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Compared with open resection, laparoscopic resection of rectal cancers is associated with improved short-term outcomes, but high-level evidence showing similar long-term outcomes is scarce. We aimed to compare survival outcomes of laparoscopic surgery with open surgery for patients with mid-rectal or low-rectal cancer. The Comparison of Open versus laparoscopic surgery for mid or low REctal cancer After Neoadjuvant chemoradiotherapy (COREAN) trial was an open-label, non-inferiority, randomised controlled trial done between April 4, 2006, and Aug 26, 2009, at three centres in Korea. Patients (aged 18–80 years) with cT3N0–2M0 mid-rectal or low-rectal cancer who had received preoperative chemoradiotherapy were randomly assigned (1:1) to receive either open or laparoscopic surgery. Randomisation was stratified by sex and preoperative chemotherapy regimen. Investigators were masked to the randomisation sequence; patients and clinicians were not masked to the treatment assignments. The primary endpoint was 3 year disease-free survival, with a non-inferiority margin of 15%. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00470951. We randomly assigned 340 patients to receive either open surgery (n=170) or laparoscopic surgery (n=170). 3 year disease-free survival was 72·5% (95% CI 65·0–78·6) for the open surgery group and 79·2% (72·3–84·6) for the laparoscopic surgery group, with a difference that was lower than the prespecified non-inferiority margin (–6·7%, 95% CI −15·8 to 2·4; p<0·0001). 25 (15%) patients died in the open group and 20 (12%) died in the laparoscopic group. No deaths were treatment related. Our results show that laparoscopic resection for locally advanced rectal cancer after preoperative chemoradiotherapy provides similar outcomes for disease-free survival as open resection, thus justifying its use. National Cancer Center, South Korea.

Epithelial–mesenchymal transition (EMT)-related cancers generally elicit low immune responses. EMT is regulated by several microRNAs (miRNAs) in cancers. Thus, this study aimed to evaluate the prognostic potential of EMT-related miRNAs as biomarkers in colorectal cancer (CRC). Formalin-fixed paraffin-embedded tumor and normal tissue and plasma samples were obtained from 65 patients with pathologically confirmed CRC. In addition, plasma samples were obtained from 30 healthy volunteers. Immunohistochemical staining for E-cadherin, ZEB1, PD-1, PD-L1, CD3, CD4, CD8, Foxp3, and CD68 was conducted on tissue samples. Droplet digital polymerase chain reaction (ddPCR) analysis was performed to evaluate miR-21-5p, 34a-5p, 138-5p, 200a-3p, 200b-5p, 200c-3p, 630, 1246, and 1290 expression in tissue samples and miR-630, 1246, and 1290 expression in plasma samples. miR-21-5p, 34a-5p, 630, 1246, and 1290 expression was higher in tumor tissues than in normal tissues ( P  < 0.05). EMT was significantly associated with reduced tumor-infiltrating T cells. Moreover, miR-21-5p, miR-34a-5p, miR-200a-3p, and miR-200c-3p expression was negatively correlated with T cell density ( P  < 0.05). High tissue levels of miR-200c-3p were associated with poor overall survival (OS) ( P  < 0.001). CRC patients with the EMT phenotype had poor OS; however, PD-L1 positivity and abundant PD-1 positive immune cells were correlated with better OS (P < 0.05). miR-1246 and miR-1290 levels were significantly higher in the plasma of patients with CRC than in the plasma of healthy controls ( P  < 0.05). High plasma levels of miR-1290 were correlated with advanced stage and poor OS ( P  < 0.05). The tissue expression of miR-200c-3p and plasma levels of miR-1290 measured by ddPCR indicate their potential as prognostic biomarkers for CRC.

Downregulation of human leukocyte antigen (HLA) class I has been postulated to be a mechanism of adaptive immune escape in various tumors, especially microsatellite instability–high (MSI‐H) colorectal cancer (CRC). In this study, we aimed to investigate HLA class I and β2‐microglobulin (β2M) expression in MSI‐H and microsatellite‐stable (MSS) CRCs and determine its prognostic impact. The representative areas from the tumor center (TC) and tumor periphery (TP) from 300 CRCs, including 161 MSI‐H and 139 MSS cases, were selected to construct a tissue microarray. Immunohistochemistry (IHC) for HLA A/B/C, β2M, CD3, and CD8 was performed. Reduced HLA A/B/C expression was detected in 113 (70.2%) MSI‐H and 54 (38.8%) MSS cases, while reduced β2M expression was observed in 69 (42.9%) MSI‐H and 17 (12.2%) MSS cases. Although reduced β2M expression was associated with higher pathological tumor (pT) stage in MSI‐H CRC with borderline significance, no association was found between HLA A/B/C and β2M expression and survival. Interestingly, reduced HLA A/B/C expression in MSS was associated with higher stage, and reduced HLA A/B/C and β2M expression was an independent prognostic factor in multivariate analysis. In conclusion, reduced HLA A/B/C and β2M expression was frequently observed in immunotherapy‐naive MSI‐H CRC, suggesting the possibility of primary resistance to immune checkpoint inhibitor. Interestingly, downregulation of HLA A/B/C and β2M was associated with poor prognosis in MSS cancers. Overall, IHC for HLA A/B/C and β2M might be a feasible predictive or prognostic tool in CRC. Reduced HLA A/B/C and β2M expression is frequently observed in immunotherapy‐naive MSI‐H CRC, suggesting the possibility of primary resistance to immune checkpoint inhibitors. Interestingly, downregulation of HLA A/B/C and β2M was associated with poor survival in MSS cancers, but not in MSI‐H tumors, indicating that cell‐mediated antitumoral immune response may also play an important role in MSS CRC. Together, IHC for HLA A/B/C and β2M can be a predictive or prognostic tool in CRC.

This study aimed at determining the incidence and clinical implications of HER2 status in primary colorectal cancer (CRC). HER2 status was investigated in two retrospective cohorts of 365 consecutive CRC patients (cohort 1) and 174 advanced CRC patients with synchronous or metachronous distant metastasis (cohort 2). HER2 status was determined by performing dual-color silver in-situ hybridization (SISH), mRNA in-situ hybridization (ISH), and immunohistochemistry (IHC). The incidence of HER2 protein overexpression (IHC 2+/3+) was approximately 6% (22 of 365 in cohort 1; 10 of 174 in cohort 2). HER2 gene amplification was observed in 5.8% of the patients from cohort 1 and 6.3% of the patients from cohort 2. HER2 gene amplification was more frequently observed in CRCs located in the rectum than in the right and left colon (P = 0.013 in cohort 1; P = 0.009 in cohort 2). HER2 status, determined by IHC, ISH, and dual-color SISH, was not significantly associated with aggressive CRC behaviour or patients' prognosis in both the cohorts. Of the combined cohort with a total of 539 cases, the concordance rate was 95.5% between dual-color SISH and IHC detection methods. On excluding equivocally immunostained cases (IHC 2+), the concordance rate was 97.7%. HER2 mRNA overtranscription, detected by ISH, significantly correlated with protein overexpression and gene amplification (P<0.001). HER2 gene amplification was identified in a minority of CRC patients with high concordance rates between dual-color SISH and IHC detection methods. Although HER2 status did not predict patients' prognosis, our findings may serve as a basis for future studies on patient selection for HER2 targeted therapy.

In this randomized trial involving young adults with suspected appendicitis, low-dose abdominal computed tomography (CT) was noninferior to standard-dose abdominal CT, with similar rates of negative appendectomy and appendiceal perforation in the two study groups. Owing to the many advantages that computed tomography (CT) has over other diagnostic tests, including ultrasonography, 1 – 3 CT has assumed a paramount position in the evaluation of adults with suspected appendicitis. Despite historical debate, 4 the increased use of CT has been consistently found to coincide with a reduction in the rate of negative (unnecessary) appendectomies without an increase in the rate of appendiceal perforations — two important reciprocal measures of quality of care that represent, respectively, a false positive diagnosis and a delayed diagnosis. 5 – 10 The routine use of CT in patients suspected of having appendicitis has also been reported . . .

Programmed cell death ligand‐1 (PD‐L1) detection assays have not been standardized for patients with colorectal cancer, and the prognostic value of PD‐L1 expression is unclear. We compared the PD‐L1 expression patterns in colorectal cancer samples using various immunohistochemical assays using 3 primary PD‐L1 antibodies (assay 1, MIH1; assay 2, E1L3; and assay 3, 22C3) and investigated the prognostic implication of PD‐L1 expression using each. Additionally, PD‐L1 gene amplification was evaluated using FISH. The percentage scorings and positivity rates of the 3 assays differed; the degrees of correlation and concordance between assays 2 and 3 were relatively high, whereas assay 1 was an outlier. Multivariate analyses indicated that PD‐L1 positivity in tumor cells and its negativity in tumor‐infiltrating lymphocytes were independent predictors of poorer overall and disease‐free survival in patients with colorectal cancer. PD‐L1 gene amplification was found in 2 patients (PD‐L1/CEP ratio, 5.60 and 5.84, respectively); both had strong PD‐L1 expression according to immunohistochemistry. Overall, our study showed that PD‐L1 expression status in tumor and immune cells is an independent prognostic factor in patients with colorectal cancer. Standardizations of both PD‐L1 detection using immunohistochemistry and the cut‐off for positivity are necessary. Finally, PD‐L1 gene amplification was found in a small fraction of samples, suggesting the possibility of an ancillary test for PD‐L1 evaluation. We undertook this study to evaluate programmed cell death ligand‐1 (PD‐L1) expression in colorectal cancer with immunohistochemistry using 3 different antibodies as well as multiple cut‐off points for denoting PD‐L1 positivity. We also evaluated the CD274/PD‐L1 gene copy number in colorectal cancers using FISH.

In this study, we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer (CRC). To this end, 186 microsatellite instability-high (MSI-H) and 153 microsatellite stable (MSS) CRCs were subjected to immunohistochemistry (IHC) analysis for the expression of CD274 and mismatch repair proteins. CD274 expression was evaluated in tumor cells at the center (TC) and periphery (TP), and immune cells at the center (IC) and periphery (IP) of CRC. IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density. Additionally, samples were screened for the B-Raf (BRAF)-V600E mutation using a Cobas 4800 System and IHC. In total, CD274 TC , CD274 TP , CD274 IC , and CD274 IP were observed in 43 (23.1%), 47 (25.3%), 107 (57.5%), and 102 (54.8%) of the MSI-H CRCs examined, and in three (2.0%), four (2.6%), 47 (30.7%), and 56 (36.6%) of the 153 MSS CRCs tested. Meanwhile, intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 (12.9%) and 47 (25.3%) MSI-H CRCs, respectively. Notably, in both MSI-H and MSS CRC, CD274 IC and CD274 IP were independently associated with improved prognosis ( P  < 0.05), while BRAF mutation was associated with CD274 TP , poor differentiation, sporadic type, and hMLH1(−)/hMSH2(+)/hMSH6(+)/PMS2(−) in MSI-H CRC ( P  < 0.006). In conclusion, CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients. A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies.

Background To develop and compare delta-radiomics signatures from 2- (2D) and 3-dimensional (3D) features that predict treatment outcomes following preoperative chemoradiotherapy (CCRT) and surgery for locally advanced rectal cancer. Methods In total, 101 patients (training cohort, n  = 67; validation cohort, n  = 34) with locally advanced rectal adenocarcinoma between 2008 and 2015 were included. We extracted 55 features from T2-weighted magnetic resonance imaging (MRI) scans. Delta-radiomics feature was defined as the difference in radiomics feature before and after CCRT. Signatures were developed to predict local recurrence (LR), distant metastasis (DM), and disease-free survival (DFS) from 2D and 3D features. The least absolute shrinkage and selection operator regression was used to select features and build signatures. The delta-radiomics signatures and clinical factors were integrated into Cox regression analysis to determine if the signatures were independent prognostic factors. Results The radiomics signatures for LR, DM, and DFS were developed and validated using both 2D and 3D features. Outcomes were significantly different in the low- and high-risk patients dichotomized by optimal cutoff in both the training and validation cohorts. In multivariate analysis, the signatures were independent prognostic factors even when considering the clinical parameters. There were no significant differences in C-index from 2D vs. 3D signatures. Conclusions This is the first study to develop delta-radiomics signatures for rectal cancer. The signatures successfully predicted the outcomes and were independent prognostic factors. External validation is warranted to ensure their performance.

Background/Aim: We aimed to investigate the role of radiogenomic and deep learning approaches in predicting the KRAS mutation status of a tumor using radiotherapy planning computed tomography (CT) images in patients with locally advanced rectal cancer. Patients and Methods: After surgical resection, 30 (27.3%) of 110 patients were found to carry a KRAS mutation. For the radiogenomic model, a total of 378 texture features were extracted from the boost clinical target volume (CTV) in the radiotherapy planning CT images. For the deep learning model, we constructed a simple deep learning network that received a three-dimensional input from the CTV. Results: The predictive ability of the radiogenomic score model revealed an AUC of 0.73 for KRAS mutation, whereas the deep learning model demonstrated worse performance, with an AUC of 0.63. Conclusion: The radiogenomic score model was a more feasible approach to predict KRAS status than the deep learning model.