• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/therapy
• Tumor Microenvironment
• Neoplasm Metastasis

• Lung cancer
• metastasis
• pleural invasion
• pretreatment evaluation

• Brain metastasis
• Colorectal cancer
• Gene expression signature
• Metastatic organotropism

• Humans
• Brain Neoplasms/secondary
• Brain Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/genetics
• Male
• Female
• Middle Aged
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Aged
• Transcriptome
• Liver Neoplasms/secondary
• Liver Neoplasms/genetics
• Liver Neoplasms/metabolism
• Prognosis
• Gene Expression Profiling
• ROC Curve
• Adult
• Gene Expression Regulation, Neoplastic

• Ludwig-Maximilians-Universität München (1024)

• cancer
• evolution

• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/pathology
• Mutation
• Selection, Genetic
• Biomarkers, Tumor/genetics
• Mutation, Missense
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/pathology

• RR170048 Cancer Prevention and Research Institute of Texas
• U19CA203654 NIH HHS
• National Institutes of Health

• BRAF
• KRAS
• NRAS
• PIK3CA
• clinicopathological feature
• colorectal cancer

• he Science and Technology Program of Meizhou
• the Social Development Science and Technology Program Project of Meizhou

Peritoneal metastasis (PM) after primary surgery for colorectal cancer (CRC) has the worst prognosis. Prediction and early detection of metachronous PM (m-PM) have an important role in improving postoperative prognosis of CRC. However, commonly used imaging methods have limited sensitivity to detect PM early. We aimed to establish a nomogram model to evaluate the individual probability of m-PM to facilitate early interventions for high-risk patients.

To establish and validate a nomogram model for predicting the occurrence of m-PM in CRC within 3 years after surgery.

We used the clinical data of 878 patients at the Second Hospital of Jilin University, between January 1, 2014 and January 31, 2019. The patients were randomly divided into training and validation cohorts at a ratio of 2:1. The least absolute shrinkage and selection operator (LASSO) regression was performed to identify the variables with nonzero coefficients to predict the risk of m-PM. Multivariate logistic regression was used to verify the selected variables and to develop the predictive nomogram model. Harrell’s concordance index, receiver operating characteristic curve, Brier score, and decision curve analysis (DCA) were used to evaluate discrimination, distinctiveness, validity, and clinical utility of this nomogram model. The model was verified internally using bootstrapping method and verified externally using validation cohort.

LASSO regression analysis identified six potential risk factors with nonzero coefficients. Multivariate logistic regression confirmed the risk factors to be independent. Based on the results of two regression analyses, a nomogram model was established. The nomogram included six predictors: Tumor site, histological type, pathological T stage, carbohydrate antigen 125, v-raf murine sarcoma viral oncogene homolog B mutation and microsatellite instability status. The model achieved good predictive accuracy on both the training and validation datasets. The C-index, area under the curve, and Brier scores were 0.796, 0.796 [95% confidence interval (CI) 0.735-0.856], and 0.081 for the training cohort and 0.782, 0.782 (95%CI 0.690-0.874), and 0.089 for the validation cohort, respectively. DCA showed that when the threshold probability was between 0.01 and 0.90, using this model to predict m-PM achieved a net clinical benefit.

We have established and validated a nomogram model to predict m-PM in patients undergoing curative surgery, which shows good discrimination and high accuracy.

• Colorectal cancer
• Metachronous peritoneal metastasis
• Risk factor
• Nomogram

Colorectal cancer is one of the common malignant tumors of the digestive system in clinical practice. Due to the anatomical characteristics of the colorectum itself, colorectal cancer is prone to liver metastasis. Approximately 15%-25% of colorectal cancer cases are complicated with liver metastasis at diagnosis, 15%-25% are complicated with liver metastasis after radical resection of colorectal cancer, and 80%-90% with liver metastasis cannot undergo radical resection initially. The 5-year survival rate is less than 5%, and liver metastasis is the main cause of death in patients with colorectal cancer. In recent years, with the clinical application of effective chemotherapy and molecular targeted drugs, as well as the rapid development of surgical techniques, an individualized safe, efficient, fast, treatment plan can be formulated according to patients' age, primary colorectal tumor location, degree of differentiation, Ras and B-Raf gene status, tumor size, number and distribution of metastases in the liver. By shrinking the tumor volume in the liver and increasing the residual liver volume, liver metastatic tumors can undergo surgical resection or disease-free status can be achieved in patients with liver metastasis. As a result, patients with colorectal liver metastases can achieve a 5-year survival rate of 30%-57%, which greatly improves the prognosis after operation. According to the postoperative adverse factors, individualized preventive measures are worked out to reduce the impact of adverse factors and improve the prognosis of patients with colorectal liver metastases. In this paper, we systematically discuss the clinical strategy of conversion therapy and surgical treatment for unresectable colorectal cancer liver metastases by reviewing the relevant domestic and foreign literature, so as to provide a theoretical reference for the selection of clinical treatment and program for patients with unresectable colorectal cancer liver metastases.

• Colorectal carcinoma
• Liver metastasis
• Conversion therapy
• Clinical strategy
• Surgery

• akt
• braf
• colorectal cancer
• kras
• nras
• pik3ca

• Class I Phosphatidylinositol 3-Kinases/genetics
• Class I Phosphatidylinositol 3-Kinases/metabolism
• Codon/therapeutic use
• Colorectal Neoplasms/pathology
• ErbB Receptors/genetics
• GTP Phosphohydrolases
• Humans
• Membrane Proteins
• Microsatellite Instability
• Mutation
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins B-raf/genetics
• Proto-Oncogene Proteins B-raf/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Proto-Oncogene Proteins p21(ras)/genetics
• Proto-Oncogene Proteins p21(ras)/metabolism
• Romania

• brain metastasis
• colorectal cancer
• prognosis
• survival
• treatment

• Bevacizumab/therapeutic use
• Brain Neoplasms/pathology
• Colorectal Neoplasms/pathology
• Humans
• Prognosis
• Retrospective Studies

Colorectal cancer remains a public health issue and most colon cancer patients succumb to the development of metastases. Using a specific protocol of pressure-assisted interstitial fluid extrusion to recover soluble biomarkers, we identified paladin as a potential colon cancer liver metastases biomarker.

Using shRNA gene knockdown, we explored the biological function of paladin in colon cancer cells and investigated the phospho-proteome within colon cancer cells. We successively applied in vitro migration assays, in vivo metastasis models and co-immunoprecipitation experiments.

We discovered that paladin is required for colon cancer cell migration and metastasis, and that paladin depletion altered the phospho-proteome within colon cancer cells. Data are available via ProteomeXchange with identifier PXD030803. Thanks to immunoprecipitation experiments, we demonstrated that paladin, was interacting with SSH1, a phosphatase involved in colon cancer metastasis. Finally, we showed that paladin depletion in cancer cells results in a less dynamic actin cytoskeleton.

Paladin is an undervalued protein in oncology. This study highlights for the first time that, paladin is participating in actin cytoskeleton remodelling and is required for efficient cancer cell migration.

• colorectal cancer
• decision curve analysis
• exploratory laparoscopy
• nomogram
• occult peritoneal metastasis

• National Natural Science Foundation of China
• Sun Yat-sen University

Early detection of synchronous colorectal peritoneal metastases (CPMs) is difficult due to the absence of typical symptoms and the low accuracy of imaging examinations. Increasing the knowledge of the risk factors for synchronous CPM may be essential for early diagnosis and improving their management. This study aimed to identify the risk factors for synchronous CPM.

The study was registered at PROSPERO (CRD42020198548). The PubMed, Embase and Cochrane Library databases were searched for studies comparing the clinicopathological and molecular features between patients with or without synchronous CPM. The pooled data were assessed by a random-effects model.

Twenty-five studies were included. A synchronous CPM was positively associated with female sex (OR 1.299; 1.118 to 1.509; P = 0.001), PROK1/PROKR2-positivity (OR 2.244; 1.031 to 4.884; P = 0.042), right-sided colon cancer (OR 2.468; 2.050 to 2.970; P < 0.001), poorly differentiated grade (OR 2.560; 1.537 to 4.265; P < 0.001), BRAF mutation (OR 2.586; 1.674 to 3.994; P < 0.001), mucinous adenocarcinoma (OR 3.565; 2.095 to 6.064; P < 0.001), signet-ring cell carcinoma (OR 4.480; 1.836 to 10.933; P = 0.001), N1-2 (OR 5.665; 3.628 to 8.848; P < 0.001), T4 (OR 12.331; 7.734 to 19.660; P < 0.001) and elevated serum CA19-9 (OR 12.868; 5.196 to 31.867; P < 0.001).

These evidence-based risk factors are indicators that could predict the presence of synchronous CPMs and can improve their management.

www.crd.york.ac.uk/prospero, identifier: CRD42020198548.

• National Natural Science Foundation of China
• Sun Yat-sen University

• colon cancer
• microsatellite instability

Colorectal cancer (CRC) remains one of the main causes of cancer death in developed countries. Yet, it is potentially preventable, by removing the precursor lesions - adenomas or serrated lesions. Several studies proved that this intervention reduces CRC mortality and that the first colonoscopy’s results can guide surveillance strategies. More recently, it became clear that several carcinogenesis pathways may lead to sporadic CRC. CRC is a heterogeneous disease, characterized by multiple molecular subtypes. Three main pathways have been implicated in the development of CRC: Chromosomal instability, microsatellite instability, and the “serrated” pathways, with overlapping features between them. This and other molecular and genetic based CRC classifications are known to have clinical implications, spanning from familial risk assessment to therapy choices. The authors review basic science data and provide insight on current implications for the management of patients with CRC.

• Colorectal cancer
• Carcinogenesis pathways
• Microsatellite instability
• APC
• KRAS
• BRAF

• Colorectal cancer
• Imaging
• Liquid biopsy
• Tissue and serum tumor markers

• Biomarkers, Tumor
• Colorectal Neoplasms/diagnostic imaging
• Humans
• Liquid Biopsy
• Neoplasm Recurrence, Local
• Radiologists

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), often combined with systemic therapy, can be offered to selected colorectal peritoneal metastases (PM) patients. However, clinical heterogeneity and the lack of high-level evidence challenges determination of the correct treatment strategy. This review aims to provide an overview of current strategies to predict survival of colorectal PM patients treated with CRS and HIPEC, guiding clinicians to select a suitable treatment-strategy and to inform patients about their prognosis. First, the prognostic relevance of several clinicopathological prognostic factors, such as extent of PM, location of primary tumor, histology type, and the presence of lymph node or liver metastases will be discussed. Subsequently, special attention will be given to recent developments in several aspects of tumor biology such as RAF/RAS mutations, circulating tumor DNA, immunoprofiling, and consensus molecular subtypes. Finally, currently available prognostic models to predict survival will be evaluated, concluding these models perform moderate to good, but most of them partly rely on intra-operative data. New insights in tumor biology, as well as the reliable assessment of extent of peritoneal disease by diffusion weighted MRI pose promising opportunities to establish an adequate and clinically meaningful preoperative prognostic model in the near future.

• colorectal neoplasms
• cytoreductive surgery
• hyperthermic intraperitoneal chemotherapy
• peritoneal metastases
• prognosis
• survival

Metastatic spread is the most important life-threatening feature of colorectal cancer and is supposed to be mainly driven by alterations in different carcinogenic pathways. The present study compared mutation and expression profiles of distinctive biomarkers in colorectal cancer patients with different clinical metastatic patterns. As for a case-control study, patients were matched according to T category, grading and primary tumour site. Overall, 246 patients with either exclusive lung metastasis (N = 82), exclusive liver metastasis (N = 82) or non-metastatic colorectal cancer (N = 82) were identified. Paraffin-embedded specimens were examined for mutations in the RAS and RAF genes and for the expression of β-catenin and CD133. Clinical endpoints were presence or absence of distant metastasis, formation of metastasis in lungs versus the liver and survival. MAPK pathway mutations in either the KRAS, NRAS or BRAF gene were associated with the development of lung metastasis (63.4%) compared to the control group (47.6%; p = 0.04). MAPK pathway alterations plus high β-catenin expression were associated with metastasis to the lungs but not to the liver (28.0% vs. 13.4%; p = 0.02). High CD133 expression correlated with the development of liver metastasis compared to the control group (30.5% vs. 14.6%; p = 0.02). This data indicates that different patterns of distant spread are associated with specific biomarker alterations and may represent different molecular subtypes of colorectal cancer. However, underlying mechanisms of metastasis formation in different anatomic sites remains unclear. Since knowledge of the anticipated site of distant spread would substantially impact clinical management, further research is needed to identify solid biomarkers for different metastatic patterns.

• Biomarker
• CD133
• Lung metastasis
• MAPK pathway mutations
• Metastatic colorectal cancer
• β-catenin

• Ablation
• Gastrointestinal tumours
• Image-guided intervention
• Locoregional treatment
• Oligometastases

Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

With the development of chemotherapy regimens, targeted therapies, and hepatic surgery, the survival of patients with colorectal liver metastases (CRLM) has dramatically improved. Imaging plays a central role for the diagnosis, staging, and treatment allocation in these patients. To interpret CRLM on imaging, radiologists must be familiar with the main imaging features of untreated tumors as well as the modifications induced by systemic therapies, and their meaning in relation to pathological tumor response and tumor biology. CRLM have the same histological features as the primary tumor. Most are “non-otherwise specified” (NOS) adenocarcinomas. The mucinous tumor is the most common of the rare subtypes. In NOS tumors, imaging usually differentiates central areas of necrosis from peripheral proliferating tumors and desmoplastic reaction. Areas of mucin mixed with fibrosis are seen in mucinous subtypes to help differentiate the metastases from other tumors cysts or hemangiomas. After treatment, the viable tumor is gradually replaced by ischemic-like necrosis and fibrosis, and remnants cells are mainly located on the periphery of tumors. Imaging can help predict the degree of tumor response, but changes can be difficult to differentiate from the pretherapeutic appearance. When chemotherapy is interrupted or in case of resistance to treatment, a peripheral infiltrating halo of tumor growth may appear. The purpose of the article is to illustrate the significance of the imaging features of colorectal liver metastases during systemic therapy, using radiopathological correlations.

• Imaging
• Metastasis
• Radiopathological correlation

• BRAF
• Colorectal cancer
• Iran
• KRAS
• Prognostic value
• Survival

• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Female
• Humans
• Iran/epidemiology
• Male
• Microsatellite Instability
• Middle Aged
• Mutation
• Prognosis
• Proto-Oncogene Proteins B-raf/genetics
• Proto-Oncogene Proteins p21(ras)/genetics
• Survival Analysis

Brain metastases (BMs) from digestive cancers are rare; therefore, no optimal treatment modality has been defined.

We retrospectively reviewed the clinical data of 68257 patients with digestive cancers. Propensity score matching (PSM) was used to balance patient backgrounds between groups. Survival differences between different treatment modalities were compared. Univariate and multivariate Cox proportional hazards models were performed to identify prognostic factors on overall survival (OS).

270 patients with BM entered the study. In the entire group, the median survival time after diagnosis of brain metastases was 10.25 months (95% CI: 8.41–12.09 months); local treatment could significantly prolong OS (respectively, P < 0.01; even after PSM, P < 0.01); combination treatment was more effective than single treatment modality (respectively, P < 0.01; even after PSM, P < 0.01). However, each combination modality was identically effective (P > 0.05). When patients were divided into three groups based on 1, 2-3, or more than 3 metastatic lesion(s), same results were identified between local treatment and without local treatment (1 lesion, P < 0.01; 2-3 lesions, P < 0.01; more than 3 lesions, P < 0.01, respectively) and combination and single treatment (P < 0.01, P=0.02, P=0.03, respectively). However, there was no difference between different combined treatments (P > 0.05). Multivariate analysis revealed that performance status (P < 0.01), presence of extracranial metastasis (P=0.04), number of BM (P < 0.01), and local treatment for BM (P < 0.01) were independent prognostic factors.

Regardless of the number of brain lesions, local treatment achieved higher overall survival times than no local treatment, and combination therapy could offer survival benefit to patients as compared with single therapy.

• extrahepatic disease progression
• liver-limited disease
• metastatic colorectal cancer

• COSMIC
• Cancer genes
• Catalog of somatic mutations in Cancer
• Frameshift mutations
• Missense
• Nonsense
• Somatic mutations

Markers of tumour biology may be valuable prognostic indicators after hepatic resection of colorectal cancer liver metastases (CRLMs). Identification of the aggressiveness of these metastases might inform the appropriateness of hepatic surgery.

Patients undergoing liver resection for CRLMs between January 2001 and July 2013 in four tertiary hospitals were reviewed. A mathematical model to estimate CRLM doubling times was constructed for patients with metachronous metastases. Tumour doubling time was investigated in relation to the features of colorectal cancer, including KRAS status. The hazard rate for recurrence and death following hepatectomy was explored through the Kernel‐smoothed estimator.

Of 1063 patients undergoing liver resection for CRLMs, 361 with metachronous metastases undergoing single‐stage hepatectomy were analysed. The mean doubling time in patients not receiving chemotherapy between surgery for colorectal cancer and CRLM was 71·4 days. Tumour doubling time was shorter in patients with more advanced primary tumour stages, with mutant KRAS and in those who did not receive chemotherapy. For fast‐growing CRLMs (doubling time less than 48 days), the risk of recurrence was highest within the first postoperative year, and was about 7 per cent per month.

Primary features of colorectal cancer were linked to aggressiveness of CRLMs as measured by doubling time.

• colorectal liver metastases
• intratumoral genetic heterogeneity
• mutations
• pathological response

• Cerebral metastases
• Colorectal cancer
• Treatment

• Brain Neoplasms/secondary
• Brain Neoplasms/therapy
• Cerebrum
• Colorectal Neoplasms/pathology
• Humans
• Neurosurgical Procedures
• Radiosurgery
• Radiotherapy, Adjuvant
• Survival Rate

To establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization.

Retrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk.

Sixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP.

PI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.

• MAPK
• PI3K
• biomarkers
• colorectal
• radioembolization

• Pulmonary metastasectomy (PM)
• inflammation
• prognosis
• selection criteria

• Development of metastases
• Incidence
• Localization
• Metachronous metastases
• Metastatic colorectal cancer
• Synchronous metastases

• CXCR4–CXCL12–CXCR7 axis
• KRAS mutation
• PD-1/PD-L1
• colorectal cancer liver metastases (CRLM)
• toll-like receptors (TLRs)