Neoadjuvant chemoradiation therapy combined with immunotherapy for microsatellite stable ultra-low rectal cancer (CHOICE II): study protocol of a multicentre prospective randomised clinical trial.

INTRODUCTION: Neoadjuvant chemoradiotherapy (nCRT) could bring tumour shrinking and downstaging and increase the probability of organ preservation for patients with low rectal cancer. But for ultra-low rectal cancer, there is little possibility for organ preservation. Immunotherapy has been shown to have significant survival benefits in microsatellite instability-high patients but poor response in microsatellite stable (MSS) patients. Studies have demonstrated that radiotherapy and immunotherapy have synergistic effects in cancer treatment. There is no existing evidence about the clinical efficacy of immunotherapy combined with nCRT for patients with MSS ultra-low rectal cancer. METHOD AND ANALYSIS: This trial is an open-labelled multicentre prospective randomised controlled trial (NCT05215379) with two parallel groups and allocation ratio 1:1 (nCRT+immunotherapy vs nCRT group). Eligible participants will be aged 18-75 years, with a desire for anus preservation, confirmed cT1-3aN0-1M0 rectal adenocarcinoma, confirmed MSS type, inferior margin of ≤5 cm from the anal verge. The primary endpoint of this trial is complete clinical response (cCR) rate. Immunotherapy is added after 1 week of chemoradiotherapy for two cycles, and then the patients will be administered two cycles of immunotherapy and CAPOX. The evaluations will be carried out after the completion of the whole neoadjuvant therapy. We expect the programme to improve the cCR rate and the quality of life for patients with ultra-low rectal cancer. ETHICS AND DISSEMINATION: This trial was approved by the Ethics committee of Changhai Hospital and other medical centres (Grant number:CHEC2022-118). The results of this study will provide further insight into the clinical efficacy of immunotherapy in combination with nCRT in patients with MSS ultra-low rectal cancer. TRIAL REGISTRATION NUMBER: NCT05215379.

Clinicopathological features and prognosis of synchronous and metachronous colorectal cancer: a retrospective cohort study.

BACKGROUND: To investigate the clinicopathological features and prognosis of synchronous and metachronous multiple primary colorectal cancer. MATERIALS AND METHODS: Patients who underwent operation for synchronous and metachronous colorectal cancer at the colorectal surgery department of Shanghai Changhai Hospital between January 2000 and December 2021 were included. Perioperative indicators were comprehensively compared and included in the survival analyses. RESULTS: In total, 563 patients with synchronous ( n =372) and metachronous ( n =191) colorectal cancer were included. Patients with synchronous colorectal cancer were more likely to have a long onset time, positive carcinoembryonic antigen, advanced TNM stage, large tumor, perineural invasion, p53 high expression, and mismatch repair proficient. Compared with metachronous colorectal cancer, patients with synchronous colorectal cancer showed worse 5-year overall survival (68.6±3.0% vs 81.9±3.5%, P =0.018) and 5-year disease-free survival (61.2±3.1% vs 71.0±3.9%, P =0.022). In the subgroup analysis, segmental resection was an independent risk factor for the long-term outcomes of bilateral synchronous colorectal cancer. CONCLUSIONS: Clinicopathological and molecular features were different between synchronous and metachronous colorectal cancer. Patients with synchronous colorectal cancer showed a worse prognosis than those with metachronous colorectal cancer. Bilateral synchronous colorectal cancer requires extended resection to achieve improved long-term outcomes.

Optimal examined lymph node number for accurate staging and long-term survival in rectal cancer: a population-based study.

BACKGROUND: Although the recommended minimal examined lymph node (ELN) number in rectal cancer (RC) is 12, this standard remains controversial because of insufficient evidence. We aimed to refine this definition by quantifying the relationship between ELN number, stage migration and long-term survival in RC. METHODS: Data from a Chinese multi-institutional registry (2009-2018) and the Surveillance, Epidemiology, and End Results (SEER) database (2008-2017) on stages I-III resected RC were analysed to determine the relationship between ELN count, stage migration, and overall survival (OS) using multivariable models. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a Locally Weighted Scatterplot Smoothing (LOWESS) smoother, and structural breakpoints were determined using the Chow test. The relationship between ELN and survival was evaluated on a continuous scale using restricted cubic splines (RCS). RESULTS: The distribution of ELN count between the Chinese registry ( n =7694) and SEER database ( n =21 332) was similar. With increasing ELN count, both cohorts exhibited significant proportional increases from node-negative to node-positive disease (SEER, OR, 1.012, P <0.001; Chinese registry, OR, 1.016, P =0.014) and serial improvements in OS (SEER: HR, 0.982; Chinese registry: HR, 0.975; both P <0.001) after controlling for confounders. Cut-point analysis showed an optimal threshold ELN count of 15, which was validated in the two cohorts, with the ability to properly discriminate probabilities of survival. CONCLUSIONS: A higher ELN count is associated with more precise nodal staging and better survival. Our results robustly conclude that 15 ELNs are the optimal cut-off point for evaluating the quality of lymph node examination and stratification of prognosis.

Comparison of functional and oncological outcome of conformal sphincter preservation operation, low anterior resection, and abdominoperineal resection in very low rectal cancer: a retrospective comparative cohort study with propensity score matching.

PURPOSE: Conformal sphincter preservation operation (CSPO) procedure is a sphincter preservation procedure for preserving the anal canal function for very low rectal cancers. This study investigated the functional and oncological outcome of conformal sphincter preservation operation by comparing with low anterior resection (LAR) and abdominoperineal resection (APR). METHODS: This is a retrospective comparative study. Patients who received conformal sphincter preservation operation (n = 52), low anterior resection (n = 54), or abdominoperineal resection (n = 69) were included between 2011 and 2016 in a tertiary referral hospital. Propensity score matching was applied to adjust the baseline characteristics which may influence the choice of the surgical procedure. RESULTS: Twenty-one pairs of conformal sphincter preservation operation vs. low anterior resection and 29 pairs of conformal sphincter preservation operation vs. abdominoperineal resection were selected. The first group had a higher tumor location than the second group. Compared with the low anterior resection group, the conformal sphincter preservation operation group had shorter distal resection margins; however, no significant differences were identified in daily stool frequency, Wexner incontinence score, local recurrence, distant metastasis, overall survival, and disease-free survival between both groups. Compared with the abdominoperineal resection group, the conformal sphincter preservation operation group had shorter operative time and shorter postoperative hospital stay. No significant differences were identified in local recurrence, distant metastasis, overall survival, and disease-free survival. CONCLUSION: Conformal sphincter preservation operation is oncologically safe compared to APR and LAR, and has similar functional findings to LAR. Studies comparing CSPO with intersphincteric resection should be performed.

Single-cell sequencing technology in colorectal cancer: a new technology to disclose the tumor heterogeneity and target precise treatment.

Colorectal Cancer (CRC) is one of the most common gastrointestinal tumors, and its high tumor heterogeneity makes traditional sequencing methods incapable of obtaining information about the heterogeneity of individual cancer cells in CRC. Therefore, single-cell sequencing technology can be applied to better analyze the differences in genetic and protein information between cells, to obtain genomic sequence information of single cells, and to more thoroughly analyze the cellular characteristics and interactions in the CRC microenvironment. This will provide a more comprehensive understanding of colorectal cancer development and metastasis and indicate the treatment plan and prognosis. In this study, we review the application of single-cell sequencing to analyze the tumor microenvironment of CRC, explore the mechanisms involved in CRC metastasis and progression, and provide a reference for potential treatment options.

DSTN Hypomethylation Promotes Radiotherapy Resistance of Rectal Cancer by Activating the Wnt/ß-Catenin Signaling Pathway.

PURPOSE: Although surgical resection combined with neoadjuvant radiation therapy can reduce the local recurrence rate of rectal cancer, not all patients benefit from neoadjuvant radiation therapy. Therefore, screening for patients with rectal cancer who are sensitive or resistant to radiation therapy has great clinical significance. METHODS AND MATERIALS: Patients with rectal cancer were selected according to postoperative tumor regression grade, and tumor samples were taken for detection. Differential genes between radiation-resistant and radiation-sensitive tissues were screened and validated by Illumina Infinium MethylationEPIC BeadChip, proteomics, Agena MassARRAY methylation, reverse transcription quantitative real-time polymerase chain reaction, and immunohistochemistry. In vitro and in vivo functional experiments verified the role of DSTN. Protein coimmunoprecipitation, western blot, and immunofluorescence were used to investigate the mechanisms of DSTN-related radiation resistance. RESULTS: DSTN was found to be highly expressed (P < .05) and hypomethylated (P < .01) in rectal cancer tissues resistant to neoadjuvant radiation therapy. Follow-up data confirmed that patients with high expression of DSTN in neoadjuvant radiation therapy-resistant rectal cancer tissues had shorter disease-free survival (P < .05). DSTN expression increased after methyltransferase inhibitor inhibition of DNA methylation in colorectal cancer cells (P < .05). In vitro and in vivo experiments showed that knockdown of DSTN promoted the sensitivity of colorectal cancer cells to radiation therapy, and overexpression of DSTN promoted the resistance of colorectal cancer cells to radiation (P < .05). The Wnt/ß-catenin signaling pathway was activated in colorectal cancer cells overexpressing DSTN. ß-catenin was highly expressed in radiation therapy-resistant tissues, and there was a linear correlation between the expression of DSTN and ß-catenin (P < .0001). Further studies showed that DSTN can bind to ß-catenin and increase its stability. CONCLUSIONS: The degree of DNA methylation and the expression level of DSTN can be used as biomarkers to predict the sensitivity of neoadjuvant radiation therapy for rectal cancer. DSTN and ß-catenin are also expected to become a reference for the selection of neoadjuvant radiation therapy.

An easy-to-use artificial intelligence preoperative lymph node metastasis predictor (LN-MASTER) in rectal cancer based on a privacy-preserving computing platform: multicenter retrospective cohort study.

BACKGROUND: Although the surgical treatment strategy for rectal cancer (RC) is usually based on the preoperative diagnosis of lymph node metastasis (LNM), the accurate diagnosis of LNM has been a clinical challenge. In this study, we developed machine learning (ML) models to predict the LNM status before surgery based on a privacy-preserving computing platform (PPCP) and created a web tool to help clinicians with treatment-based decision-making in RC patients. PATIENTS AND METHODS: A total of 6578 RC patients were enrolled in this study. ML models, including logistic regression, support vector machine, extreme gradient boosting (XGB), and random forest, were used to establish the prediction models. The areas under the receiver operating characteristic curves (AUCs) were calculated to compare the accuracy of the ML models with the US guidelines and clinical diagnosis of LNM. Last, model establishment and validation were performed in the PPCP without the exchange of raw data among different institutions. RESULTS: LNM was detected in 1006 (35.3%), 252 (35.3%), 581 (32.9%), and 342 (27.4%) RC patients in the training, test, and external validation sets 1 and 2, respectively. The XGB model identified the optimal model with an AUC of 0.84 [95% confidence interval (CI), 0.83-0.86] compared with the logistic regression model (AUC, 0.76; 95% CI, 0.74-0.78), random forest model (AUC, 0.82; 95% CI, 0.81-0.84), and support vector machine model (AUC, 0.79; 95% CI, 0.78-0.81). Furthermore, the XGB model showed higher accuracy than the predictive factors of the US guidelines and clinical diagnosis. The predictive XGB model was embedded in a web tool (named LN-MASTER) to predict the LNM status for RC. CONCLUSION: The proposed easy-to-use model showed good performance for LNM prediction, and the web tool can help clinicians make treatment-based decisions for patients with RC. Furthermore, PPCP enables state-of-the-art model development despite the limited local data availability.

Multiregion single cell analysis reveals a novel subtype of cancer-associated fibroblasts located in the hypoxic tumor microenvironment in colorectal cancer.

BACKGROUND: The tumor microenvironment (TME) plays a critical role in shaping tumor progression and determining the outcome of the therapeutic response. In this study, we aimed to generate a comprehensive cellular landscape of the colorectal cancer (CRC) TME. METHODS: We generated a comprehensive single-cell atlas by collecting CRC cases that have been uploaded to the online database and conducting an in-depth secondary analysis. We then carried out spatial transcriptomic sequencing and multiple immunohistochemical analyses to verify the results of the single-cell analysis. Moreover, we applied our findings to the TCGA database and used tissue microarray (TMA) on CRC tissue specimens to validate clinical prognosis. FINDINGS: We re-analyzed the transcriptomes of 23785 cells, revealing a pattern of cell heterogeneity in the tumor region, leading-edge region, and non-tumor region. A subtype of COL11A1+INHBA+ tumor-resident cancer-associated fibroblasts (CAFs) was identified, and marker genes, transcription factors, and tissue-specific expression differences were noted and suggested to have potential roles in promoting cancer. We further confirmed that COL11A1+INHBA+ tumor-resident CAFs are mainly located in the hypoxic TME and we propose that they interact with CD44+ CRC cells via INHBA. Elevation of INHBA in CRC is associated with a poor prognosis. INTERPRETATION: Our results demonstrated a single cell landscape of CRC in different regions and identified in hypoxic TME a special subtype of CAFs producing INHBA, which promotes CRC development and correlates with poor prognosis. This special subtype of CAFs is a candidate target for translational research.

Development and Validation of an 8-Gene Signature to Improve Survival Prediction of Colorectal Cancer.

Background: Most prognostic signatures for colorectal cancer (CRC) are developed to predict overall survival (OS). Gene signatures predicting recurrence-free survival (RFS) are rarely reported, and postoperative recurrence results in a poor outcome. Thus, we aim to construct a robust, individualized gene signature that can predict both OS and RFS of CRC patients. Methods: Prognostic genes that were significantly associated with both OS and RFS in GSE39582 and TCGA cohorts were screened via univariate Cox regression analysis and Venn diagram. These genes were then submitted to least absolute shrinkage and selection operator (LASSO) regression analysis and followed by multivariate Cox regression analysis to obtain an optimal gene signature. Kaplan-Meier (K-M), calibration curves and receiver operating characteristic (ROC) curves were used to evaluate the predictive performance of this signature. A nomogram integrating prognostic factors was constructed to predict 1-, 3-, and 5-year survival probabilities. Function annotation and pathway enrichment analyses were used to elucidate the biological implications of this model. Results: A total of 186 genes significantly associated with both OS and RFS were identified. Based on these genes, LASSO and multivariate Cox regression analyses determined an 8-gene signature that contained ATOH1, CACNB1, CEBPA, EPPHB2, HIST1H2BJ, INHBB, LYPD6, and ZBED3. Signature high-risk cases had worse OS in the GSE39582 training cohort (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.42 to 1.67) and the TCGA validation cohort (HR = 1.39, 95% CI = 1.24 to 1.56) and worse RFS in both cohorts (GSE39582: HR = 1.49, 95% CI = 1.35 to 1.64; TCGA: HR = 1.39, 95% CI = 1.25 to 1.56). The area under the curves (AUCs) of this model in the training and validation cohorts were all around 0.7, which were higher or no less than several previous models, suggesting that this signature could improve OS and RFS prediction of CRC patients. The risk score was related to multiple oncological pathways. CACNB1, HIST1H2BJ, and INHBB were significantly upregulated in CRC tissues. Conclusion: A credible OS and RFS prediction signature with multi-cohort and cross-platform compatibility was constructed in CRC. This signature might facilitate personalized treatment and improve the survival of CRC patients.

Machine learning-based random forest predicts anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Anastomotic leakage (AL) is one of the commonest and most serious complications after rectal cancer surgery. The previous analyses on predictors for AL included small-scale patients, and their prediction models performed unsatisfactorily. METHODS: Clinical data of 5,220 patients who underwent anterior resection for rectal cancer were scrutinized to create a prediction model via random forest classifier. Additionally, data of 836 patients served as the test dataset. Patients diagnosed with AL within 6 months' follow-up were recorded. A total of 20 candidate factors were included. Receiver operating characteristic (ROC) curve was conducted to determine the clinical efficacy of our model, and compare the predictive performance of different models. RESULTS: The incidence of AL was 6.2% (326/5,220). A multivariate logistic regression analysis and the random forest classifier indicated that sex, distance of tumor from the anal verge, bowel stenosis or obstruction, preoperative hemoglobin, surgeon volume, diabetes, neoadjuvant chemoradiotherapy, and surgical approach were significantly associated with AL. After propensity score matching, the temporary stoma was not identified as a protective factor for AL (P=0.58). Contrastingly, the first year of performing laparoscopic surgery was a predictor (P=0.009). We created a predictive random forest classifier based on the above predictors that demonstrated satisfactory prediction efficacy. The area under the curve (AUC) showed that the random forest had higher efficiency (AUC =0.87) than the nomogram (AUC =0.724). CONCLUSIONS: Our findings suggest that eight factors may affect the incidence of AL. Our random forest classifier is an innovative and practical model to effectively predict AL, and could provide rational advice on whether to perform a temporary stoma, which might reduce the rate of stoma and avoid the ensuing complications.

Preoperative nomogram to predict survival following colorectal cancer liver metastasis simultaneous resection.

BACKGROUND: Simultaneous resection for patients with synchronous colorectal cancer liver metastases (CRLM) remains an optimal option for the sake of curability. However, few studies so far focus on outcome of this subgroup of patients (who receive simultaneous resection for CRLM). Substantial heterogeneity exists among such patients and more precise categorization is needed preoperatively to identify those who may benefit more from surgery. In this study, we formulated this internally validated scoring system as an option. METHODS: Clinicopathological and follow-up data of 234 eligible CRLM patients undergoing simultaneous resection from January 2010 to March 2019 in our center were included for analysis. Patients were randomized to either a training or validation cohort. We performed multivariable Cox regression analysis to determine preoperative factors with prognostic significance using data in training cohort, and a nomogram scoring system was thus established. Time-dependent receiver operating characteristic (ROC) curve and calibration plot were adopted to evaluate the predictive power of our risk model. RESULTS: In the multivariable Cox regression analysis, five factors including presence of node-positive primary defined by enhanced CT/MR, preoperative CEA level, primary tumor location, tumor grade and number of liver metastases were identified as independent prognostic indicators of overall survival (OS) and adopted to formulate the nomogram. In the training cohort, calibration plot graphically showed good fitness between estimated and actual 1- and 3-year OS. Time-dependent ROC curve by Kaplan-Meier method showed that our nomogram model was superior to widely used Fong's score in prediction of 1- and 3-year OS (AUC 0.702 vs. 0.591 and 0.848 vs. 0.801 for 1- and 3-year prediction in validation cohort, respectively). Kaplan-Meier curves for patients stratified by the assessment of nomogram showed great discriminability (P<0.001). CONCLUSIONS: In this retrospective analysis we identified several preoperative factors affecting survival of synchronous CRLM patients undergoing simultaneous resection. We also constructed and validated a risk model which showed high accuracy in predicting 1- and 3-year survival after surgery. Our risk model is expected to serve as a predictive tool for CRLM patients receiving simultaneous resection and assist physicians to make treatment decision.

Corrigendum to "The Prognostic Significance of Tumor Deposit Count for Colorectal Cancer Patients after Radical Surgery".

[This corrects the article DOI: 10.1155/2020/2052561.].

The Prognostic Significance of Tumor Deposit Count for Colorectal Cancer Patients after Radical Surgery.

BACKGROUND: The prognostic value of tumor deposit (TD) count in colorectal cancer (CRC) patients has been rarely evaluated. This study is aimed at exploring the prognostic value of TD count and finding out the optimal cutoff point of TD count to differentiate the prognoses of TD-positive CRC patients. METHOD: Patients diagnosed with CRC from Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2010, to December 31, 2012, were analyzed. X-tile program was used to identify the optimal cutoff point of TD count in training cohort, and a validation cohort was used to test this cutoff point after propensity score matching (PSM). Univariate and multivariate Cox proportional hazard models were used to assess the risk factors of survival. RESULTS: X-tile plots identified 3 (P < 0.001) as the optimal cutoff point of TD count to divide the patients of training cohort into high and low risk subsets in terms of disease-specific survival (DSS). This cutoff point was validated in validation cohort before and after PSM (P < 0.001, P = 0.002). More TD count, which was defined as more than 3, was validated as an independent risk prognostic factor in univariate and multivariate analysis (P < 0.001). CONCLUSION: More TD count (TD count ≥ 4) was significantly associated with poor disease-specific survival in CRC patients.

[A case of large pulmonary embolism in trunk and branches with main manifestation of syncope, vomiting and shock].

OBJECTIVE: Pulmonary embolism (PE) refers to the endogenous or exogenous emboli blocking pulmonary trunk or branches, causing clinical and pathophysiological syndrome of pulmonary circulation disorder, the incidence rate is high. Sometimes PE patients were lack of specific symptoms and signs, or without any symptoms, which often result in misdiagnosis, un-timely diagnosis, and the delay of treatment. A PE case with syncope, vomiting and shock, which was proved to be pulmonary artery trunk and branch wide embolism later, was presented so as to improve the understanding of the disease.