Additional file 1 : Supplementary Table 1. Participant demographics and baseline characteristics. Supplementary Table 2. Performance of the first-level cancer detection model. Supplementary Table 3. Performances of the cancer detection model on different subgroups based on clinical characteristics. Supplementary Table 4. Cancer detection model robustness test using downsampled (4× to 1× coverage depths) WGS data. Each downsampled coverage depth was repeated five times. Supplementary Table 5. Performances of the cancer detection model on extra healthy volunteer and at-risk patient cohort. Supplementary Table 6. The performance of the second level cancer origin model shown in the confusion matrix table. Supplementary Table 7. Cancer origin model robustness test using downsampled (4× to 1× coverage depths) WGS data. Each downsampled coverage depth was repeated five times.
Previous studies found patients with POLE exonuclease domain mutations (EDMs) in targeted exons were related to significant better outcomes in stage II-III colorectal cancer (CRC). The detailed mutational profile of the entire POLE exonuclease domain, tumor mutation burden (TMB) and immune cell infiltration in POLE EDMs tumors, and the prognostic value of such mutations in stage II CRCs were largely unknown to us. This study was to clarify the characteristics, immune response and prognostic value of somatic POLE EDMs in stage II CRC. A total of 295 patients with stage II CRC were sequenced by next-generation sequencing with a targeted genetic panel. Simultaneous detection of the immune cells was conducted using a five-color immunohistochemical multiplex technique. The detailed molecular characteristics, tumor-infiltrating lymphocyte (TIL) and prognostic effect of POLE EDMs in stage II CRC were analyzed. For stage II CRCs, the POLE EDMs were detected in 3.1% of patients. Patients with POLE EDMs were more prone to be microsatellite instability-high (MSI-H) (33.3% vs 11.2%, p=0.043), younger at diagnosis (median 46 years vs 62 years, p<0.001) and more common at right-sided location (66.7% vs 23.1%; p=0.003). All patients with POLE EMDs were assessed as extremely high TMB, with a mean TMB of 200.8. Compared with other stage II CRCs, POLE EDMs displayed an enhanced intratumoral cytotoxic T cell response, evidenced by increased numbers of CD8+TILs and CD8A expression. Patients with stage II CRCs could be classified into three risk subsets, with significant different 5 years disease-free survival rates of 100% for POLE EDMs, 82.0% for MSI-H and 63.0% for MSS, p=0.013. In conclusion, characterized by a robust intratumoral T cell response, ultramutated POLE EDMs could be detected in a small subset of stage II CRCs with extremely high TMB. Patients with POLE EDMs had excellent outcomes in stage II CRCs, regardless of MSI status. Sequencing of all the exonuclease domain of POLE gene is recommended in clinical practice.
Survival outcomes are significantly different in stage II colorectal cancer (CRC) patients with diverse clinicopathological features. The objective of this study is to establish a credible prognostic nomogram incorporating easily obtained parameters for stage II CRC patients.A total of 1708 stage II CRC patients seen at Fudan University Shanghai Cancer Center (FUSCC) from 2008 to 2013 were retrospectively analyzed in this study. Cases were randomly separated into a training set (n = 1084) and a validation set (n = 624). Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors that were subsequently incorporated into a nomogram. The performance of the nomogram was evaluated by the predicted concordance index (C-index) and ROC curve to calculate the area under the curve (AUC). The clinical utility of the nomogram was evaluated using decision curve analysis (DCA).In univariate and multivariate analyses, eight parameters were correlated with disease-free survival (DFS), which were subsequently selected to generate a prognostic nomogram based on DFS. For DFS predictions, the C-index values of the nomogram were 0.842 (95% confidence interval (CI) 0.710-0.980), and 0.701 (95% CI 0.610-0.770) for the training and validation sets, respectively. The AUC values of the ROC curves for the nomogram to predicted 1, 3 and 5-year survival were 0.869, 0.858, and 0.777 (training group) and 0.673, 0.714, and 0.706 (validation group), respectively. The recurrence probability calibration curve showed good consistency between actual observations and nomogram-based predictions. DCA showed better clinical application value for the nomogram than the TNM staging system.A novel nomogram was established and validated in a large population, and the nomogram is a simple-to-use tool for physicians to facilitate postoperative personalized prognostic evaluation and determine therapeutic strategies for stage II CRC patients.
In this paper,layered cathode material LiCoO2 were synthesized by self-propagating high temperature synthesis and heat-treatment technology.X-ray diffractometer and scanning electron microscopy(SEM)were used to investigate the effects of annealing temperature,annealing time and the mole ratio of Li to Co on purity,crystal structure and microstructure of LiCoO2.The results show the optimum condition as follows:molar ratio of Li to Co was 1.03∶1,molar ratio of NH4NO3 to Co was 4∶3,molar ratio of C6H12N4 to Co was 4∶3,annealing temperature was 800℃and annealing time was 1.5h.Under the optimum condition,the percentage of LiCoO2 phase in the products was as high as 99.25%,and the crystal has good layer structure.
Precise methods for risk stratification to guide adjuvant chemotherapy for stage III colon cancers are needed. Here, we combined circulating tumor DNA (ctDNA) with consensus molecular subtype (CMS) to improve risk stratification in stage III colon cancers.We conducted a prospective, observational cohort study of 165 patients with stage III colon cancers. Somatic variants in tumor tissues and plasmas collected pre- and post-chemo were detected via a targeted sequencing panel of 197 cancer-related genes. CMSs classification was characterized using a targeted RNA sequencing panel of 788 genes.We analyzed 151 pre-chemo and 124 post-chemo plasmas, while 130 patients were CMSs classified. ctDNA was detectable in 15.9% pre-chemo and 8.9% post-chemo samples. Significantly worse recurrence-free survival (RFS) was seen if ctDNA was detectable in pre-chemo samples (hazard ratio [HR], 3.585; P < 0.001) or in post-chemo samples (HR, 3.337; P = 0.005). Pre-chemo ctDNA (HR, 5.538; P < 0.001) and post-chemo ctDNA status (HR, 3.272; P = 0.037) remained independently associated with RFS in multivariate analysis. According to the redefined recurrence risk stratification, mid-risk patients (ctDNA-negative with CMS4/T4 or N2 tumors) were 5.3 times (HR, 5.269; P = 0.025) more likely to relapse than low-risk patients (ctDNA-negative with CMS1-3/T3N1 tumors), while high-risk patients (ctDNA-positive) were 14.6 times (HR, 14.590; P < 0.001) more likely to relapse.Postoperative ctDNA indicating residual disease, combined with CMSs classification and clinical risk reflecting the intrinsic characteristics of tumors, can redefine risk stratification of stage III colon cancers and better predict relapse.
Previous studies on liquid biopsy-based early detection of advanced colorectal adenoma (advCRA) or adenocarcinoma (CRC) were limited by low sensitivity. We performed a prospective study to establish an integrated model using fragmentomic profiles of plasma cell-free DNA (cfDNA) for accurately and cost-effectively detecting early-stage CRC and advCRA. The training cohort enrolled 310 participants, including 149 early-stage CRC patients, 46 advCRA patients and 115 healthy controls. Plasma cfDNA samples were prepared for whole-genome sequencing. An ensemble stacked model differentiating healthy controls from advCRA/early-stage CRC patients was trained using five machine learning models and five cfDNA fragmentomic features based on the training cohort. The model was subsequently validated using an independent test cohort (N = 311; including 149 early-stage CRC, 46 advCRA and 116 healthy controls). Our model showed an area under the curve (AUC) of 0.988 for differentiating advCRA/early-stage CRC patients from healthy individuals in an independent test cohort. The model performed even better for identifying early-stage CRC (AUC 0.990) compared to advCRA (AUC 0.982). At 94.8% specificity, the sensitivities for detecting advCRA and early-stage CRC reached 95.7% and 98.0% (0: 94.1%; I: 98.5%), respectively. Promisingly, the detection sensitivity has reached 100% and 97.6% in early-stage CRC patients with negative fecal occult or CEA blood test results, respectively. Finally, our model maintained promising performances (AUC: 0.982, 94.4% sensitivity at 94.8% specificity) even when sequencing depth was down-sampled to 1X. Our integrated predictive model demonstrated an unprecedented detection sensitivity for advCRA and early-stage CRC, shedding light on more accurate noninvasive CRC screening in clinical practice.
Background: Colon signet-ring cell carcinoma (SRCC) is a rare type of malignant dedifferentiated adenocarcinomas, and associated with poor survival. However, an in-depth study of the biological features of colon SRCC is hampered by lack of in vitro model. Our study was designed to establish and characterize cell cultures from SRCC for further translational and biological research. Methods: By harnessing the power of organoid culture system, we established a human colon SRCC organoid line from surgical sample of one patient with colon SRCC. The organoid line was characterized at the morphology, histology, ultrastructure, chromosome stability level and its tumorigenic ability was verified by xenografts. Capture-based targeted DNA sequencing combining with drug screen based on a bespoke 88 compound library identified the possible target and the treatment response was confirmed by in vivo organoid system and in vitro xenografts.Findings: Our data showed that the colon SRCC organoid line, YQ-173, resemble histological and growth characteristics of the original tumor cells and have high tumor formation rate. DNA sequencing indicated JAK2 might be the treatment target. In vitro drug screen found that AT9283 and Pacritinib could be the effective JAK2 inhibitors, which was consistent with in vivo xenografts' response.Interpretation: We report, for the first time, the establishment of SRCC organoid line allowing in-depth study of SRCC biology, as well as a strategy to assess in vitro drug testing in a personalized fashion.Funding: This work was supported by National Natural Science Foundation of China (31470826, 31670858, 81672374), Science and Technology Commission of Shanghai Municipality (16411966300), and Shanghai Sailing Program (19YF1409500).Declaration of Interest: The authors declare no potential conflicts of interest. Ethical Approval: The tissue was obtained with informed consent for experimentation with the patient and this study was approved by the ethical committee of Fudan University Shanghai Cancer Center. All animal experiments were performed according to the guidelines for the care and use of laboratory animals and were approved by Institutional Animal Care and Use Committee of Fudan University.
Abstract Objective To study the pattern and treatment outcome of rectal cancer (RC) with concurrent locoregional recurrence (LR) and distant metastasis (DM) after total mesorectal excision (TME) and to identify patient-, disease-, and treatment-related factors associated with differences in prognosis after concurrent LR and DM. Methods RC patients who were diagnosed with concurrent LR and DM after TME from May 2015 to June 2019 were included in our study. All patients received single or multiple treatment modalities under the guidance of multidisciplinary team (MDT) of colorectal cancer in Fudan University Shanghai Cancer Center.The prognostic of various clinicopathological factors for survival calculated by Kaplan-Meier curves and Cox regression analysis. Results A total of 74 RC patients with conurrent LR and DM after TME were eligible for analysis with median follow-up of 27 months. Median survival of patients included was 34 months and 30 patients (41%) died. 59 patients (80%) underwent comprehensive treatments. Patients with oligometastatic disease (OMD) achieved no evidence of disease (NED) status more frequently than those with multiple metastases ( P = 0.003). In the univariate analysis, patients achieving NED, diagnosed with OMD and five or less peritoneal metastases tended to have longer survival after LR and DM diagnosis ( P < 0.05). In the multivariate analysis, attaining NED status was the only independent factor for survival (hazard ratio (HR), 2.419; P = 0.032). Survival after concurrent LR and DM in the non-NED group was significantly shorter than in the NED group (median survival, 32 vs 46 months; HR, 2.7; P = 0.014). Conclusion The pattern and treatment outcome of RC with concurrent LR and DM after TME has changed with development of multiple treatment modalities. Although the prognosis is still poor, pursuing NED status through comprehensive treatments may improve the survival of RC patients with concurrent LR and DM after TME.
202 Background: Liver fibrosis, resulted from several liver diseases, are increasing up to 25% in population globally. It remains undetermined how much of an impact liver fibrosis have on the development of hepatic metastasis and relapse in colorectal cancer (CRC). Hence the aim of this study was to clarify the role of liver fibrosis on hepatic metastasis and relapse in CRC undergoing curative therapy. Methods: We enrolled consecutive 1652 patients with radical surgery as the discovery cohort, and the validation set enrolled 432 CRC patients with hepatic metastasis treatment. To determine the degree of liver fibrosis, the NFS, FIB4 and APRI were applied. The influence of liver fibrosis on hepatic metastasis and relapse was assessed by survival analyses. Nomograms with fibrosis score incorporated was established to identify the incremental value for individualized relapse estimation, which was then assessed with respect to calibration, discrimination, and clinical usefulness. Results: The high liver fibrosis score patients had significantly worse outcomes than low score in 5-year hepatic metastasis (22.6 vs . 8.7%) in discovery cohort, and RFS (58.2 vs. 44.1%) in validation cohort. Multivariate analysis revealed liver fibrosis score as an independent prognostic factor. The distribution analysis also demonstrated higher liver fibrosis score a powerful prognostic factor for hepatic metastasis and relapse. Incorporating the liver fibrosis score into the nomogram resulted in better performance evaluated by C-index and AUC than TNM staging system and clinicopathologic nomograms. Importantly, in validation cohort, the discriminatory capacity of the fibrosis score incorporated was superior to that of the CRS score in predicting RFS, as demonstrated by the C-index and AUC. The concordance study showed well agreement among NFS, FIB4 and APRI in predicting DFS and RFS. Among these three noninvasive liver fibrosis scores, NFS score performed the best in predicting hepatic specific DFS and RFS. Conclusions: The liver fibrosis was a powerful predictor of hepatic specific DFS and RFS in CRC. Fibrosis niche may be a favorable microenvironment for metastatic formation in the liver.
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