Colorectal Cancer Lung Metastases Research Articles

Habitat-based radiomics analysis for evaluating immediate response in colorectal cancer lung metastases treated by radiofrequency ablation

PurposeTo create radiomics signatures based on habitat to assess the instant response in lung metastases of colorectal cancer (CRC) after radiofrequency ablation (RFA).MethodsBetween August 2016 and June 2019, we retrospectively included 515 lung metastases in 233 CRC patients who received RFA (412 in the training group and 103 in the test group). Multivariable analysis was performed to identify independent risk factors for developing the clinical model. Tumor and ablation regions of interest (ROI) were split into three spatial habitats through K-means clustering and dilated with 5 mm and 10 mm thicknesses. Radiomics signatures of intratumor, peritumor, and habitat were developed using the features extracted from intraoperative CT data. The performance of these signatures was primarily evaluated using the area under the receiver operating characteristics curve (AUC) via the DeLong test, calibration curves through the Hosmer-Lemeshow test, and decision curve analysis.ResultsA total of 412 out of 515 metastases (80%) achieved complete response. Four clinical variables (cancer antigen 19–9, simultaneous systemic treatment, site of lung metastases, and electrode type) were utilized to construct the clinical model. The Habitat signature was combined with the Peri-5 signature, which achieved a higher AUC than the Peri-10 signature in the test set (0.825 vs. 0.816). The Habitat+Peri-5 signature notably surpassed the clinical and intratumor radiomics signatures (AUC: 0.870 in the test set; both, p < 0.05), displaying improved calibration and clinical practicality.ConclusionsThe habitat-based radiomics signature can offer precise predictions and valuable assistance to physicians in developing personalized treatment strategies.

Identification and prognostic analysis of candidate biomarkers for lung metastasis in colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent types of malignant tumors. It's vital to explore new biomarkers and potential therapeutic targets in CRC lung metastasis through adopting integrated bioinformatics tools. Multiple cohort datasets and databases were integrated to clarify and verify potential key candidate biomarkers and signal transduction pathways in CRC lung metastasis. DAVID, STRING, UALCAN, GEPIA, TIMER, cBioPortal, THE HUMAN PROTEIN ATLAS, GSEA 4.3.2, FUNRICH 3.1.3, and R 4.2.3 were utilized in this study. The enriched biological processes and pathways modulated by the differentially expressed genes (DEGs) were determined with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes. The search tool Retrieval of Interacting Genes and Cytoscape were used to construct a protein-protein interaction network among DEGs. Four hundred fifty-nine colorectal primary cancer and lung metastatic gene expression profiles were screened from 3 gene expression profiles (GSE41258, GSE68468, and GSE41568). Forty-one upregulated genes and 8 downregulated genes were identified from these 3 gene expression profiles and verified by the transcriptional levels of hub genes in other GEO datasets and The Cancer Genome Atlas database. Two pathways (immune responses and chemokine receptors bind chemokines), 13 key DEGs, 6 hub genes (MMP3, SFTPD, ABCA3, CLU, APOE, and SPP1), and 2 biomarkers (APOE, SPP1) with significantly prognostic values were screened. Forty-nine DEGs were identified as potential candidate diagnostic biomarkers for patients with CRC lung metastasis in present study. Enrichment analysis indicated that immune responses and chemokine receptors bind chemokines may play a leading role in lung metastasis of CRC, and further studies are needed to validate these findings.

Kaempferol inhibits colorectal cancer metastasis through circ_0000345 mediated JMJD2C/β-catenin signalling pathway

BackgroundRecurrence and metastasis are the main causes of disease deterioration in colorectal cancer (CRC) patients, yet efficient therapeutic strategies are lacking. Natural compounds for efficient antitumour therapeutics are becoming increasingly prominent. Kaempferol, one of the main components of flavonoids in plants, displays a variety of pharmacological activities. Our preliminary experiments suggested that kaempferol could inhibit CRC metastasis and is significantly associated with the β-catenin signalling pathway. Moreover, we also defined the regulatory roles of JMJD2C in β-catenin signalling in our previous work. PurposeThis study aims to reveal the mechanism by which kaempferol inhibits CRC progression and regulates the JMJD2C/β-catenin signalling pathway. MethodsThe migratory capabilities of CRC cells after kaempferol intervention were measured by scratch wound healing and transwell assays. Circ_0000345 knockdown CRC stable cell lines were generated by lentivirus infection. The possible mechanism of kaempferol on circ_0000345 was verified by molecular-protein docking and verification program cellular thermal shift assay (CETSA). A dual luciferase reporter gene assay was carried out for the targeting relationship among circ_0000345, miR-205-5p and JMJD2C. Fluorescence in situ hybridization (FISH) was performed to determine the expression of circ_0000345 in tumour tissues. A pulmonary metastatic model of CRC in vitro was built to assess the antimetastatic effect and mechanism of kaempferol in vivo. ResultsIn vitro, kaempferol inhibits the ability to migrate of CRC cells by reducing the activation of the JMJD2C/β-catenin signalling pathway. MiR-205-5p is a key bridge for kaempferol to inhibit the expression of JMJD2C. The function of miR-205-5p is impeded by circ_0000345, which shows higher expression levels in human metastatic CRC tissues than nonmetastatic CRC tissues, and its formation is regulated by the RNA-binding proteins HNRNPK and HNRNPL. Mechanistically, kaempferol physically interacts with HNRNPK and HNRNPL to suppress JMJD2C by downregulating the expression of circ_0000345. In vivo, kaempferol suppresses CRC lung metastasis. Kaempferol inhibits the activation of JMJD2C/β-catenin signalling through reducing the expression of circ_0000345 in the CRC lung metastasis model. ConclusionCirc_0000345 enhances activation of the JMJD2C/β-catenin signalling pathway through miR-205-5p to promote CRC metastasis. Kaempferol inhibits CRC metastasis through the circ_0000345-mediated JMJD2C/β-catenin signalling pathway, and this effect is influenced as a direct consequence of the binding of kaempferol with HNRNPK and HNRNPL. This provides promising therapeutic and/or adjuvant agents for advanced CRC and sheds light on the multifaceted role of phytomedicine in cancer.

Survival outcomes of lung metastases from colorectal cancer treated with pulmonary metastasectomy or modern systemic chemotherapy: a single institution experience

BackgroundAlthough pulmonary metastasectomy is an accepted treatment strategy for resectable lung metastases (LM) from colorectal cancer (CRC), its survival benefits are controversial. In contrast, recent advancements in chemotherapy have significantly improved metastatic CRC prognosis. This study aimed to evaluate survival outcome of LM from CRC in the age of newly developed chemotherapy.MethodsWe retrospectively reviewed 50 patients who underwent complete resection and 22 patients who received chemotherapy as definitive treatment for LM from resected CRC at our hospital. The present study was limited to patients who started treatment for isolated LM after molecular targeted drugs became available in Japan.ResultsOverall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS) rates after pulmonary resection were 64.5%, 66.4%, and 32.6% at five years, respectively. OS and CSS rates of chemotherapy patients were 26.8% and 28.3% at five years, with a median progression-free survival time of 10.0 months. When compared the characteristics of surgical and chemotherapy patients, patients with pN factors of CRC (p = 0.013), smaller size (p < 0.001), larger number (p < 0.001), and bilateral (p < 0.001) LM received chemotherapy. Univariate analysis showed that multiple LM and rectal lesions were poor prognostic factors for OS (p = 0.012) and DFS (p = 0.017) in surgical patients, and rectal lesions were a poor prognostic factor for OS (p = 0.013) in chemotherapy patients.ConclusionsPulmonary metastasectomy showed a favorable survival in patients with LM from CRC. Despite the high recurrence rate after metastasectomy and recent advances in chemotherapy, surgical resection could still be considered as a valid option among multidisciplinary treatments.Trial registrationThe research plan was approved by the Institutional Review Board of Shinko Hospital (No. 2142) on February 7, 2022.

Intravenous injection of tumor extracellular vesicles suppresses tumor growth by reducing the regulatory T cell phenotype.

Colorectal cancer is a disease of unmet medical need. Although extracellular vesicles (EVs) have been implicated in anti-tumor responses, discrepancies were observed among studies. We analyzed the role of tumor-derived EVs (TEVs) in tumor progression in vivo by focusing on regulatory T (Treg) cells, which play essential roles in tumor development and progression. A mouse model of colorectal cancer lung metastasis was generated using BALB/c mice by tail vein injection of the BALB/c colon adenocarcinoma cell line Colon-26. TEVs derived from Colon-26 and BALB/c lung squamous cell carcinoma ASB-XIV were retrieved from the culture media supernatants. A TEV equivalent to 10µg protein was injected every other day for 2weeks. Histology and immunohistochemistry studies revealed that lung tumors reduced in the Colon-26-EV group when compared to the phosphate-buffered saline (PBS) group. The population of CD4 + FoxP3 + cells in the lung was upregulated in the PBS group mice when compared to the healthy mice (P < 0.001), but was significantly downregulated in the Colon-26-EV group mice when compared to the PBS group mice (P < 0.01). Programmed cell death protein 1, glucocorticoid-induced TNFR-related protein, and CD69 expression in lung Treg cells were markedly upregulated in the PBS group when compared to the healthy mice, but downregulated in the Colon-26-EV group when compared to the PBS group. The changes in expression were dose-dependent for Colon-26-EVs. ASB-EVs also led to significantly downregulated Treg cell expression, although non-cancer line 3T3-derived EVs did not. Our study suggests that TEVs possess components for tumor suppression.

Radiofrequency ablation of lung metastases of colorectal cancer: could early radiomics analysis of the ablation zone help detect local tumor progression?

To determine whether radiomics data can predict local tumor progression (LTP) following radiofrequency ablation (RFA) of colorectal cancer (CRC) lung metastases on the first revaluation chest CT. This case-control single-center retrospective study included 95 distinct lung metastases treated by RFA (in 39 patients, median age: 63.1 years) with a contrast-enhanced CT-scan performed 3 months after RFA. Forty-eight radiomics features (RFs) were extracted from the 3D-segmentation of the ablation zone. Several supervised machine-learning algorithms were trained in 10-fold cross-validation on reproducible RFs to predict LTP, with/without denoising CT-scans. An unsupervised classification based on reproducible RFs was built with k-means algorithm. There were 20/95 (26.7%) relapses within a median delay of 10 months. The best model was a stepwise logistic regression on raw CT-scans. Its cross-validated performances were: AUROC = 0.72 (0.58-0.86), area under the Precision-Recall curve (AUPRC) = 0.44. Cross-validated balanced-accuracy, sensitivity and specificity were 0.59, 0.25 and 0.93, respectively, using p = 0.5 to dichotomize the model predicted probabilities (vs 0.71, 0.70 and 0.72, respectively using p = 0.188 according to Youden index). The unsupervised approach identified two clusters, which were not associated with LTP (p = 0.8211) but with the occurrence of per-RFA intra-alveolar hemorrhage, post-RFA cavitations and fistulizations (p = 0.0150). Predictive models using RFs from the post-RFA ablation zone on the first revaluation CT-scan of CRC lung metastases seemed moderately informative regarding the occurrence of LTP. Radiomics approach on interventional radiology data is feasible. However, patterns of heterogeneity detected with RFs on early re-evaluation CT-scans seem biased by different healing processes following benign RFA complications.

P-324 Clinicopathological characteristics of patients with colorectal cancer lung metastasis under different conditions

P-324 Clinicopathological characteristics of patients with colorectal cancer lung metastasis under different conditions

MicroOrganoSpheres as a clinically applicable precision oncology platform for the discovery of novel therapies in colorectal cancer.

3592 Background: Patient-derived models of cancer, such as cell lines, patient-derived organoids, and patient-derived xenografts, are useful models of patient response in the clinic. However, these models are often not clinically applicable within the time periods necessary to inform clinical decision making, as they can take weeks to months to develop. An ideal platform using patient-derived models would be generated from a core biopsy with a subsequent drug screen within 10-14 days to minimize delay in therapy. We recently reported the development of MicroOrganoSpheres (MOS) that can be used in drug screens within 14 days of obtaining a biopsy. In the current study, we use this MOS system as precision oncology platform in colorectal cancer (CRC) to identify new therapies and predict response to therapy. Methods: CRC patient tissue samples were collected under a Duke Institutional Review Board approved protocol (Pro00089222). Resections or biopsies were mechanically and enzymatically digested to obtain a single cell suspension. Cells were then plated in Matrigel at a ratio of 20,000 cells:5 µL Matrigel to establish “mini-bulk” organoid cultures. After establishment for 5-7 days, cultures were harvested with subsequent generation of MOS at a ratio of 50 cells per MOS. After growing for 3-4 days, MOS were used for dose-response curves using oxaliplatin, SN38, and 5-Fluorouracil (5-FU) as well as high-throughput drug screens with the NCI Approved Oncology Drugs Set VI library. Results: We developed and optimized a MOS pipeline on over 50 CRC specimens, including 9 primary rectal, 35 primary CRC, 12 CRC liver metastasis, and 1 CRC lung metastasis lines with a success rate of 80% and an average of 10-21days from biopsy to MOS generation. The high success of generating CRC MOS in a clinically applicable time frame led to the next phase of the project where a total of 10 CRC MOS were tested against standard of care chemotherapy agents used in CRC (oxaliplatin, irinotecan and 5-FU) as well as the NCI Approved Oncology Drugs Set VI within 14-21days of establishment. We noted a range of sensitivity of approximately 100-fold for standard of care agents. The most sensitive drugs found in the high-throughput screen were Bortezomib, Carfilzomib, and Panobinostat and the most resistant were Gefitinib, Chlorambucil, and Procarbazine hydrochloride. Conclusions: These results demonstrate that our MOS pipeline can be used as a precision oncology platform within a clinically applicable time frame to potentially guide therapy. We are now in the process of correlating drug response in MOS to patient outcome data and these findings will be presented at the annual meeting.

Circular RNA ACACA negatively regulated p53-modulated mevalonate pathway to promote colorectal tumorigenesis via regulating miR-193a/b-3p/HDAC3 axis.

This study aimed to explore the biological functions and underlying mechanism of circRNA acetyl-CoA carboxylase alpha (circACACA) in colorectal cancer (CRC). The RNA and protein levels were detected by qRT-PCR and western blot assays. The malignant capacities of CRC cells were analyzed by cell counting kit-8 (CCK-8), colony formation, flow cytometry, and transwell assays. The target relationship between miR-193a/b-3p and circACACA/histone deacetylase 3 (HDAC3) was determined by luciferase reporter assay and RNA immunoprecipitation. The binding of HDAC3 to the p53 promoter was validated by chromatin immunoprecipitation (ChIP). CRC cell growth and lung metastasis were evaluated in nude mice in vivo. High expression of circACACA was found in CRC tissues and cells, which was closely associated with the advanced tumor, lymph node, metastasis (TNM) stage, metastasis, and low overall survival rate. circACACA downregulation effectively delayed CRC cell proliferation and metastasis, but triggered apoptosis via inactivating the mevalonic acid (MVA) pathway. However, circACACA overexpression resulted in the opposite effects. Mechanistically, circACACA enhanced HDAC3 expression through sponging miR-193a/b-3p, which activated theMVA pathway via inhibiting the acetylation and transcription of p53. Moreover, rescue experiments confirmed that miR-193a/b-3p inhibition reversed the inhibitory effect of circACACA deficiency on CRC growth and metastasis. Moreover, circACACA overexpression-mediated malignant phenotypes of CRC cells were abrogated by HDAC3 knockdown. circACACA promoted CRC progression via regulating themiR-193a/b-3p/HDAC3/p53 axis to activate theMVA pathway, providing evidence for circACACA as a promising therapeutic target for CRC.

Targeting CD73 increases therapeutic response to immunogenic chemotherapy by promoting dendritic cell maturation.

The CD39-CD73-adenosinergic pathway converts adenosine triphosphate (ATP) to adenosine for inhibiting anti-tumor immune responses. Therefore, targeting CD73 to reinvigorate anti-tumor immunity is considered the novel cancer immunotherapy to eradicate tumor cells. To fully understand the critical role of CD39/CD73 in colon adenocarcinoma (COAD), this study aims to comprehensive investigate the prognostic significance of CD39 and CD73 in stage I-IV COAD. Our data demonstrated that CD73 staining strongly marked malignant epithelial cells and CD39 was highly expressed in stromal cells. Attractively, tumor CD73 expression was significantly associated with tumor stage and the risk of distant metastasis, which suggested CD73 was as an independent factor for colon adenocarcinoma patients in univariate COX analysis [HR = 1.465, 95%CI = 1.084-1.978, p = 0.013]; however, high stromal CD39 in COAD patients was more likely to have favorable survival outcome [HR = 1.458, p = 1.103-1.927, p = 0.008]. Notably, high CD73 expression in COAD patients showed poor response to adjuvant chemotherapy and high risk of distant metastasis. High CD73 expression was inversely associated with less infiltration of CD45+ and CD8+ immune cells. However, administration with anti-CD73 antibodies significantly increased the response to oxaliplatin (OXP). Blockade of CD73 signaling synergistically enhanced OXP-induced ATP release, which is a marker of immunogenic cell death (ICD), promotes dendritic cell maturation and immune cell infiltration. Moreover, the risk of colorectal cancer lung metastasis was also decreased. Taken together, the present study revealed tumor CD73 expression inhibited the recruitment of immune cells and correlated with a poor prognosis in COAD patients, especially patients received adjuvant chemotherapy. Targeting CD73 to markedly increased the therapeutic response to chemotherapy and inhibited lung metastasis. Therefore, tumor CD73 may be an independent prognostic factor as well as the potential of therapeutic target for immunotherapy to benefit colon adenocarcinoma patients.

Bevacizumab in first-line therapy in lung metastases of colorectal cancer: An ARCAD pooled analysis.

118 Background: Anti-VEGF is widely used in the treatment (trt) of metastatic colorectal cancer (mCRC). Only studies with bevacizumab (BEV) have shown survival benefit (bnf) in first line trt. The magnitude of bnf might differ based on the metastatic (met) site and the chemotherapy regimen (CTR) with which BEV is partnered. ARCAD database contains individual patient data (IPD) of randomized trials that evaluated BEV+ CT. In this pooled analysis, we aimed to evaluate BEV bnf in mCRC with lung metastases (mets) either as single or multiple sites. Methods: IPD from four trials (AVF2107g, N016966, AVF2192g, AGITG) comparing CT +/- BEV were pooled. The primary endpoint, overall survival (OS), was estimated using Kaplan-Meier method and prognostic value of lung mets was evaluated by stratified Cox models according to number and type of met sites and CTRs, oxaliplatin or irinotecan (OX/IRI) based. The predictive bnf of BEV was evaluated by interaction test (int) between trt and lung mets status in subgroups and considered as significant (sig) with a P &lt; 0.1. Results: 2728 patients (pts) with known met sites and survival data were pooled. 1020 pts had single met site, 133 had only lung mets. 1708 pts had multiple met sites, 1008 had lung mets. Pts characteristics were well balanced. Sig OS bnf of BEV was observed in the whole population. In pts subgroup according to the presence or absence of lung mets, sig bnf of BEV were observed with a non-sig int ( Pint=.590). Non-sig bnf of BEV was observed in pts with single site regardless of met site (lung or no lung) or CTR. Sig bnf of BEV was observed in pts with multiple sites without lung mets whatever the CTRs. While sig bnf of BEV was observed in pts with multiple sites with lung mets, we found a sig int between BEV and OX/IRI-based regimens ( Pint=.022). The bnf of BEV was observed with IRI-based regimen but not in OX-based regimen. The bnf of BEV appears greater in multiple sites without lung mets than with lung mets with a sig stratified log-rank test ( PLRT&lt;.001). Conclusions: In pts with multiple sites mCRC, a statistically sig OS bnf of BEV added to CT was observed mainly among pts without lung mets. The overall effect of CT partner choice when combined with BEV can be different. In pts with single site, BEV did not seem to improve OS but the evaluation of efficacy of BEV in presence or absence lung mets was based on small number of pts and needs to be evaluated in trials with larger pts sample, especially trials including pts with single site lung mets. [Table: see text]

A CT-based radiomics approach to predict immediate response of radiofrequency ablation in colorectal cancer lung metastases.

To objectively and accurately assess the immediate efficacy of radiofrequency ablation (RFA) on colorectal cancer (CRC) lung metastases, the novel multimodal data fusion model based on radiomics features and clinical variables was developed. This case-control single-center retrospective study included 479 lung metastases treated with RFA in 198 CRC patients. Clinical and radiological data before and intraoperative computed tomography (CT) scans were retrieved. The relative radiomics features were extracted from pre- and immediate post-RFA CT scans by maximum relevance and minimum redundancy algorithm (MRMRA). The Gaussian mixture model (GMM) was used to divide the data of the training dataset and testing dataset. In the process of modeling in the training set, radiomics model, clinical model and fusion model were built based on a random forest classifier. Finally, verification was carried out on an independent test dataset. The receiver operating characteristic curves (ROC) were drawn based on the obtained predicted scores, and the corresponding area under ROC curve (AUC), accuracy, sensitivity, and specificity were calculated and compared. Among the 479 pulmonary metastases, 379 had complete response (CR) ablation and 100 had incomplete response ablation. Three hundred eighty-six lesions were selected to construct a training dataset and 93 lesions to construct a testing dataset. The multivariate logistic regression analysis revealed cancer antigen 19-9 (CA19-9, p<0.001) and the location of the metastases (p< 0.05) as independent risk factors. Significant correlations were observed between complete ablation and 9 radiomics features. The best prediction performance was achieved with the proposed multimodal data fusion model integrating radiomic features and clinical variables with the highest accuracy (82.6%), AUC value (0.921), sensitivity (80.3%), and specificity (81.4%). This novel multimodal data fusion model was demonstrated efficient for immediate efficacy evaluation after RFA for CRC lung metastases, which could benefit necessary complementary treatment.

Research Progress on Multifactor Therapy for Lung Metastasis of Colorectal Cancer

Research Progress on Multifactor Therapy for Lung Metastasis of Colorectal Cancer

CT-Guided Percutaneous Cryoablation for Lung Metastasis of Colorectal Cancer: A Case Series.

This study aimed to evaluate the efficacy of computed tomography (CT) guided percutaneous cryoablation (CA) for the management of lung metastases in patients with metastatic colorectal cancer (mCRC). Retrospective analysis was performed on 38 mCRC patients with lung metastases, who underwent CT-guided percutaneous CA at our center from May 1, 2020 to November 1, 2021. The technical success rate, 1-year local control (LC) rate, recurrence-free survival (RFS) and treatment-related complications were analyzed. The CA procedure was successfully performed in all patients, with a technical success rate of 100%. The 1-year LC rate was 94.7% (36/38), while 16 patients experienced new distant lung metastases during the follow-up period. The median RFS was 20 months (95% CI: 13.0-27.0). The median RFS of patients with and without extrapulmonary metastasis was 15 and 23 months, respectively. Complications were reported in 18 (47.4%) patients following the CA procedure. Pneumothorax was discovered in 15 (39.5%) patients, and five of these patients (13.2%) required chest tube intubation. Two patients (5.3%) presented with hemoptysis during the CA procedure. One patient developed subcutaneous emphysema as detected in the post-procedure follow-up imaging. All patients tolerated the peri-procedural pain well under local anesthesia, and the mean visual analog scale (VAS) score was 2.8. Lung CA is a safe and well-tolerated treatment with a satisfactory local control rate for patients with lung metastases derived from mCRC.

Dosimetric Parameters are Associated with Local Control after SBRT for Colorectal Cancer Lung Metastases

<h3>Purpose/Objective(s)</h3> Recent data suggest that higher stereotactic body radiotherapy (SBRT) prescription doses, and hence biologically effective doses (BED), are associated with improved local control (LC) for patients who receive SBRT for colorectal cancer (CRC) oligometastasis. However, the immense heterogeneity of SBRT dose distributions, even at isoeffective prescription doses, has made it challenging to extrapolate reported prescription dose thresholds into contemporary plan optimization. Our objective was to characterize dosimetric predictors of LC after SBRT for CRC lung metastases. We hypothesized that the internal target volume (ITV) and planning target volume (PTV) doses covering 90% of the volume (D90) and minimum doses (Dmin) would be associated with local control. <h3>Materials/Methods</h3> This was a retrospective cohort study including patients who received SBRT to CRC lung metastases at a single cancer center between 2013-2019. Dosimetric parameters including the D90 and Dmin of both the ITV and PTV were collected and converted to BED using the linear quadratic model assuming an alpha/beta of 10 Gy. The Kaplan-Meier method was used to estimate LC, and univariate analyses were performed with the Cox proportional hazards regression model. <h3>Results</h3> 53 CRC lung metastases amongst 28 patients were included for analysis. Median dose and number of fractions were 50 Gy (IQR 50-54 Gy) and 5 (IQR 3-5) fractions, respectively, with a median BED of 100 Gy (IQR 100-151.2 Gy). Median follow-up after SBRT was 27 months (IQR 17 – 38 months). By last follow-up, 18 of 53 (34%) metastases had progressed, of which only 4 (22%) were isolated sites of first-progression. The 2-year LC was 66.0% (95% CI 54.3% – 81.6%). On univariate analysis, lung metastasis size (HR 1.601 per cm, 95% CI 1.052 – 2.436) and BEDs including the ITV D90 (HR 0.83 per 10 Gy, 95%CI 0.75–0.93, p = 0.002) and Dmin (HR 0.821 per 10 Gy, 95% CI 0.73–0.93, p = 0.002), and PTV D90 (HR 0.79, 95%CI 0.68–0.93, p = 0.004) and Dmin (HR 0.80, 95% CI 0.66–0.97, p = 0.025) were associated with LC. When BED dose thresholds were chosen based on bottom quartile, improved 2-year LC was associated with ITV D90 BED ≥118 Gy (84.6% vs. 21.4% p < 0.0001) and Dmin BED ≥ 114 Gy (81.5% vs. 30.5% p < 0.0001). This remained true among the 29 lesions treated with the most common prescription dose of 50 Gy in 5 fractions (90.0% vs. 22.2%, p < 0.0001 and 83.5% vs. 37.5%, p = 0.011, respectively). <h3>Conclusion</h3> BEDs of over 118 Gy to at least 90% of the ITV volume (D90) and a minimum dose of 114 Gy were associated with improved LC after SBRT for CRC lung metastases. These data may be informative in-patient selection and plan optimization, particularly in challenging circumstances where the target is adjacent to critical organs at risk. With the favorable LC achieved with dose-escalated SBRT and the infrequency of isolated in-field first-progression events, SBRT remains an excellent local treatment option for CRC lung metastasis.

Identification of the effects of COVID-19 on patients with pulmonary fibrosis and lung cancer: a bioinformatics analysis and literature review.

Coronavirus disease 2019 (COVID-19) poses a serious threat to human health and life. The effective prevention and treatment of COVID-19 complications have become crucial to saving patients’ lives. During the phase of mass spread of the epidemic, a large number of patients with pulmonary fibrosis and lung cancers were inevitably infected with the SARS-CoV-2 virus. Lung cancers have the highest tumor morbidity and mortality rates worldwide, and pulmonary fibrosis itself is one of the complications of COVID-19. Idiopathic lung fibrosis (IPF) and various lung cancers (primary and metastatic) become risk factors for complications of COVID-19 and significantly increase mortality in patients. Therefore, we applied bioinformatics and systems biology approaches to identify molecular biomarkers and common pathways in COVID-19, IPF, colorectal cancer (CRC) lung metastasis, SCLC and NSCLC. We identified 79 DEGs between COVID-19, IPF, CRC lung metastasis, SCLC and NSCLC. Meanwhile, based on the transcriptome features of DSigDB and common DEGs, we identified 10 drug candidates. In this study, 79 DEGs are the common core genes of the 5 diseases. The 10 drugs were found to have positive effects in treating COVID-19 and lung cancer, potentially reducing the risk of pulmonary fibrosis.

418P Colorectal cancer lung metastases resection and its impact on survival in the oligometastatic setting

Colorectal cancer lung metastases (CRLM) are a common form of newly diagnosed advanced disease and relapse after radical treatment (ttm) of early-stage tumours. In oligometastatic patients (pts), pulmonary resection is usually considered in some point of the multimodal ttm approach. Nevertheless, the real benefit of lung metastasectomy and perioperative chemotherapy in survival is in constant debate and strong prognostic factors are still lacking.

Study on the Action Mechanism of the Yifei Jianpi Tongfu Formula in Treatment of Colorectal Cancer Lung Metastasis Based on Network Analysis, Molecular Docking, and Experimental Validation.

Objective The lung is the second most common site of colorectal cancer (CRC) metastasis. This study aims to investigate the therapeutic effects and potential action mechanisms of Yifei Jianpi Tongfu formula (YJTF) in CRC lung metastasis in a comprehensive and systematic way by network analysis, molecular docking, and experimental verification. Methods The main ingredients in YJTF were screened from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID), and the disease-related targets from the Online Mendelian Inheritance in Man (OMIM) and GeneCards and the compound-related targets from SwissTargetPrediction were collected. Then, Metascape was used for pathway annotation and enrichment analysis, and meanwhile, a protein-protein interaction (PPI) network was constructed. Molecular docking was carried out to investigate interactions between the active compounds and the potential targets. The in vivo effect of YJTF on CRC lung metastasis was observed in a tail vein injection mouse model. Results A total of 243 active compounds and 81 disease-related targets of YJTF were selected for analysis. The results of multiple network analysis showed that the core targets of YJTF were enriched onto various cancer-related pathways, especially focal adhesion and adherens junction. The results of molecular docking demonstrated that all core compounds (quercetin, kaempferol, luteolin, apigenin, and isorhamnetin) were capable of binding with AKT1, EGFR, SRC, ESR1, and PTGS2. Experimental validation in vivo demonstrated that YJTF combined with oxaliplatin could significantly reduce the number of lung metastases and improve the quality of life in mice. Further research suggested that YJTF inhibited CRC lung metastasis probably by modulating epithelial-to-mesenchymal transition (EMT). Conclusions According to the analysis, YJTF can be considered as an effective adjuvant therapy for CRC lung metastasis.

Long-term outcome following microwave ablation of lung metastases from colorectal cancer.

PurposeTo retrospectively evaluate the safety and efficacy of percutaneous computed tomography (CT)-guided microwave ablation (MWA) in colorectal cancer (CRC) lung metastases, and to analyze prognostic factors.Materials and methodsData were collected from 31 patients with CRC lung metastases from May 2013 to September 2017. They had removed the CRC, no extrapulmonary metastases, no more than three metastases in the lung, the maximum diameter of the lesions was ≤3 cm, and all the lung metastases could be completely ablated. The ablation procedures were performed using a KY-2000 microwave multifunctional therapeutic apparatus. Efficacy is assessed two to four weeks after ablation, and follow-up are performed every three months for two years. The primary outcome was overall survival (OS). The secondary outcomes were progression-free survival (PFS), and complications. Cox regression analysis was used for the evaluation of the statistical significance of factors affecting the end result of MWA therapy. The Kaplan–Meier method was used for estimation of survival rates.ResultsA total of 45 metastatic lung lesions from CRC in 31 patients were treated with CT-guided MWA procedures. The median OS was 76 months. The one, two, three, and five-year survival rates were 93.5%, 80.6%, 61.3%, and 51.6%, respectively. Multivariate analysis showed that the primary tumor from the rectum (P = 0.009) and liver metastases at the diagnosis of lung metastases (P = 0.043) were risk factors affecting OS, while PFS was a protective factor. The median PFS was 13 months. The maximum diameter of lung metastases lesions (P = 0.004) was a risk factor. The interval between pulmonary metastases and MWA (P=0.031) was the protective factor. Pneumothorax was observed in 13 out of 36 procedures. Four patients developed pneumothorax requiring drainage tube insertion. No patient deaths occurred within 30 days of ablation. Three out of 31 patients (9.67%) were found to have local recurrence of the original lung metastatic ablation foci.ConclusionMWA therapy may be safely and effectively used as a therapeutic tool for the treatment of selected CRC pulmonary metastases, and the prognosis is better in patients without liver metastases at the diagnosis of lung metastases.

Berberine inhibited the formation of metastasis by intervening the secondary homing of colorectal cancer cells in the blood circulation to the lung and liver through HEY2

BackgroundMetastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. PurposeThis study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. MethodsIn this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. ResultsWe found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, β-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. ConclusionsWe revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and β-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis.