL118 is a reduction in survivin levels, which downregulates the expression of RAD51, a key marker of homologous recombination, and attenuates DNA repair processes. Given that SN38 is the active metabolite of irinotecan, FL118 reduces cell viability and RAD51 in SN38-resistant LOVO cells. Conclusions: Our findings provide effective insights into the antitumor activity of FL118 and its potential as a therapeutic agent for overcoming irinotecan resistance in CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) are commonly used for acid reduction in patients with peptic ulcer disease or esophageal reflux. Previous studies have shown that acid-reducing agents (ARAs) might affect bevacizumab treatment. This study found that PPI use worsened the oncological outcomes in patients with metastatic colorectal cancer (mCRC) undergoing bevacizumab treatment. There was a negative dose–response relationship when compared to H2RA use. Physicians should consider the benefits and risks of long-term use of ARAs, especially PPIs, in mCRC patients treated with bevacizumab. Background: Approximately one-third of patients with advanced colorectal cancer (CRC) and treated with bevacizumab are prescribed proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs). However, there is limited data on the effects of PPIs and H2RAs in these patients. To investigate the oncological outcomes of PPI and H2RA use in CRC patients treated with bevacizumab, we performed a retrospective cohort study using the Taiwan National Health Insurance Research Database and Taiwan Cancer Registry Database from 2005 to 2020. Methods: In CRC patients treated with bevacizumab, the PPI users and H2RA users were matched with patients without acid-reducing agents (ARAs) by 1:4 propensity score matching. PPI users and H2RA users were matched with propensity scoring in a 1:1 ratio. We divided patients into 4 cumulative PPI dosage levels to assess the dose–response relationship. The primary endpoints were 5-year overall survival and cancer-specific survival. Results: Compared with ARA non-users, both H2RA users and PPI users were associated with reduced overall survival. PPI users were associated with more significant negative effects on overall survival. Compared with H2RA users, PPI users were associated with lower 5-year overall survival (aHR: 1.19, 95% CI: 1.09–1.31) and cancer-specific survival (aHR: 1.20, 95% CI: 1.09–1.31). A similar dose–response relationship was observed for PPI users in terms of 5-year overall survival and cancer-specific overall survival. Conclusions: Compared to H2AR use, PPI use was associated with dose-dependent poorer oncological outcomes in metastatic CRC patients treated with bevacizumab. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is the second highest cause of cancer mortality globally. Surgery is often performed to remove the cancer and improve survival. Special dyes, called fluorescent agents, can help surgeons identify the tumour tissue and guide them during the operation to precisely remove the cancer, thereby improving patient outcomes. The exact benefit of fluorescence-guided surgery in the management of colorectal cancer is not clearly established, necessitating this systematic review and meta-analysis of the literature to assess the safety and efficacy of this surgery. A total of 35 studies of 3217 patients were included in this analysis. This showed that fluorescence-guided surgery is a safe and effective approach, potentially reducing intraoperative blood loss and postoperative complication rates, when compared to surgery without the use of fluorescence agents. Further prospective clinical trials are required to establish the long-term oncological benefit of fluorescence-guided surgery. Background: The use of fluorescence agents and imaging systems is a promising adjunct in the surgical management of colorectal cancer. This systematic review and meta-analysis aimed to assess the safety and efficacy of fluorescence-guided surgery in the management of colorectal cancer, with a comparison to conventional (non-fluorescence-guided) surgery. Methods: A literature search of MEDLINE, Embase, Emcare, and CINAHL databases was performed for studies that reported data on the outcomes of fluorescence-guided surgery, with or without a comparison group undergoing conventional surgery, for colorectal cancer between January 2000 and January 2024. A meta-analysis was performed using random-effect models, and between-study heterogeneity was assessed. Results: 35 studies of 3217 patients with colorectal cancer were included: 26 studies (964 patients) reported on fluorescence-guided surgery and 9 studies (2253 patients) reported on fluorescence versus conventional surgery. The weighted mean of the cancer detection rate of fluorescence-guided surgery was 71% (95% CI 0.55–0.85), with no significant difference in lymph node yield ratio (WMD −0.04; 95% CI −0.10–0.02; p = 0.201) between fluorescence and conventional surgery groups. There was a significantly lower blood loss (WMD −4.38; 95% CI −7.05–−1.70; p = 0.001) and complication rate (WMD −0.04; 95% CI −0.07–0.00; p = 0.027) in the fluorescence-guided surgery group, with a potentially lower anastomotic leak rate (WMD −0.05; 95% CI −0.10–0.01; p = 0.092). Conclusions: Fluorescence-guided surgery is a safe and effective approach in the management of colorectal cancer, potentially reducing blood loss and complications. Further randomised controlled trials are required comparing fluorescence-guided surgery with conventional surgery to determine its prognostic benefit and where it should precisely fit within the management pathway of colorectal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: As the incidence of colorectal cancer (CRC) increases among younger adults, the need for discussions regarding treatment-related infertility is growing. Treatment-related infertility is distressing to patients, and data show that patients desire pre-treatment fertility counseling and would take advantage of opportunities for fertility preservation. That said, counseling occurs far too infrequently, and surgeons are vastly underutilized for these conversations. In this review, we highlight the current knowledge regarding infertility and counseling in patients undergoing CRC treatment and provide an overview of the connection between abdominal and pelvic surgery on male and female infertility. Further, we identify topics of importance when conducting infertility counseling and elucidate the role of surgeons in these important conversations. As the incidence of colorectal cancer (CRC) increases among younger adults, the need for discussions regarding treatment-related infertility is growing. The negative impacts of gonadotoxic chemotherapy and pelvic radiation are well documented, but the role that surgical intervention for CRC plays in infertility is less clear. Additionally, treatment-related infertility counseling occurs infrequently. This review provides an overview of the connection between abdominal and pelvic surgery on male and female infertility and elucidates the role of surgeons in counseling to alleviate psychological distress in newly diagnosed patients. A review of the literature revealed that pelvic surgery leads to increased adhesion formation, which is known to be associated with female infertility. Furthermore, nerve damage from pelvic surgery has significant implications for ejaculatory issues in males and sexual dysfunction in both males and females, which ultimately impact pregnancy success. Patients have significant distress related to treatment-related infertility, and pre-treatment fertility counseling has been shown to alleviate some of this psychological burden. Nevertheless, many patients do not receive counseling, particularly in surgical clinics, despite surgeons often being the first providers to see newly diagnosed non-metastatic patients. Efforts should be made to enact protocols that ensure fertility conversations are being had with patients in surgical clinics and that patients are being referred to fertility specialists appropriately. This patient-centered approach will lessen the psychological burden placed on patients during a vulnerable time in their lives. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is a leading cause of death in Spain, but early detection through screening can significantly reduce the risk of death. However, many people in Spain do not participate in these screening programs, like the faecal occult blood test and colonoscopy. To better understand the benefits of screening, we conducted a study comparing patients diagnosed through screening with those diagnosed after developing symptoms. Our study included 315 people diagnosed with CRC at a public hospital in Elda, Spain, from 2014 to 2018, with follow-up until 2023 or death. We found that patients diagnosed through screening were more likely to have early-stage cancer and a family history of CRC, while those diagnosed after symptoms appeared were more likely to have advanced cancer and other chronic diseases. People diagnosed based on symptoms had a higher risk of death from CRC and other causes. Our findings show that CRC screening leads to earlier diagnosis, improving survival rates. These results support the need for public health policies that encourage widespread participation in CRC screening programs to save lives. Background and objective: Colorectal cancer (CRC) is the leading cause of mortality in Spain, with screening programs, such as the faecal occult blood test and colonoscopy, having shown effectiveness in reducing CRC incidence and mortality. Despite these advancements, CRC screening uptake remains low in Spain, highlighting the need for studies comparing outcomes between screening-diagnosed and symptom-diagnosed patients to better understand the impact on overall survival and to quantify the clinical benefit in prognosis at diagnosis and at the end of follow-up. Methods: We conducted a retrospective cohort study with the following objectives: to compare stage at diagnosis, all-cause mortality, and disease-specific mortality among people diagnosed with CRC based on screening and based on symptoms; to identify the risk factors associated with mortality in this population; and to evaluate the effectiveness of screening on survival and early detection. Our study included people diagnosed with CRC in the public hospital of Elda (Spain) from 2014 to 2018; follow-up was until 2023 or death. Our primary outcome was all-cause mortality, which we analysed using Kaplan–Meier curves. We also investigated CRC-specific mortality and other-cause mortality. Results: Our sample included 315 people (186 with symptom-based diagnoses, 129 with screening-based diagnoses). The mean length of follow-up was 62.8 months. The screening group had a higher prevalence of a family history of CRC (p = 0.008), a distal tumour location (p = 0.002), and a cancer stage of 0 or I (p < 0.001). The symptoms group had a higher prevalence of a proximal CRC (p = 0.002), other chronic diseases (p < 0.001), and stages II, III, and IV (p < 0.001). Two variables were associated with mortality: stage IV at diagnosis and previous cancers. People with a symptom-based diagnosis had a higher prevalence of stage IV at diagnosis and a higher cumulative incidence of CRC mortality and all-cause mortality at the end of follow-up (p < 0.05). The Kaplan–Meier curves also showed a higher rate of all-cause mortality in the symptoms group throughout the follow-up. Conclusion: CRC screening enables an earlier diagnosis and improves survival. These findings support public health policies that promote accessible and effective screening. [ABSTRACT FROM AUTHOR]

Simple Summary: According to increasing life expectancy, an increasing number of elderly people need colorectal resective surgery to treat colorectal disease, especially colorectal cancer. In the last years the surgical techniques were deeply modified, also in colorectal surgery, with progressively higher rate of minimally invasive surgery and with a progressively higher rate of adhesion to fast-track protocols. The introduction of these new factors significantly modified the post-operative outcomes after colorectal resective surgery, but in elderly patients these advantages were less evident in literature. The aim of this study was to evaluate and quantify the impact of advanced age on short-term postoperative outcomes. Background/Objectives: Life expectancy for people in their 60s is 24.3 years in high-income countries. Health systems face the burden of disease in the elderly population and must assess the impact of treatments such as major surgery. The aim of this study is to quantify the impact of advanced age on short-term postoperative outcomes after resective colorectal surgery (RCRS). Methods: All patients who underwent RCRS at our institution between July 2022 and November 2023 were entered into a database. Preoperative, perioperative, and early (within 30 days) postoperative data were recorded. Patients were categorized into a young group (under 75 years, YG) and an elderly group (over 75 years, EG). A retrospective comparative analysis of postoperative outcomes was performed between the two groups; postoperative complications were graded according to the Clavien classification. Results: Fifty-three and ninety-five patients were in the EG and YG, respectively. Indications for RCRS was cancer in 83% of EG patients and 61.1% of YG patients (p = 0.006), and the clinical presentation, localization, and rate of neoadjuvant treatment in oncological patients were comparable. Another indication for RCRS was complicated diverticular disease (17% of EG patients and 38.9% of YG patients; p = 0.006). With respect to the baseline characteristics, the ASA and CCI scores were worse in the EG (p = 0.001). No significant differences in the surgical approach, mini-invasive approach, conversion rate, definitive stoma creation, or number of harvested lymph nodes were found between the two groups. Overall, EG reported a higher relative risk (RR) of short-term postoperative complications (1.64, CI: 1.03–2.63), but no significant differences were found in terms of grade ≥3 complications (RR: 0.9, CI: 0.23–3.44). In the EG, a higher risk of ICU admission (RR:2.69, CI: 1.5–4.8) and a one-day longer postoperative hospital stay (6 vs. 5 days) were reported. Conclusions: Advanced age does not seem to contraindicate RCRS, especially in colorectal cancer patients. The impact of elderly age on short-term outcomes seems to be minimal and acceptable. [ABSTRACT FROM AUTHOR]

Simple Summary: This research identifies the critical metabolic syndrome components that lead to a higher risk of developing colorectal cancer. This is a crucial step in creating colon cancer screening guidelines based on the presence of some specific MetS components or combinations of components. This pivotal insight could inform future CRC screening strategies. Finally, our findings could fill the knowledge gaps in current research areas relevant to metabolic syndrome and colorectal cancer. Background/Objectives: Dysfunctions of metabolic syndrome (MetS) have been identified as a significant risk factor for colorectal cancer (CRC). However, current colon cancer guidelines do not classify patients with MetS as high risk, thereby leaving these individuals vulnerable. Consequently, we explored the relationship between MetS, its individual components, and the development of CRC in a cohort of patients with MetS to assess the necessity for CRC screening in these individuals. Methods: This study included patients ages 18 and older that received a service from the Marshall-Health (MH) practice plan, Cabell-Huntington Hospital (CHH), MU/JCESOM's Edwards Comprehensive Cancer Center (ECCC), or the University of Kentucky HealthCare (UKHC) system between 2010 and 2018. We implemented log-binomial regression models to assess the individual and collective effects of MetS components after adjusting other CRC risk factors. Results: Given that CRC prevalence increases in the older population (aged 65 years and above), and that multiple components of MetS are observed within the same population, we analyzed the concurrent impact of all MetS components on CRC. Log-binomial regression models were implemented to assess the risk of CRC due to MetS components after adjusting other risk factors. Conclusions: We identified specific components that markedly increased CRC risk, suggesting that individuals with these components should be prioritized for early screening. These findings could significantly influence early CRC screening protocols, with the ultimate aim to reduce mortality associated with the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Inorganic polyphosphate, a molecule composed of a few to several hundred orthophosphates, is involved in disparate pathological processes, including cancer development and progression. In this study, by analyzing biopsies derived from 50 subjects carrying colorectal cancer, collected by the Histopathology Unit of IRCCS "S. de Bellis," we showed a significant discrepancy in the level of inorganic polyphosphate between tumoral and peritumoral counterparts, with the former displaying a higher concentration. Moreover, by employing in vitro and ex vivo approaches, we revealed the involvement of inorganic polyphosphate in colorectal cancer cell proliferation. Additionally, we identified the calcium channel TRPM8 as the inorganic polyphosphate receptor responsible for propagating the signal downstream and, ultimately, enhancing the expression of proliferative markers. Thus, our results recognize inorganic polyphosphate as a novel pivotal biomarker linked with colorectal cancer growth. Background: Colorectal cancer (CRC) is characterized by a pro-inflammatory microenvironment and features high-energy-supply molecules that assure tumor growth. A still less studied macromolecule is inorganic polyphosphate (iPolyP), a high-energy linear polymer that is ubiquitous in all forms of life. Made up of hundreds of repeated orthophosphate units, iPolyP is essential for a wide variety of functions in mammalian cells, including the regulation of proliferative signaling pathways. Some evidence has suggested its involvement in carcinogenesis, although more studies need to be pursued. Moreover, iPolyP regulates several homeostatic processes in animals, spanning from energy metabolism to blood coagulation and tissue regeneration. Results: In this study, we tested the role of iPolyP on CRC proliferation, using in vitro and ex vivo approaches, in order to evaluate its effect on tumor growth. We found that iPolyP is significantly increased in tumor tissues, derived from affected individuals enrolled in this study, compared to the corresponding peritumoral counterparts. In addition, iPolyP signaling occurs through the TRPM8 receptor, a well-characterized Na+ and Ca2+ ion channel often overexpressed in CRC and linked with poor prognosis, thus promoting CRC cell proliferation. The pharmacological inhibition of TRPM8 or RNA interference experiments performed in established CRC cell lines, such as Caco-2 and SW620, showed that the involvement of TRPM8 is essential, greater than that of the other two known iPolyP receptors, P2Y1 and RAGE. The presence of iPolyP drives cancer cells towards the mitotic phase of the cell cycle by enhancing the expression of ccnb1, which encodes the Cyclin B protein. In vitro 2D and 3D data reflected the ex vivo results, obtained by the generation of CRC-derived organoids, which increased in size. Conclusions: These results indicate that iPolyP may be considered a novel and unexpected early biomarker supporting colorectal cancer cell proliferation. [ABSTRACT FROM AUTHOR]

Simple Summary: Histopathological and molecular factors could play a role in determining LNM in colon cancer. Extended lymphadenectomies in right-sided patients have been associated with complications. We demonstrated that histopathological and molecular analysis can be useful in predicting LNM and therefore identify high risk patients which could potentially benefit from D3 lymphadenectomy/CME. Background: Lymphadenectomy plays a central role in the treatment of localized colon cancer. While in left colon cancer the D3 lymphadenectomy/CME is considered the standard of care, lymphatic stations to be removed in right colon cancer are still a matter of discussion. The individuation of LNM risk factors could help in choosing the lymphadenectomy in right-sided tumors. This study aims to analyze the correlation of histopathological and molecular characteristics with lymph node metastasis, both in right- and left-sided colon cancer, and their impact on survival; Methods: We conducted a single-center observational retrospective study. The following data were collected and analyzed for each patient: demographics, histopathological and molecular data, and intraoperative and perioperative data. Statistical analyses were performed, including descriptive statistics, multivariate logistic regression and survival analysis; Results: An association between tumor size (pT, p < 0.001), grading (p = 0.013), budding (p < 0.001), LVI (79,4% p < 0.001) and LNM was observed. A multivariate analysis identified pT4 (OR 5.45, p < 0.001) and LVI+ (OR 10.7, p < 0.001) as significant predictors of LNM. Right-sided patients presented a worse OS when associated with LNM, while no significant difference was observed in N0 patients; Conclusions: histological and molecular analysis can help identify high risk patients, which could benefit from extended lymphadenectomies. These patients could be ideal candidates for the D3 lymphadenectomy/CME. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is becoming more common in low- and middle-income countries (LMICs). The challenges faced by communities in LMICs, settings with few resources available, can be compared to rural America, where resources are also limited. Common barriers to taking care of colorectal cancer patients in these communities are variation in individual provider behavior, social determinants of health such as poverty, how healthcare systems are set up, and the number of specialty doctors practicing in these communities. This review also highlights how LMICs and rural American communities have addressed these problems, through projects such as training new specialty doctors, collaborating with larger hospitals, and technological innovation. Finally, as an example, we highlight a new colorectal surgery fellowship program that addresses the barriers to providing colorectal cancer care in a low-resource setting at both the individual patient and provider level, all the way to the systems level. Background/Objectives: Colorectal cancer remains a significant global health challenge, particularly in resource-limited settings where patient-centered outcomes following surgery are often suboptimal. Although more prevalent in low- and middle-income countries (LMICs), segments of the United States have similarly limited healthcare resources, resulting in stark inequities even within close geographic proximity. Methods: This review compares and contrasts colorectal cancer outcomes in LMICs with those in resource-constrained communities in rural America, utilizing an established implementation science framework to identify key determinants of practice for delivering high-quality colorectal cancer care. Results: Barriers and innovative, community-based strategies aimed at improving patient-centered outcomes for colorectal cancer patients in low resource settings are identified. We explore innovative approaches and community-based strategies aimed at improving patient-centered outcomes, highlighting the newly developed colorectal surgery fellowship in Sub-Saharan Africa as a model of innovation in this field. Conclusions: By exploring these diverse contexts, this paper proposes actionable solutions and strategies to enhance surgical care of colorectal cancer and patient outcomes, ultimately aiming to inform global health practices, inspire collaboration between LMIC and rural communities, and improve care delivery across various resource settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal neoplasia developing from ulcerative colitis mucosa (CRNUC) can be divided into ulcerative colitis-associated neoplasia (UCAN) and non-UCAN; however, it is often difficult to distinguish UCAN from non-UCAN during a biopsy diagnosis. We investigated whether a genomic analysis could improve the diagnostic accuracy of UCAN using biopsy specimens. The pathological diagnosis of biopsy specimens using only hematoxylin and eosin (HE) staining had a sensitivity of 33% and an accuracy of 38% for UCAN diagnosis. On the other hand, the combination of the HE pathology and p53 immunohistochemical staining had a sensitivity of 73% and an accuracy of 85% for UCAN diagnosis, while the combination of HE staining and a TP53 mutation had a sensitivity of 87% and an accuracy of 88% for UCAN diagnosis. An evaluation of TP53 mutations in biopsy specimens may be useful for diagnosing UCAN. However, further studies with larger sample sizes are required before this can be applied in clinical practice. Background/Objectives: Colorectal neoplasia developing from ulcerative colitis mucosa (CRNUC) can be divided into ulcerative colitis-associated neoplasia (UCAN) and non-UCAN; however, it is often difficult to distinguish UCAN from non-UCAN during a biopsy diagnosis. We investigated whether a genomic analysis could improve the diagnostic accuracy of UCAN using biopsy specimens. Methods: In step 1, 14 CRNUCs were used to examine whether the genomic landscape of biopsy and resection specimens matched. In step 2, we investigated the relationship between the genomic landscapes and the pathological diagnosis of 26 CRNUCs. The cancer genome was analyzed by deep sequencing using a custom panel of 27 genes found to be mutated in our previous CRNUC analysis. Results: In step 1, of the 27 candidate genes, 14 were mutated. The concordance rate of the pathogenic mutations in these 14 genes between the biopsy and resection specimens was 29% (4/14), while that of the pathogenic mutations in TP53 and KRAS was 79% (11/14). In step 2, the pathological diagnosis of biopsy specimens using only hematoxylin and eosin (HE) staining had a sensitivity of 33% and an accuracy of 38% for UCAN diagnosis. On the other hand, the combination of the HE pathology and p53 immunohistochemical staining had a sensitivity of 73% and an accuracy of 85% for UCAN diagnosis, while the combination of HE staining and a TP53 mutation had a sensitivity of 87% and an accuracy of 88% for UCAN diagnosis. Conclusions: An evaluation of TP53 mutations in biopsy specimens may be useful for diagnosing UCAN. However, further studies with larger sample sizes are required before this can be applied in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: The purpose of the present study was to determine the role of changes in the stage of colorectal cancer (CRC, Stage 0 to 4, with 0 be very early stage and 4 late stage) at diagnosis over time, and its impact on overall survival (OS) in our Health Network system. Two datasets were used, the Health Network (n = 1385) and a national dataset (n = 202,391). There was a significant increase in early CRC stages at diagnosis (Stage 0–1), and late diagnosis (Stage 4) with a concomitant decrease in the diagnosis of CRC Stage 2. The present findings confirmed CRC stage migration in our Health Network System, along with a national trend conducive to an increased OS for early CRC stages. Background/Objectives: Due to an increased rate of surveillance colonoscopy, we aim to determine the impact of stage migration on the incidence and overall survival (OS) of patients who underwent pathological staging of colorectal cancer (CRC) at our Health Network System. Methods: Two datasets were included: subjects from the tumor registry at a regional Comprehensive Cancer Center (n = 1385) and subjects from the Surveillance, Epidemiology, and End Results (SEER) national database (n = 202,391). Results: A significant increase in the diagnosis of CRC Stage 1 and 4 was observed, with a decrease in stage 2, and no change in Stage 3 in the National datasets (p < 0.01). There was an increase in Stage 4 CRC diagnosis, with a concurrent decrease in stage 2, and no changes in stages 1 and 3 in the regional dataset (p < 0.05). OS followed the expected and progressive decrease in OS by stage (from 1 to 4, p < 0.01). Conclusions: The present findings confirmed CRC stage migration in our Health Network System, along with a national trend conducive to an increased OS for early CRC stages. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Traditional methods for predicting patient outcomes rely heavily on the physical characteristics of tumors. Our research aims to develop a new, simple risk score that uses three specific molecular markers found in tumor tissues. By examining the presence and levels of these markers, we hope to better predict which patients have a higher risk of poor outcomes. This can help doctors make more informed decisions about treatment options. Our findings may lead to improved survival rates by identifying high-risk patients who need more aggressive treatment and sparing low-risk patients from unnecessary procedures. Introduction: Several new molecular markers in colorectal carcinomas have been discovered; however, classical histopathological predictors are still being used to predict survival in patients. We present a novel risk score, which uses molecular markers, to predict outcomes in patients with colorectal carcinoma. Methods: The immunohistochemistry of tissue micro arrays was used to detect and quantify H2BUB1, RBM3 and Ki-67. Different intensities of staining were categorized for these markers and a score was established. A multivariate analysis was performed and survival curves were established. Results: 1791 patients were evaluated, and multivariate analysis revealed that our risk score, the 3-biomarker classifier, is an independent marker to predict survival. We found a high risk-score to be associated with dismal median survival for the patients. Conclusions: A more personalized score might be able to better discriminate low- and high-risk patients and suggest adjuvant treatment compared to classical pathological staging. Our score can serve as a tool to predict outcomes in patients suffering from colorectal carcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer remains a major health challenge with high mortality rates and increasing diagnoses among younger adults. This study introduces a new method to predict patient survival using machine learning, a technique that can greatly enhance early diagnosis and treatment. The aim of our study is to apply eight different machine learning algorithms to a large data set of patients with colorectal cancer in Brazil and optimize these models with advanced parameter tuning tools. The best performing models achieved around 80% accuracy in predicting survival rates over one, three, and five years, as well as overall and cancer-specific mortality. This approach promises to improve clinical decision making by providing more accurate survival predictions, ultimately helping better patient care and management. Background: Colorectal cancer is one of the most prevalent forms of cancer and is associated with a high mortality rate. Additionally, an increasing number of adults under 50 are being diagnosed with the disease. This underscores the importance of leveraging modern technologies, such as artificial intelligence, for early diagnosis and treatment support. Methods: Eight classifiers were utilized in this research: Random Forest, XGBoost, CatBoost, LightGBM, Gradient Boosting, Extra Trees, the k-nearest neighbor algorithm (KNN), and decision trees. These algorithms were optimized using the frameworks Optuna, RayTune, and HyperOpt. This study was conducted on a public dataset from Brazil, containing information on tens of thousands of patients. Results: The models developed in this study demonstrated high classification accuracy in predicting one-, three-, and five-year survival, as well as overall mortality and cancer-specific mortality. The CatBoost, LightGBM, Gradient Boosting, and Random Forest classifiers delivered the best performance, achieving an accuracy of approximately 80% across all the evaluated tasks. Conclusions: This research enabled the development of effective classification models that can be applied in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Faecal immunochemical testing is used to help aid the detection of bowel cancers and other serious bowel problems. It is a stool test that looks for non-visible blood. It has been shown that doing more than one test may improve the rate of detection of serious bowel problems; however, the evidence for this is not well described and has not been reviewed. We aimed to review the available data for using more than one test in different risk groups, exploring the effect on positivity and workload for additional tests along with assessing how well multiple tests work at detecting bowel cancer and other problems. The results of this are important as they help in the development of services to detect colorectal cancer. Background: Faecal immunochemical testing (FIT) is widely used in bowel screening programmes and assessing symptomatic patients for suspected colorectal cancer (CRC). The evidence for single test performance of FIT in both settings is considerable; however, the use of a repeat test to increase sensitivity remains uncertain. We aimed to review what increase in test positivity would be generated by additional FITs, whether a repeated FIT detects previously missed CRC and advanced colorectal neoplasia (ACRN), and to estimate the sensitivity of double-FIT strategies to diagnose CRC and ACRN. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) was performed using key search terms. Studies reporting the use of more than one FIT in the same screening round or planned assessment of a single symptomatic patient episode were included. Studies were categorised by the reported study population into asymptomatic, mixed (cohorts of combined asymptomatic, symptomatic, or high-risk surveillance), or symptomatic cohorts. Results: A total of 68 studies were included for analysis (39 asymptomatic, 21 mixed, 7 symptomatic, and 1 study with discrete asymptomatic and symptomatic data). At a threshold of 10 µg Hb/g, the two-test positivity ranged between 8.1 and 34.5%, with an increase from the second test of 3–9.2 percentage points. Four out of five studies comparing one versus two tests for diagnosing CRC at 10 µg Hb/g identified additional cases with the second test, with a minimum of 50% reduction in missed CRC. At a threshold of 20 µg Hb/g, the second test increased the positivity by 1.3–6.7 percentage points, with a two-test positivity of between 5.1 and 25.0%. Using a threshold of 20 µg Hb/g, five out of seven studies had a 25% reduction in missed CRC. A meta-analysis estimated the double-FIT sensitivity at 10 µg Hb/g for CRC in mixed-risk and symptomatic cohorts to be 94% and 98%, respectively. Conclusions: Repeated use of FIT helps to diagnose more cases of CRC with a moderate increase in positivity. A double-FIT strategy at 10 µg Hb/g in mixed and symptomatic cohorts has a very high sensitivity for CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: MicroRNAs (miRNAs) play a significant role in the initiation and progression of colorectal cancer and are extensively well-studied in this context. However, the interplay between miRNAs and RNA-binding proteins, especially HuR, is yet to be fully understood. In this review, we summarize the regulatory role of the HuR-miRNA axis in colorectal cancer, highlighting its importance for an improved diagnostic or prognostic approach. Colorectal cancer (CRC) remains a significant global health burden with high incidence and mortality. MicroRNAs (miRNAs) are small non-protein coding transcripts, conserved throughout evolution, with an important role in CRC tumorigenesis, and are either upregulated or downregulated in various cancers. RNA-binding proteins (RBPs) are known as essential regulators of miRNA activity. Human antigen R (HuR) is a prominent RBP known to drive tumorigenesis with a pivotal role in CRC. In this review, we discuss the regulatory role of the HuR/miRNA axis in CRC. Interestingly, miRNAs can directly target HuR, altering its expression and activity. However, HuR can also stabilize or degrade miRNAs, forming complex feedback loops that either activate or block CRC-associated signaling pathways. Dysregulation of the HuR/miRNA axis contributes to CRC initiation and progression. Additionally, HuR-miRNA regulation by other small non-coding RNAs, circular RNA (circRNAs), or long-non-coding RNAs (lncRNAs) is also explored here. Understanding this HuR-miRNA interplay could reveal novel biomarkers with better diagnostic or prognostic accuracy. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to the lack of cancer cell-specific markers in colorectal cancer (CRC), the utility of antibody-mediated therapies in this disease setting has been limited. Here, we evaluated whether markers of cancer-associated fibroblasts (CAFs) may more specifically target CRCs. We identified fibroblast activation protein (FAP) as a strong candidate for targeting CRC. FAP is highly expressed in a majority of cancers and is absent in over 90% of normal tissues. These data indicate that FAP may be a strong candidate for antibody conjugate therapy and support the continued development of FAP-targeting conjugate therapies. Additionally, we identified associations between CAF marker co-expression and immunostimulatory pathways. CAF markers might be useful as targets for immune engaging therapies, with combinations of CAF markers holding promise to identify those patients most likely to respond. Overall, these data provide the basis for potential further studies investigating the utility of CAF markers to target CRCs. In colorectal cancer (CRC), attempts to identify cancer cell-specific markers to guide antibody-mediated therapeutics have failed to uncover markers that are both exclusive to cancer tissues and abundant across CRCs. Alternatively, cancer-associated fibroblasts (CAFs), which are abundant in the tumor microenvironment and upregulate unique surface markers, are not found in healthy tissues. Here, we evaluated the expression patterns of CAF-associated proteins α-smooth muscle actin (αSMA), fibroblast activation protein (FAP), podoplanin (PDPN), matrix metalloproteinase-2 (MMP2), transgelin (TAGLN), and THY1. While αSMA and THY1 were abundant in cancer tissues, high abundance in normal tissues limited their targeting potential. FAP was present in 94.5% of primary and metastatic CRC tissues and absent in 93.7% of adjacent normal colon and liver tissues assessed. These results indicate that FAP is a promising target for antibody conjugates with potential for broad application in CRC. Co-expression analyses showed that CRCs simultaneously expressing high levels of PDPN, MMP2, and THY1 were enriched for immune-related signatures, indicating potential for antibody-mediated immune engagers. Overall, this work highlights the potential of CAF proteins to act as therapeutic targets for novel anticancer agents and become important therapeutic biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival of patients with colorectal cancer liver metastasis can be prognosticated based on the presence or absence of desmoplastic histopathologic growth patterns. Patient survival is improved if the liver tumor has at least a 50% desmoplastic histopathologic growth pattern. Determing the patients tumor histopathological features is essential to prognosis outcomes and treatment management. Introduction: Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis, with an overall 5-year survival rate of 5–10%. Two distinct histopathological growth patterns (HGPs) of CRCLM are known to have significantly differing rates of patient survival and response to treatment. We set out to review the results of 275 patients who underwent liver resection for CRCLM at the McGill University Health Center (MUHC) and analyze their clinical outcome, mutational burden, and pattern of cancer progression in light of their HGPs, and to consider their potential effect on surgical decision making. Methods: We performed a retrospective multivariate analysis on clinical data from patients with CRCLM (n = 275) who underwent liver resection at the McGill University Health Center (MUHC). All tumors were scored using international consensus guidelines by pathologists trained in HGP scoring. Results: A total of 109 patients (42.2%) were classified as desmoplastic and angiogenic, whereas 149 patients (57.7%) were non-desmoplastic and vessel co-opting. The 5-year survival rates for angiogenic patients compared with vessel co-opting patients were 47.1% and 13%, respectively (p < 0.0001). Multivariate analysis showed patients with vessel co-opting CRCLM had a higher incidence of extrahepatic metastatic disease (p = 0.0215) compared with angiogenic CRCLM. Additionally, KRAS mutation status was a marker of increased likelihood of disease recurrence (p = 0.0434), as was increased number of liver tumors (p = 0.0071) and multiple sites of extrahepatic metastatic disease (p < 0.0001). Conclusions: Multivariate analysis identified key clinical prognostic and molecular features correlating with the two HGPs. Determining liver tumor HGPs is essential for patient prognostication and treatment optimization. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic ablative radiation (SAbR) is a focused, high-dose radiation technique used to treat cancers that have spread to the adrenal glands. One of the feared consequences of this therapy is causing adrenal insufficiency in patients, which is a lack of adrenal function; however, the rates and severity at which this occurs in patients are still poorly studied. We studied patients with 66 treated adrenal glands using SAbR, which demonstrated that this technique was effective at controlling cancer sites with a control rate of 75% at 1 year. The risk of patients developing adrenal insufficiency in the entire cohort was significant at 14%, with a median time of 4.3 months. There was a higher risk in patients who had both adrenal glands treated with SAbR, or who had received a prior surgical removal of their other adrenal gland prior to SAbR therapy, with 44% of these patients developing adrenal insufficiency. Background: Adrenal metastases are often treated with stereotactic ablative radiation (SAbR). We aimed to assess the incidence, timing, and factors associated with the development of primary adrenal insufficiency (PAI) following SAbR. Methods: A retrospective cohort study comprised 66 consecutive patients (73% men, median age 61 years) who underwent SAbR for adrenal metastasis. Results: The series encompassed metastases from renal cell carcinoma (41%), lung tumors (38%), colorectal adenocarcinoma (9%), melanoma (5%), and others (7%). Median follow-up was 17 months from SAbR. Nine (14%) patients developed PAI at a median of 4.3 months (range, 0.7–20.2). The incidence of PAI was 44% in patients with prior adrenalectomy receiving unilateral SAbR, 44% with bilateral SAbR, 2% with unaffected contralateral gland, and 0% with bilateral metastases treated with unilateral SAbR. PAI was associated with prior adrenalectomy (odds ratio [OR] 32) and bilateral SAbR (OR 8.2), but not age, sex, metastasis size, or biological effective dose. Post-SAbR 6-month and 1-year local control rates were 82% and 75%, respectively. Conclusions: Patients undergoing SAbR for adrenal metastasis are at high risk of developing PAI. PAI is associated with bilateral SAbR and contralateral adrenalectomy. PAI is unlikely with a remaining unaffected adrenal gland or in the setting of bilateral adrenal metastases with unilateral SAbR. [ABSTRACT FROM AUTHOR]

Simple Summary: WEE1 negatively regulates the G2/M cell cycle checkpoint, allowing sufficient DNA damage repair before mitosis. Cancer cells often have a defective G1/S checkpoint and rely on the G2/M checkpoint for DNA damage repair. In this study, we investigated the association between WEE1 expression and clinicopathological features of colorectal cancer (CRC) using surgical specimens. Using various CRC cell lines with different mutation statuses, we compared the effects of the WEE1 inhibitor adavosertib on cell proliferation, cell cycle, and apoptosis induction, especially focusing on p53 and KRAS mutations involved in the G1/S checkpoint. We also performed therapeutic experiments with adavosertib in an orthotopic transplanted CRC mouse model using two cell lines with different mutation statuses to evaluate its antitumor effect and impact on the tumor immune microenvironment. Our findings indicate that WEE1 inhibitors can be used for treating CRC, particularly in cases with p53 mutations. Inhibition of WEE1, a key regulator of the G2/M checkpoint of the cell cycle, induces apoptosis by initiating mitosis without repairing DNA damage. However, the effects of WEE1 inhibitors on the tumor immune microenvironment in colorectal cancer (CRC) remain unclear. Here, we investigated the association between WEE1 expression and CRC clinicopathological features using surgically resected CRC specimens and assessed the antitumor effects of a WEE1 inhibitor using CRC cell lines and orthotopic transplantation mouse models. WEE1 expression was not correlated with the clinicopathological features of CRC. The WEE1 inhibitor suppressed cell proliferation in a concentration-dependent manner in all CRC cell lines. It also increased the percentage of cells in the G2/M phase and apoptotic cells, especially in cell lines with p53 mutations, but did not alter these cell percentages in most p53 wild-type cell lines. In the orthotopic mouse model of CRC, tumor volume was significantly reduced in the WEE1 inhibitor-treated group compared to that in the control group. RNA sequencing and immunohistochemistry analyses of mouse tumors revealed that treatment with the WEE1 inhibitor activated tumor immunity and suppressed stromal reactions. These results demonstrate the potential antitumor effects of WEE1 inhibitors in CRC, particularly in patients with p53 mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: Forkhead-box M1 (FOXM1) is a proliferation-associated transcription factor, overexpressed in almost all the cancers, making its regulation worth investigating. FOXM1 is known to bind to the promoters of certain microRNAs, a class of biomolecules involved in post-transcriptional gene regulation. Database mining followed by Venn analysis led us to the shortlisting of seven microRNAs, among which microRNA-532-3p showed the strongest interaction with FOXM1 3'UTR. The ectopic overexpression of miR-532-3p in colorectal cancer (CRC) cells led to decreased FOXM1 levels which resulted in the alteration of CRC functionalities. These altered phenotypes were supported by a change in the expression of proliferation and EMT markers. In conclusion, the present study suggested that the regulation of FOXM1 by microRNA-532-3p via its interaction with FOXM1 3'UTR inhibited CRC proliferation, migration, and invasion. Colorectal cancer (CRC) is a heterogeneous disease and classified into various subtypes, among which transcriptional alterations result in CRC progression, metastasis, and drug resistance. Forkhead-box M1 (FOXM1) is a proliferation-associated transcription factor which is overexpressed in CRC and the mechanisms of FOXM1 regulation have been under investigation. Previously, we showed that FOXM1 binds to promoters of certain microRNAs. Database mining led to several microRNAs that might interact with FOXM1 3'UTR. The interactions between shortlisted microRNAs and FOXM1 3'UTR were quantitated by a dual-luciferase reporter assay. MicroRNA-532-3p interacted with the 3'UTR of the FOXM1 mRNA transcript most efficiently. MicroRNA-532-3p was ectopically overexpressed in colorectal cancer (CRC) cell lines, leading to reduced transcript and protein levels of FOXM1 and cyclin B1, a direct transcriptional target of FOXM1. Further, a clonogenic assay was conducted in overexpressed miR-532-3p CRC cells that revealed a decline in the ability of cells to form colonies and a reduction in migratory and invading potential. These alterations were reinforced at molecular levels by the altered transcript and protein levels of the conventional EMT markers E-cadherin and vimentin. Overall, this study identifies the regulation of FOXM1 by microRNA-532-3p via its interaction with FOXM1 3'UTR, resulting in the suppression of proliferation, migration, and invasion, suggesting its role as a tumor suppressor in CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Viral infection poses cancer risk and the PD-1/PD-L1 immune check point plays a critical role in this process. Despite the success of the existing anti-PD-1 and PD-L1 antibodies, significant challenges remain due to drug resistance and serious side effects. We have developed a novel anti-PD-1 antibody P1801 which has significant PD-1 blocking and antitumor activities. It displayed unique binding properties distinctive from pembrolizumab and nivolumab with limited ADCC- and CDC-mediated lysis of normal immune cells. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, a new-generation interferon-alfa-based therapy which also has antiviral and antitumor activities, for the treatment of cancer. Programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) interact to form an immune checkpoint fostering viral infection and viral oncogene-induced tumorigenesis. We generated a novel anti-human PD-1, humanized monoclonal antibody P1801 and investigated its pharmacologic, pharmacokinetic (PK), and pharmacodynamic properties. In vitro binding assays revealed that P1801 uniquely binds to human PD-1 and inhibits its interaction with PD-L1/2. It showed a minor effect on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). P1801 significantly induced the release of IL-2 from activated T-cells but not from nonactivated T-cells. A dose-dependent linear PK profile was observed for the cynomolgus monkeys treated with repeated doses of P1801 at 5 mg/kg to 200 mg/kg once weekly. A four-week repeat-dose toxicity study revealed that P1801 given weekly was safe and well tolerated at doses ranging from 5 to 200 mg/kg/dose. No pathological abnormalities were noted. In humanized PD-1 mice harboring human PD-L1-expressing colon tumor cells, P1801 administered intraperitoneally twice per week at 12 mg/kg significantly inhibited tumor growth and prolonged mouse survival. P1801 displayed unique binding properties different from pembrolizumab and nivolumab. Therefore, it showed distinctive immunological reactions and significant antitumor activities. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, which also has antiviral and antitumor activities, for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Screening for breast, colorectal, and cervical cancer is correlated with diagnosis at an earlier stage, less extensive surgery, and reduced mortality and fewer complications. Adherence rates to cancer screening are lower for individuals with low socio-economic conditions and educational attainment. These social disparities are only partially reduced by free screening through national initiatives. Education and information and appropriate expenditure for preventive care have the potentials to increase adherence to screening for colorectal, breast, and cervical cancer with the possibility of reduced cancer mortality. The findings of our study highlight the importance of the implementation of nationally organized screening programs for several other types of cancers that are often detected after the occurrence of symptoms. Nationally organized screening programs for several types of cancers, like esophageal, gastric, and pancreatic cancer, in regions with a high prevalence may increase the possibility of diagnosis at earlier stages and improved early and late results. The objective of this study was to determine the correlation between adherence to cancer screening programs and earlier diagnosis of the 14 most common types of cancers in the adult population, before and during the COVID-19 pandemic. National data concerning number of admissions and operations in Italy for adult patients admitted with oncologic problems during the COVID-19 pandemic (2020 to 2022) and in the pre-pandemic period (2015 to 2019) were analyzed. We selected 14 types of cancer that present the most common indications for surgery in Italy. This study included 1,365,000 adult patients who had surgery for the 14 most common types of cancer in the period 2015–2022, and interviews concerning adherence rates to screening for breast, colorectal, and cervical cancer were conducted for 133,455 individuals. A higher decrease in the number of operations for the 14 types of cancer (−45%) was registered during the first three acute phases of the pandemic, and it was more evident for screenable cancers like breast, colorectal, and cervical cancer (p < 0.001). During the first year of the COVID-19 pandemic, the number of screened individuals for breast, colorectal, and cervical cancer decreased by 33.8% (from 7,507,893 to 4,969,000) and the number of diagnoses and operations for these three types of cancer decreased by 10.5% (from 107,656 to 96,405). The increase and return to normality of the number of screened individuals in the last year of the pandemic (2022) and in the first post-pandemic year (2023) was associated with a return to the pre-pandemic levels of diagnoses and operations. The adherence rates were lower for individuals living in rural areas, with low socio-economic status, and unmarried persons; however, the most statistically significant factor for reduced adherence was a lower level of educational attainment. Free screening through nationally organized programs reduced social disparities. There were no significant differences between the pre-pandemic and pandemic periods for several types of cancers (stomach, esophagus, pancreas, liver) that are diagnosed for the occurrence of symptoms and for which nationally organized programs might increase the possibility of earlier diagnosis and improved clinical outcomes. Education, information, and appropriate expenditure for preventive care have the potential to reduce cancer mortality. Nationally organized screening programs for several types of cancers, which are often detected for the occurrence of symptoms, may increase the possibility of diagnosis at earlier stages. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores whether Escherichia coli carrying the polyketide synthetase (pks) gene cluster in colorectal cancer (CRC) liver metastasis tissues influence immune responses and cancer recurrence patterns. Analyzing tissues from 239 patients, we found that pks+ E. coli was present in 66.7% of liver metastasis cases. Higher levels of pks+ E. coli were associated with lower levels of the serum C-reactive protein, fewer densities of CD4+ cells and CD163+ cells in the tumor microenvironment, and a reduction in the number of organs affected by recurrent metastasis. These findings suggest that pks+ E. coli may influence both systemic and local immune responses, potentially reducing the diversity of affected metastatic organs. Colibactin, a genotoxin produced by Escherichia coli strains harboring the polyketide synthetase (pks) gene cluster, causes DNA damage and somatic mutations. pks+ E. coli is enriched in primary colorectal cancer (CRC) and is associated with clonal driver mutations, but its role in CRC liver metastasis is unclear. We assessed the association of pks+ E. coli in CRC liver metastasis tissues with systemic and local immune responses and the number of organs involved in recurrence using specimens and clinicopathological data from 239 patients with CRC liver metastasis who underwent metastasectomy. The levels of pks+ E. coli in fresh-frozen specimens were quantified as "very low" (<50th percentile), "low" (50th to 75th percentiles), and "high" (>75th percentile) using a digital PCR. Immunohistochemical analysis of tumor-infiltrating immune cells was performed using tissue microarrays. Systemic inflammation was evaluated using serum C-reactive protein (CRP) levels. pks+ E. coli was detected in 66.7% (157 of 239) liver metastasis tissues. Higher levels of pks+E. coli were associated with decreased serum CRP levels and reduced densities of CD4+ cells and CD163+ cells in the tumor-immune microenvironment. The "high" pks+ E. coli group had fewer metastatic organs involved than the "very low" pks+ E. coli group (mean number of organs: 1.00 vs. 1.23). These findings suggest that pks+ E. coli play a modulating role in CRC metastasis. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is one of the most common causes of death worldwide. Today, this disease does not have an effective treatment, leading to the exploration of novel pharmacological molecules. In this paper, we design and synthesize with a new synthetic route the lipophilic cation derived from gallic acid (TPP+C10) and gentisic acid (GA-TPP+C10), both able to reach mitochondria and uncouple the electron transport chain. Our results show that combining 5-fluorouracil with GA-TPP+C10 has a synergistic cytotoxic effect on CRC cells. Both compounds show antimigratory effects, decreasing signaling pathways and biomarkers. Our results show that mitochondrial agents could be an alternative to standard CRC drugs against this disease. Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Hereditary colorectal cancer syndromes (HCCS) and inflammatory bowel disease (IBD) carry a high risk of developing colorectal cancer (CRC). The co-occurrence of IBD and HCCS is extremely rare. Individuals with HCCS and IBD are prone to developing CRC at a younger age compared to those without IBD, with patients who have ulcerative colitis at such an especially high risk. The interplay between chronic inflammation and genetic predispositions remains poorly understood. Background and aims: Hereditary colorectal cancer syndromes (HCCS), including familial adenomatous polyposis (FAP) and Lynch syndrome (LS), are the two most important high-risk conditions for colorectal cancer (CRC). Inflammatory bowel disease (IBD) increases the risk by two to six times compared with that in the general population. The intersection of these two conditions has rarely been documented in literature. We aimed to summarize the prevalence, pathogenesis, and current evidence-based management of IBD and HCCS and the underlying molecular mechanisms of accelerated carcinogenesis due to combined inflammation and genetic predisposition. Methods: PubMed and Scopus were searched until June 2024 to identify relevant studies investigating the epidemiology, pathogenesis, and management of IBD and coexisting hereditary CRC syndromes. Results: Co-occurrence of IBD and hereditary CRC syndromes is exceptionally uncommon. Individuals with LS and IBD tend to develop CRC at a younger age than those without IBD, with patients with ulcerative colitis facing particularly elevated risks. The interaction between mismatch deficiency and chronic inflammation requires further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Obesity is a clear risk factor for future colorectal cancer (CRC), but its impact on mortality remains to be fully elucidated. Prior studies have had methodologic limitations, and key variables remain under-investigated. In this study of prospectively collected data from the Multiethnic Cohort, pre-diagnosis BMI trajectories were not associated with CRC-specific or all-cause mortality. Factors associated with mortality included African American race or Hawaiian ethnicity, smoking, and diabetes. Accounting for long-term BMI trajectories before diagnosis and other relevant factors demonstrates that obesity is not protective of mortality after CRC diagnosis. Background: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis. Methods: Utilizing the Multiethnic Cohort, we included adults aged 18–75 between 1 January 1993 and 1 January 2019 with a diagnosis of CRC and at least three available BMIs. The primary exposure, BMI, was subjected to group-based trajectory modeling (GBTM). We evaluated all-cause and CRC-specific mortality, using Cox proportional hazard (PH) models. Results: Of 924 persons, the median age was 60 years, and 54% were female. There was no statistically significant association between pre-cancer BMI trajectory and either all-cause or cancer-specific mortality. In competing risk analysis, the risk of CRC-specific mortality was higher for African Americans (HR = 1.56, 95% CI [1.00–2.43], p = 0.048) and smokers (HR = 1.59, 95% CI [1.10–2.32], p = 0.015). Risk of all-cause mortality was higher for Hawaiian persons (HR = 2.85, 95% CI [1.31–6.21], p = 0.009) and persons with diabetes (HR = 1.83, 95% CI [1.08–3.10], p = 0.026). Conclusions: Pre-diagnosis BMI trajectories were not associated with mortality after CRC diagnosis, whereas race/ethnicity, diabetes, and smoking were associated with an increased risk of death. Our findings suggest the obesity paradox alone does not account for mortality after CRC diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This review provides a comprehensive overview of the current knowledge on mutational signatures in colorectal cancer (CRC), highlighting their potential clinical applications. It discusses the challenges and limitations in translating these analyses into clinical practice and proposes strategies to overcome these obstacles. Additionally, it provides insights into future directions and emerging proof-of-concept studies that highlight the translational potential of mutational signature analysis in improving patient care and outcomes in CRC. A multitude of exogenous and endogenous processes have the potential to result in DNA damage. While the repair mechanisms are typically capable of correcting this damage, errors in the repair process can result in mutations. The findings of research conducted in 2012 indicate that mutations do not occur randomly but rather follow specific patterns that can be attributed to known or inferred mutational processes. The process of mutational signature analysis allows for the inference of the predominant mutational process for a given cancer sample, with significant potential for clinical applications. A deeper comprehension of these mutational signatures in CRC could facilitate enhanced prevention strategies, facilitate the comprehension of genotoxic drug activity, predict responses to personalized treatments, and, in the future, inform the development of targeted therapies in the context of precision oncology. The efforts of numerous researchers have led to the identification of several mutational signatures, which can be categorized into different mutational signature references. In CRC, distinct mutational signatures are identified as correlating with mismatch repair deficiency, polymerase mutations, and chemotherapy treatment. In this context, a mutational signature analysis offers considerable potential for enhancing minimal residual disease (MRD) tests in stage II (high-risk) and stage III CRC post-surgery, stratifying CRC based on the impacts of genetic and epigenetic alterations for precision oncology, identifying potential therapeutic vulnerabilities, and evaluating drug efficacy and guiding therapy, as illustrated in a proof-of-concept clinical trial. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with inflammatory bowel disease (IBD) face an increased risk of colorectal cancer, necessitating a surveillance program to detect early signs of cancer. Evaluating the effectiveness and safety of IBD medications in patients with a history of previous or active cancer, as well as assessing antineoplastic drugs in those with IBD, is crucial. This review outlines known risk factors, surveillance, and appropriate management strategies for patients with IBD and concomitant history of cancer. Patients with inflammatory bowel diseases (IBDs), including both ulcerative colitis (UC) and Crohn's disease (CD), are at a higher risk of developing colorectal cancer (CRC). However, advancements in endoscopic imaging techniques, integrated surveillance programs, and improved medical therapies have led to a decrease in the incidence of CRC among IBD patients. Currently, the management of patients with IBD who have a history of or ongoing active malignancy is an unmet need. This involves balancing the risk of cancer recurrence/progression with the potential exacerbation of IBD if the medications are discontinued. The objective of this review is to provide an updated summary of the epidemiology, causes, risk factors, and surveillance approaches for CRC in individuals with IBD, and to offer practical guidance on managing IBD patients with history of previous or active cancer. [ABSTRACT FROM AUTHOR]