Mortality In Colorectal Cancer Research Articles

Hydroxygenkwanin suppresses peritoneal metastasis in colorectal cancer by modulating tumor-associated macrophages polarization

Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p–NF–κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.

Immune cell senescence and exhaustion promote the occurrence of liver metastasis in colorectal cancer by regulating epithelial-mesenchymal transformation.

Liver metastasis (LM) stands as a primary cause of mortality in metastatic colorectal cancer (mCRC), posing a significant impediment to long-term survival benefits from targeted therapy and immunotherapy. However, there is currently a lack of comprehensive investigation into how senescent and exhausted immune cells contribute to LM. We gathered single-cell sequencing data from primary colorectal cancer (pCRC) and their corresponding matched LM tissues from 16 mCRC patients. In this study, we identified senescent and exhausted immune cells, performed enrichment analysis, cell communication, cell trajectory, and cell-based in vitro experiments to validate the results of single-cell multi-omics. This process allowed us to construct a regulatory network explaining the occurrence of LM. Finally, we utilized weighted gene co-expression network analysis (WGCNA) and 12 machine learning algorithms to create prognostic risk model. We identified senescent-like myeloid cells (SMCs) and exhausted T cells (TEXs) as the primary senescent and exhausted immune cells. Our findings indicate that SMCs and TEXs can potentially activate transcription factors downstream via ANGPTL4-SDC1/SDC4, this activation plays a role in regulating the epithelial-mesenchymal transformation (EMT) program and facilitates the development of LM, the results of cell-based in vitro experiments have provided confirmation of this conclusion. We also developed and validated a prognostic risk model composed of 12 machine learning algorithms. This study elucidates the potential molecular mechanisms underlying the occurrence of LM from various angles through single-cell multi-omics analysis in CRC. It also constructs a network illustrating the role of senescent or exhausted immune cells in regulating EMT.

Forecasting Survival Rates in Metastatic Colorectal Cancer Patients Undergoing Bevacizumab-Based Chemotherapy: A Machine Learning Approach

Background: Antibiotics can play a pivotal role in the treatment of colorectal cancer (CRC) at various stages of the disease, both directly and indirectly. Identifying novel patterns of antibiotic effects or responses in CRC within extensive medical data poses a significant challenge that can be addressed through algorithmic approaches. Machine Learning (ML) emerges as a promising solution for predicting clinical outcomes using clinical and heterogeneous cancer data. In the pursuit of our objective, we employed ML techniques for predicting CRC mortality and antibiotic influence. Methods: We utilized a dataset to examine the accuracy of death prediction in metastatic colorectal cancer. In addition, we analyzed the association between antibiotic exposure and mortality in metastatic colorectal cancer. The dataset comprised 147 patients, nineteen independent variables, and one dependent variable. Our analysis involved testing different classification-supervised ML, including an oversampling pool for classification models, Logistic Regression, Decision Trees, Naive Bayes, Support Vector Machine, Random Forest, XGBboost Classifier, a consensus of all models, and a consensus of top models (meta models). Results: The consensus of the top models’ classifier exhibited the highest accuracy among the algorithms tested (93%). This model met the standards for good accuracy, surpassing the 90% threshold considered useful in ML applications. Consistent with the accuracy results, other metrics are also good, including precision (0.96), recall (0.93), F-Beta (0.94), and AUC (0.93). Hazard ratio analysis suggests that there is no discernible difference between patients who received antibiotics and those who did not. Conclusions: Our modelling approach provides an alternative for analyzing and predicting the relationship between antibiotics and mortality in metastatic colorectal cancer patients treated with bevacizumab, complementing classic statistical methods. This methodology lays the groundwork for future use of datasets in cancer treatment research and highlights the advantages of meta models.

Predicting mortality and recurrence in colorectal cancer: Comparative assessment of predictive models

IntroductionColorectal cancer (CRC), also known as colorectal cancer, is a significant disease marked by high fatality rates, ranking as the third leading cause of global mortality. The main objective of this study was to assess the accuracy of predictive models in predicting both mortality events and the probability of disease recurrence. MethodA retrospective analysis was conducted on a cohort of 284 individuals diagnosed with colorectal cancer between 2001 and 2017. Demographic and clinical data, including gender, disease stage, age at diagnosis, recurrence status, and treatment details, were meticulously recorded. We rigorously evaluated various predictive models, including Decision Trees, Random Forests, Random Survival Forests (RSF), Gradient Boosting, mboost, Deep Learning Neural Network (DLNN), and Cox regression. Performance metrics, such as sensitivity, positive predictive value (PPV), specificity, area under the receiver operating characteristic curve (ROC area), and overall accuracy, were calculated for each model to predict mortality and disease recurrence. The analysis was performed using R version 4.1.3 software and the Python programming language. ResultsFor mortality prediction, the mboost model demonstrated the highest sensitivity at 96.9% (95% CI: 0.83–0.99) and an ROC area of 0.88. It also exhibited high specificity at 80% (95% CI: 0.59–0.93), a positive predictive value of 86.1% (95% CI: 0.70–0.95), and an overall accuracy of 89% (95% CI: 0.78–0.96). Random Forests showed perfect sensitivity of 100% (95% CI: 0.85–1) but had low specificity at 0% (95% CI: 0–0.52) and poor overall accuracy (50%). On the other hand, DLNN had the lowest performance metrics for mortality prediction, with a sensitivity of 24% (95% CI: 0.222–0.268), specificity of 75% (95% CI: 0.73–0.77), and a lower positive predictive value of 42% (95% CI: 0.38–0.45). The Gradient Boosting model showed the best performance in predicting recurrence, achieving perfect sensitivity of 100% (95% CI: 0.87–1) and high specificity at 92.9% (95% CI: 0.76–0.99). It also had a high positive predictive value of 93.3% (95% CI: 0.77–0.99). Gradient Boosting, with an ROC area of 96.4%, and mboost, with an ROC area of 75%, demonstrated remarkable performance. DLNN had the lowest performance metrics for recurrence prediction, with sensitivity at 1.75% (95% CI: 0.01–0.02), specificity at 98% (95% CI: 0.97–0.98), and a lower positive predictive value at 52.6% (95% CI: 0.39–0.65). ConclusionIn summary, the mboost model demonstrated outstanding performance in predicting mortality, achieving exceptional results across various evaluation metrics. Random Forests exhibited perfect sensitivity but showed poor specificity and overall accuracy. The DLNN model displayed the lowest performance metrics for mortality prediction. In terms of recurrence prediction, the Gradient Boosting model outperformed other models with perfect sensitivity, high specificity, and positive predictive value. The DLNN model had the lowest performance metrics for recurrence prediction. Overall, the results emphasize the effectiveness of the mboost and Gradient Boosting models in predicting mortality and recurrence in colorectal cancer patients.

Colorectal cancer recurrence and its impact on survival after curative surgery: An analysis based on multistate models

AimTo investigate the usefulness of multistate models (MSM) for determining colorectal cancer (CRC) recurrence rate, to analyse the effect of different factors on tumour recurrence and death, and to assess the impact of recurrence for CRC prognosis. MethodsObservational follow-up study of incident CRC cases disease-free after curative resection in 2006–2013 (n = 994). Recurrence and mortality were analyzed with MSM, as well as covariate effects on transition probabilities. ResultsCumulative incidence of recurrence at 60 months was 13.7%. Five years after surgery, 70.3% of patients were alive and recurrence-free, and 8.4% were alive after recurrence.Recurrence has a negative impact on prognosis, with 5-year CRC-related mortality increasing from 3.8% for those who are recurrence-free 1-year after surgery to 33.6% for those with a recurrence.Advanced stage increases recurrence risk (HR = 1.53) and CRC-related mortality after recurrence (HR = 2.35). CRC-related death was associated with age in recurrence-free patients, and with comorbidity after recurrence.As expected, age≥75 years was a risk factor for non-CRC-related death with (HR = 7.76) or without recurrence (HR = 4.26), while its effect on recurrence risk was not demonstrated. ConclusionsMSM allows detailed analysis of recurrence and mortality in CRC. Recurrence has a negative impact on prognosis. Advanced stage was a determining factor for recurrence and CRC-death after recurrence.

Screening and Colonoscopy Quality Measures: Ethnic Disparities and Impact on Patients' Outcome.

Recent reports have confirmed the improving trends in colorectal cancer (CRC) incidence and outcomes. Still, disparities in incidence and mortality in CRC continue to persist between major ethnic groups despite the provision of widespread screening and improved care. We aimed to outline, from an endoscopic point of view, ethnic disparities in major endoscopic measures concerned with CRC screening and detection and track their impact on patients' outcomes. We reviewed electronic reports of patients referred for colonoscopy procedures over 20 years. We compared demographic, clinical, and endoscopic findings between major ethnic population groups in Israel. In addition, trends of screening utilization, bowel preparation, and polyp detection rates were tracked, and the incidence of CRC diagnosis was followed. A total of 51307 patients had undergone colonoscopies, of whom 16% were Arabs, and 84% were Jewish. The procedures performed for CRC screening throughout the study period were significantly lower in Arabs (5% vs. 13.1%; P < 0.0001). In parallel, for most of the follow-up period, the Arab patients had higher rates of inadequate bowel preparation (overall: 19.9% vs. 12%; P < 0.001) and a lower polyp detection rate (16.7% vs. 22.5%; P < 0.0001). Expectedly, the incidence of CRC has steadily decreased in the Jewish group, while an adverse pattern of increasing incidence was documented in the Arab patient during the follow-up period. Characterized by lower screening utilization and poor bowel preparation, the incidence of CRC development in Arab patients is increasing, while improving trends of CRC were observed in their Jewish counterparts.

Association of pre-diagnostic physical exercise and peri-diagnostic body composition with mortality in non-metastatic colorectal cancer

PurposeSarcopenia and myosteatosis, quantified via computed tomography (CT), are associated with poor colorectal cancer outcomes. These body composition estimates can be influenced by physical exercise. We explored the correlation between pre-diagnostic physical exercise, body composition close to diagnosis, and the combined prognosis impact of these factors.MethodsWe studied 519 stage I–III colorectal cancer (CRC) cases diagnosed 2000–2016 with pre-diagnostic self-reported recreational physical exercise data collected in the prospective, population-based Northern Sweden Health and Disease Study, and CT-estimated skeletal muscle index (SMI) or skeletal muscle density (SMD). Risk estimates were calculated by multivariable logistic regression and Cox proportional hazards models.ResultsNo association was seen between low pre-diagnostic physical exercise and sarcopenia/myosteatosis in the multivariable model adjusted for age, sex, educational level, tumor stage, and tumor location. In multivariable Cox regression models, the combination of low pre-diagnostic physical exercise and either sarcopenia or myosteatosis at the time of diagnosis was associated with cancer-specific mortality compared to the reference group of high physical exercise combined with no sarcopenia/myosteatosis (adjusted HR 1.94 95% CI 1.00–3.76 for sarcopenia and adjusted HR 2.39 95% CI 1.16–4.94 for myosteatosis).ConclusionsThe combined presence of low pre-diagnostic physical exercise and sarcopenia or myosteatosis was associated with increased CRC-specific mortality. Despite the positive effect on prognosis, physical exercise did not alter body composition estimates at diagnosis, which could indicate attenuation from other factors.

Radiomics and Machine Learning for prediction of two-year disease-specific mortality and KRAS mutation status in metastatic colorectal cancer

PurposeColorectal cancer is usually accompanied by liver metastases. The prediction of patient evolution is essential for the choice of the appropriate therapy. The aim of this study is to develop and evaluate machine learning models to predict KRAS gene mutations and 2-year disease-specific mortality from medical images. MethodsClinical and follow-up information was collected from patients with metastatic colorectal cancer who had undergone computed tomography prior to liver resection. The dominant liver lesion was segmented in each scan and radiomic features were extracted from the volumes of interest. The 65% of the cases were employed to perform feature selection and to train machine learning algorithms through cross-validation. The best performing models were assembled and evaluated in the remaining cases of the cohort. ResultsFor the mortality model development, 101 cases were used as training set (64 alive, 37 deceased) and 35 as test set (22 alive, 13 deceased); while for KRAS mutation models, 55 cases were used for training (31 wild-type, 24 mutated) and 30 for testing (17 wild-type, 13 mutated). The ensemble of top performing models resulted in an area under the receiver operating characteristic curve of 0.878 for mortality and 0.905 for KRAS prediction. ConclusionsPredicting the prognosis of patients with metastatic colorectal cancer is useful for making timely decisions about the best treatment options. This study presents a noninvasive method based on quantitative analysis of baseline images to identify factors influencing patient outcomes, with the aim of incorporating these tools as support systems.

Pre- and post-diagnostic dairy intake in relation to recurrence and all-cause mortality in people with stage I-III colorectal cancer.

Higher dairy consumption is associated with a lower risk of colorectal cancer (CRC), but no studies thus far have investigated its relation with recurrence in CRC. Few studies have investigated total dairy in relation to mortality in CRC, and yielded inconsistent results. In this prospective cohort study, people newly diagnosed with stage I-III CRC filled out a food frequency questionnaire at diagnosis (n = 1812) and six months after diagnosis (n = 1672). We examined associations between pre- and post-diagnostic intake of total dairy, low-fat dairy, high-fat dairy, milk, yoghurt, and cheese with recurrence and all-cause mortality using multivariable Cox proportional hazard models and restricted cubic splines (RCS). A total of 176 recurrences and 301 deaths occurred during a median follow-up of 3.0 and 5.9years, respectively. Before diagnosis, a higher low-fat dairy intake was associated with a lower risk of recurrence (HRQ4vsQ1: 0.42, 95% CI 0.26-0.67; PRCS: 0.008) and all-cause mortality (HRQ4vsQ1: 0.58, 95% CI 0.41-0.81; PRCS < 0.001), whereas a higher high-fat dairy consumption tended to be associated with an increased all-cause mortality risk (HRQ4vsQ1: 1.41, 95% CI 0.98-2.01; PRCS: 0.030). After diagnosis, only the associations between low- and high-fat dairy in relation to all-cause mortality remained. This study demonstrated that higher pre- and post-diagnostic intakes of low-fat dairy were associated with a reduced all-cause mortality risk in people with stage I-III CRC, whereas higher intakes of high-fat dairy were associated with an increased all-cause mortality risk. Also, a higher pre-diagnostic low-fat dairy intake was associated with a reduced risk of recurrence. Clinical Trials.gov identifier: NCT03191110.

Prognostic scoring system to predict mortality after surgery in resectable colorectal cancer

Link of Video Abstract: https://youtu.be/mYpKu0PcJrM Background: Colorectal cancer remains as the major problem worldwide. Numerous studies have investigated factors associated with mortality and recurrence rates in colorectal cancer. To facilitate the everyday use of mortality predictors, they should be incorporated into a prognostic scoring system. This study aimed to identify factors affecting mortality in resectable colorectal cancer patients after surgery and to develop a prognostic scoring system capable of predicting mortality in these patients. Methods: This retrospective cohort study involved colorectal cancer patients at Cipto Mangunkusumo Hospital, Indonesia, from January 2016 – April 2020 diagnosed with resectable colorectal cancer. Data were collected from medical records, operation reports, histopathology reports, and laboratory test results. Mortality was assessed three years after curative surgery. Result: A total of 214 resectable colorectal cancer patients were included in the study. Tumor size ≥ 5 cm, T3/T4 staging, absence of adjuvant chemotherapy, unachieved free circumferential margin, and CEA levels &gt; 11.4 ng/mL were significantly associated with increased three-year mortality. The constructed three-year mortality prognostic scoring system was able to predict outcomes with a sensitivity of 91.3% and a specificity of 67.6%. Conclusion: The prognostic scoring system, consisting of five variables, is significantly capable of predicting three-year mortality rates with high sensitivity

Evaluating whether KRAS/BRAF mutation status, anaemia and obstruction are associated with recurrence and mortality in non-metastatic colorectal cancer.

KRAS and BRAF testing is currently recommended in metastatic colorectal cancer. There is evidence that KRAS and BRAF mutation status may act as a prognostic biomarker in patients with non-metastatic colorectal cancer. Data is limited on whether KRAS and BRAF mutation status impacts recurrence and mortality in patients with non-metastatic colorectal cancer. A retrospective cohort study was conducted in a tertiary hospital examining outcomes in patients who had KRAS and BRAF testing for colorectal cancer in 2017. Primary outcomes were all-cause mortality and recurrence. Multivariable analysis for both outcomes, used cause specific Cox proportional hazards models with KRAS/BRAF status as exposure. For time to recurrence, a sensitivity analysis was performed with a weighted Fine-Grey model with death as a competing risk. KRAS mutation status was not associated with all-cause mortality (average Hazard Ratio (aHR) = 0.78, 95% CI 0.28-2.21) or recurrence (aHR = 0.96, 95% CI 0.32-2.86). BRAF mutation status was not associated with time to all-cause mortality (aHR = 3.06, 95% CI 0.79-11.8) or recurrence (aHR = 0.94, 95% CI 0.13-6.57). Increased risk of recurrence was significantly associated with large bowel obstruction (aHR = 2.73, 95% CI 1.16-6.45) and anaemia (aHR = 3.39, 95% CI 1.06-10.8) at time of surgery. This study did not demonstrate an association between KRAS and BRAF mutations and all-cause mortality or recurrence. A significantly increased risk of cancer recurrence was found in patients with large bowel obstruction and in patients with anaemia at time of surgery. Anaemia should be promptly investigated and corrected prior to colorectal cancer surgery.

Associations of advanced age with comorbidity, stage and primary subsite as contributors to mortality from colorectal cancer.

Although survival from colorectal cancer (CRC) has improved substantially in recent decades, people with advanced age still have a high likelihood of mortality from this disease. Nonetheless, few studies have investigated how cancer stage, subsite and comorbidities contribute collectively to poor prognosis of older people with CRC. Here, we decided to explore the association of age with mortality measures and how other variables influenced this association. Using linkage of several administrative datasets, we investigated the risk of death among CRC cases during 2003-2014. Different models were used to explore the association of age with mortality measures and how other variables influenced this association. Our results indicated that people diagnosed at a young age and with lower comorbidity had a lower likelihood of all-cause and CRC-specific mortality. Aging had a greater association with mortality in early-stage CRC, and in rectal cancer, compared that seen with advanced-stage CRC and right colon cancer, respectively. Meanwhile, people with different levels of comorbidity were not significantly different in terms of their increased likelihood of mortality with advanced age. We also found that while most comorbidities were associated with all-cause mortality, only dementia [SHR = 1.43 (1.24-1.64)], Peptic ulcer disease [SHR = 1.12 (1.02-1.24)], kidney disease [SHR = 1.11 (1.04-1.20)] and liver disease [SHR = 1.65 (1.38-1.98)] were risk factors for CRC-specific mortality. This study showed that the positive association of advanced age with mortality in CRC depended on stage and subsite of the disease. We also found only a limited number of comorbidities to be associated with CRC-specific mortality. These novel findings implicate the need for more attention on factors that cause poor prognosis in older people.

The association of preoperative high-sensitivity cardiac troponin i and long-term outcomes in colorectal cancer patients received tumor resection surgery

BackgroundThis study aimed to evaluate the association between preoperative hs-cTnI and long-term mortality and major adverse cardiovascular events (MACE) in colorectal cancer patients.MethodsThis single-center retrospective cohort study included 1105 consecutive colorectal cancer patients who received tumor resection surgery between January 2018 and June 2020. Inclusion criteria were an age ≥ 18 years and had been tested for hs-cTnI on admission within 7 days prior to tumor resection surgery. Exclusion criteria were emergent surgery, failure to received tumor resection surgery, hospital death, there was clinical evidence of unstable coronary artery disease or pulmonary embolism occurred before operation according to medical record. The primary endpoint was all-cause death. Secondary endpoint was major adverse cardiovascular events (MACE).ResultsA total of 1105 patients were enrolled: 1032 with normal hs-cTnI and 73 with elevated hs-cTnI. The mean follow-up was 24.4 ± 10.8 months, 176 patients died and 39 patients met MACE. In the elevated troponin group, 50%, 32.1% and 17.9% died from cancer, cardiovascular and other causes, while those in the normal troponin group were 75.7%, 2% and 22.3%, there was statistical difference between 2 groups (P < 0.001). Patients with elevated preoperative hs-cTnI had significantly higher mortality (P < 0.001) and more MACE (P < 0.001) compared with those with normal hs-cTnI. A propensity-matching analysis were performed, resulting in 151 patients with normal hs-cTnI and 60 patients with elevated hs-cTnI. The matched population had the similar results for all-cause death (P = 0.009) and MACE (P = 0.001). The results were consistent after further excluding 147 patients who had received chemoradiotherapy prior to surgery in subgroup analysis. The results of multivariate Cox regression analysis shown that hs-cTnI was one of the best predictors for all-cause death (hazard ratio [HR] 2.278; 95% confidence interval [CI] 1.19–4.361) and MACE (HR, 3.523; 95%CI, 1.477–8.403) in total populations, similar results were found in subgroup analysis.ConclusionsColorectal cancer patients without myocardial ischemia manifestation but with elevated hs-cTnI prior to tumor resection surgery were at increased risk for long-term all-cause death and MACE, irrespective of whether they have received chemoradiotherapy prior to surgery.

Carcinoembryonic Antigen CEA - Prognostic Value in Immediate Post-Operative Mortality in Colorectal Cancer.

This study investigates the prognostic significance of carcinoembryonic antigen (CEA) levels in predicting early postoperative mortality in patients who have undergone colorectal cancer surgery. Between 2017 and 2022, total of 325 patients were enrolled in the study, and their preoperative serum CEA levels were measured. Relevant clinical and operative data were extracted and correlations between CEA levels and postoperative mortality was analysed. Among the surgical cases, 180 patients (55.3%) exhibited elevated CEA levels. Within the early postoperative period of 30 days, 14 patients (4.3%) succumbed, comprising 8 cases (2.4%) of colon cancer and 6 cases (1.8%) of rectal cancer. Notably, only 3 cases (0.9%), consisting of 1 (0.3%) colon cancer and 2 (0.6%) rectal cancer cases, were associated with an elevated CEA level. However, no statistically significant correlations were observed between CEA levels and early postoperative mortality. Our findings indicate that increased CEA levels may not serve as a reliable non-invasive marker for identifying patients at high risk of early mortality in the context of colo-rectal cancer surgery.

Patterns of staging, treatment, and mortality in gastric, colorectal, and lung cancer among older adults with and without preexisting dementia: a Japanese multicentre cohort study

BackgroundLittle is known about dementia’s impact on patterns of diagnosis, treatment, and outcomes in cancer patients. This study aimed to elucidate the differences in cancer staging, treatment, and mortality in older cancer patients with and without preexisting dementia.MethodsUsing cancer registry data and administrative data from 30 hospitals in Japan, this multicentre retrospective cohort study examined patients aged 65–99 years who were newly diagnosed with gastric, colorectal, or lung cancer in 2014–2015. Dementia status (none, mild, and moderate-to-severe) at the time of cancer diagnosis was extracted from clinical summaries in administrative data, and set as the exposure of interest. We constructed multivariable logistic regression models to analyse cancer staging and treatment, and multivariable Cox regression models to analyse three-year survival.ResultsAmong gastric (n = 6016), colorectal (n = 7257), and lung (n = 4502) cancer patients, 5.1%, 5.8%, and 6.4% had dementia, respectively. Patients with dementia were more likely to receive unstaged and advanced-stage cancer diagnoses; less likely to undergo tumour resection for stage I, II, and III gastric cancer and for stage I and II lung cancer; less likely to receive pharmacotherapy for stage III and IV lung cancer; more likely to undergo tumour resection for all-stage colorectal cancer; and more likely to die within three years of cancer diagnosis. The effects of moderate-to-severe dementia were greater than those of mild dementia, with the exception of tumour resection for colorectal cancer.ConclusionOlder cancer patients with preexisting dementia are less likely to receive standard cancer treatment and more likely to experience poorer outcomes. Clinicians should be aware of these risks, and would benefit from standardised guidelines to aid their decision-making in diagnosing and treating these patients.

MFAP2, upregulated by m1A methylation, promotes colorectal cancer invasiveness via CLK3.

Distant metastasis is the main cause of mortality in colorectal cancer (CRC) patients. N1-methyladenosine (m1A) is a type of epitranscriptome modification. While its regulatory effect on mRNA and its role in CRC metastasis remain unclear. The m1A methylation profile of mRNAs in CRC was revealed by m1A methylated RNA immunoprecipitation sequencing. The expression of MFAP2 in tumor tissues was measured by immunohistochemistry and then correlated with the clinical characteristics and prognosis of CRC patients. The role of MFAP2 in the invasiveness of CRC cells was evaluated by transwell assays and peritoneal metastatic model in nude mice. The downstream targets of MFAP2 was screened by mass spectrometry analysis. Then the role of MFAP2-CLK3 signaling axis was verified by cotransfecting MFAP2 siRNA and CLK3 plasmid in CRC cells. Microfibril associated protein 2 (MFAP2) mRNA was overexpressed and m1A-hypermethylated in CRC. High expression of MFAP2 was closely related to lymph node metastasis and distant metastasis, leading to poor prognosis in patients with CRC. In vivo and in vitro studies showed that silencing of MFAP2 inhibited the migration, invasion and metastasis of CRC cells. CDC Like Kinase 3 (CLK3) was a potential downstream target of MFAP2. Further studies showed that MFAP2 depletion might induce autophagic degradation of CLK3, and the role of MFAP2 in the invasiveness of CRC cells was dependent on CLK3. Our results uncover a newly identified MFAP2-CLK3 signaling axis, which is a potential therapeutic target for CRC metastasis.

Novel machine learning algorithm can identify patients at risk of poor overall survival following curative resection for colorectal liver metastases.

The primary cause of mortality in colorectal cancer is metastatic disease. We investigated the ability of a machine learning (ML) algorithm to stratify overall survival (OS) of patients undergoing curative resection for colorectal liver metastases (CRLM). Patients undergoing curative liver resection for CRLM between 2010-2021 at the University Hospital RWTH Aachen were eligible for this retrospective study. Patients with recurrent metastases, incomplete resections, or early deaths, were excluded. A gradient-boosted decision tree (GBDT) model identified patients at risk of poor OS, based on clinicopathological characteristics. Differences in survival were compared with Kaplan-Meier analysis and the log-rank test. A total of 487 patients were split into training (n=389, 80%) and test cohorts (n=98, 20%). Of the latter, 20 (20%) were identified by the GBDT model as high-risk and showed significantly reduced OS (23 months vs 52 months, P=.005) and increased hazard ratio (2.434, 95%CI 1.280-4.627, P=.007). The strongest predictors were preoperative serum carcinoembryonic antigen (CEA), age, diameter of the largest metastasis, number of metastases, body mass index, and primary tumor grading. A GBDT model can identify high-risk patients regarding OS after curative resection of CRLM. Closer follow-up and aggressive systemic treatment strategies may be beneficial to these patients.

Changing patterns of multidisciplinary team treatment, early mortality, and survival in colorectal cancer.

BackgroundThis study reports early mortality and survival from colorectal cancer in relation to the pattern of treatments delivered by the multidisciplinary team (MDT) meeting at a high-volume institution in England over 14 years.MethodsAll patients diagnosed with colorectal cancer and discussed during MDT meetings from 2003 to 2016 at a single institution were reviewed. Three time intervals (2003–2007, 2008–2012, and 2013–2016) were compared regarding initial surgical management (resection, local excision, non-resection surgery, and no surgery), initial oncological therapy, 90-day mortality, and crude 2-year survival for the whole cohort. Sub-analyses were performed according to age greater or less than 80 years.ResultsThe MDT managed 4617 patients over 14 years (1496 in the first interval and 1389 in the last). Over this time, there was a reduction in emergency resections from 15.5 per cent to 9.0 per cent (P < 0.0001); use of oncological therapies increased from 34.6 per cent to 41.6 per cent (P < 0.0001). The 90-day mortality after diagnosis of colorectal cancer dropped from 14.8 per cent to 10.7 per cent (P < 0.001) and 2-year survival improved from 58.6 per cent to 65 per cent (P < 0.001). Among patients aged 80 years or older (425 and 446, in the first and last intervals respectively) there was, in addition, a progressive increase in ‘no surgery’ rate from 33.6 per cent to 50.2 per cent (P < 0.0001) and a reduction in elective resections from 42.4 per cent to 33.9 per cent (P = 0.010). The 90-day mortality after elective resection fell from 10.0 per cent (18 of 180) to 3.3 per cent (5 of 151; P = 0.013).ConclusionsSurvival from colorectal cancer improved significantly over 14 years. Among patients aged ≥80 years, major changes in the type of treatment delivered were associated with a decrease in postoperative mortality.

S-Adenosylmethionine Inhibits Colorectal Cancer Cell Migration through Mirna-Mediated Targeting of Notch Signaling Pathway.

Metastasis is a leading cause of mortality and poor prognosis in colorectal cancer (CRC). Thus, the identification of new compounds targeting cell migration represents a major clinical challenge. Recent findings evidenced a central role for dysregulated Notch in CRC and a correlation between Notch overexpression and tumor metastasis. MicroRNAs (miRNAs) have been reported to cross-talk with Notch for its regulation. Therefore, restoring underexpressed miRNAs targeting Notch could represent an encouraging therapeutic approach against CRC. In this context, S-adenosyl-L-methionine (AdoMet), the universal biological methyl donor, being able to modulate the expression of oncogenic miRNAs could act as a potential antimetastatic agent. Here, we showed that AdoMet upregulated the onco-suppressor miRNAs-34a/-34c/-449a and inhibited HCT-116 and Caco-2 CRC cell migration. This effect was associated with reduced expression of migration-/EMT-related protein markers. We also found that, in colorectal and triple-negative breast cancer cells, AdoMet inhibited the expression of Notch gene, which, by luciferase assay, resulted the direct target of miRNAs-34a/-34c/-449a. Gain- and loss-of-function experiments with miRNAs mimics and inhibitors demonstrated that AdoMet exerted its inhibitory effects by upregulating miRNAs-34a/-34c/-449a. Overall, these data highlighted AdoMet as a novel Notch inhibitor and suggested that the antimetastatic effects of AdoMet involve the miRNA-mediated targeting of Notch signaling pathway.

Once-only colonoscopy or two rounds of faecal immunochemical testing 2 years apart for colorectal cancer screening (SCREESCO): preliminary report of a randomised controlled trial

Screening for colorectal cancer is done with lower gastrointestinal endoscopy or stool-based tests. There is little evidence from randomised trials to show primary colonoscopy reduces mortality in colorectal cancer. We aimed to investigate the effect of screening with once-only colonoscopy or two rounds of faecal immunochemical test screening on colorectal cancer mortality and incidence. We did a randomised controlled trial in Sweden (SCREESCO). Residents in 18 of 21 regions who were age 60 years in the year of randomisation were identified from a population register maintained by the Swedish Tax Agency. A statistician with no further involvement in the trial used a randomised block method to assign individuals to once-only colonoscopy, two rounds of faecal immunochemical testing (OC-Sensor; 2 years apart), or a control group (no intervention; standard diagnostic pathways), in a ratio of 1:6 for colonoscopy versus control and 1:2 for faecal immunochemical testing versus control. Masking was not possible due to the nature of the trial. The primary endpoints of the trial are colorectal cancer mortality and colorectal cancer incidence. Here, we report preliminary participation rates, baseline findings, and adverse events from March, 2014, to December, 2020, in the two intervention groups after completion of recruitment and screening, up to the completion of the second faecal immunochemical testing round. Analyses were done in the intention-to-screen population, defined as all individuals who were randomly assigned to the respective study group. This study is registered with ClinicalTrials.gov, NCT02078804. Between March 1, 2014, and Dec 31, 2020, 278 280 people were included in the study; 31 140 were assigned to the colonoscopy group, 60 300 to the faecal immunochemical test group, and 186 840 to the control group. 10 679 (35·1%) of 30 400 people who received an invitation for colonoscopy participated. 33 383 (55·5%) of 60 137 people who received a postal faecal immunochemical test participated. In the intention-to-screen analysis, colorectal cancer was detected in 49 (0·16%) of 31 140 people in the colonoscopy group versus 121 (0·20%) of 60 300 in the faecal immunochemical test group (relative risk [RR] 0·78, 95% CI 0·56-1·09). Advanced adenomas were detected in 637 (2·05%) people in the colonoscopy group and 968 (1·61%) in the faecal immunochemical test group (RR 1·27, 95% CI 1·15-1·41). Colonoscopy detected more right-sided advanced adenomas than faecal immunochemical testing. There were two perforations and 15 major bleeds in 16 555 colonoscopies. No intervention-related deaths occurred. The diagnostic yield and the low number of adverse events indicate that the design from this trial, both for once-only colonoscopy and faecal immunochemical test screening, could be transferred to a population-based screening service if a benefit in disease-specific mortality is subsequently shown. Swedish regions, County Council, Regional Cancer Center Mellansverige, Swedish Cancer Society, Aleris Research and Development Fund, Eiken Chemical.