Safety and efficacy of indocyanine green fluorescence imaging-guided laparoscopic para-aortic lymphadenectomy for left-sided colorectal cancer:A preliminary case-matched study.

AIM: This study is aimed to explore the safety and feasibility of indocyanine green (ICG) fluorescence imaging guidance in laparoscopic para-aortic lymph node (PALN) dissection for left-sided colorectal cancer (CRC) patients with clinically suspected PALN metastasis. METHOD: A total of 151 patients who underwent primary tumor resection and laparoscopic PALN dissection for left-sided CRC were included, with 20 patients in the ICG group and 131 patients in the non-ICG group. The surgical outcomes, postoperative complications, and pathological results, such as the number of harvested and metastatic lymph nodes were compared between groups after propensity score matching. RESULTS: Following propensity score matching, the ICG group had 20 patients, and the non-ICG group had 53 patients, and the two groups were similar in baseline characteristics. No significant differences were observed in overall intraoperative and postoperative complications between groups, except for chylous leakage, where the ICG group had a longer time to a normal diet. The number of harvested pericolic/perirectal and intermediate lymph nodes were comparable between the two groups, while the ICG group had a significantly higher number of total harvested lymph nodes (39 [14-78] vs. 29 [11-70], P = 0.001), inferior mesenteric artery lymph nodes (IMALN, 6 [0-17] vs. 3 [0-11], P = 0.006), and PALNs (9 [3-29] vs. 5 [1-37], P = 0.001). CONCLUSION: ICG fluorescence imaging could increase the retrieval of IMALN, PALN, and total lymph nodes, and potentially improve the completeness of laparoscopic PALN dissection in patients with left-sided CRC.

Development and validation of a novel radiomics nomogram for prediction of early recurrence in colorectal cancer.

BACKGROUND: Early recurrence (ER) is a significant concern following curative resection of advanced colorectal cancer (CRC) and is linked to poor long-term survival. Reliable prediction of ER is challenging, necessitating the development of a novel radiomics-based nomogram for CRC patients. METHODS: We enrolled 405 patients, with 298 in the training set and 107 in the external test set. Radiomic features were extracted from preoperative venous-phase computed tomography (CT) images. A radiomics signature was created using univariate logistic regression analyses and the least absolute shrinkage and selection operator algorithm. Clinical factors were integrated into the analyses to develop a comprehensive predictive tool in a multivariate logistic regression model, resulting in a radiomics nomogram. Subsequently, the calibration, discrimination, and clinical usefulness of the nomogram were evaluated. RESULTS: The radiomics signature, consisting of four selected CT features, was significantly associated with ER in both the training and test datasets (P < 0.05). Independent predictors of ER included TNM stage, carcinoembryonic antigen level and differentiation grade were identified. The radiomics nomogram, incorporating all these predictors, exhibited good predictive ability in both the training set with an area under the curve (AUC) of 0.82 (95 % confidence interval (CI), 0.74-0.90) and the test set with an AUC of 0.85 (95 % CI, 0.72-0.99), surpassing the performance of any single candidate factor alone. Furthermore, additional analysis demonstrated that the nomogram was clinically useful. CONCLUSIONS: We have developed a radiomics-based nomogram that effectively predicts early recurrence in CRC patients, enhancing the potential for timely intervention and improved outcomes.

Pathways of lymph node metastasis and prognosis after right hemicolectomy for cecal cancer: results from a retrospective single center.

BACKGROUND: The recommended operation for cecum cancer (CC) is right hemicolectomy (RH) in some Western countries while the principle of D3 lymphadenectomy in Japan recommends resecting approximately 10 cm from the tumor edge. Therefore, the optimal surgical approach for cecum cancer (CC) remains controversial. We conducted this retrospective study to explore the pattern of lymph node metastasis and better surgical procedures for CC. METHODS: A total of 224 cecum cancer patients from January 1, 2014, to December 31, 2021, were retrospectively included in the final study. The pattern of lymph node metastasis (LNM) was investigated. RESULTS: A total of 113 (50.4%, 113/224) patients had pathologically confirmed LNM. The most frequent metastatic site was no. 201 lymph node (46%, 103/224), while 20 (8.9%, 20/224) patients had LNM in no. 202 lymph node, and 8 (3.6%, 8/224) patients had LNM in no. 203 lymph node. Only 1 (0.4%, 1/224) patient had LNM in no. 221 lymph node, four (1.8, 4/224%) patients had LNM in no. 223 lymph node, and no patients had LNM in no. 222 lymph node. LNM in no. 223 lymph node was significantly associated with a poor prognosis. Multivariate analysis indicated that LNM in no. 223 lymph node (HR = 4.59, 95% CI 1.18-17.86, P = 0.028) was the only independent risk factor associated with worse disease-free survival (DFS). CONCLUSIONS: The LNM in no. 223 lymph node for cecum cancer was rare. Therefore, standard right hemicolectomy excision is too extensive for most CC cases.

Prediction of prolonged resolution of chylous ascites after radical D3 resection for colorectal cancer: A population-based experience from a high-volume center.

AIM: This study was aimed to analyze the incidence, risk factors, and management of chylous ascites (CA) after radical D3 resection for colorectal cancer, and to construct a predicting nomogram for prolonged resolution of CA. METHOD: Consecutive colorectal cancer patients who underwent radical D3 resection were included. Logistic analysis was used to identify risk factors of postoperative CA, as well as prolonged CA resolution. A predictive nomogram for prolonged resolution of CA was developed and validated internally. RESULTS: Among 7167 patients included, 277 (3.8%) patients developed CA. Logistic regression analysis demonstrated that laparoscopic operation (OR 1.507; P = 0.017) and tumors fed by the superior mesenteric artery (SMA, OR 2.456; P < 0.001) were independent risk factors of postoperative CA following radical D3 surgery for colorectal cancer. Open operation (OR 0.422; P = 0.027), drainage output on the first day of treatment (OR 1.004; P = 0.016), time to oral intake (OR 1.273; P = 0.042), and time to onset (OR 1.231; P = 0.024) were independently associated with prolonged resolution of postoperative CA (≥7 days). A predictive nomogram for prolonged CA resolution was developed with a C-index of 0.725. CONCLUSION: The incidence of CA after radical D3 surgery of colorectal cancer was 3.8%. Open operation, drainage output on the first day of treatment, time to oral intake, and time to onset were independently associated with prolonged resolution of postoperative CA. A nomogram may assist in tailored treatment decision-making and counseling patient with treatment strategies.

CDKN2B antisense RNA 1 suppresses tumor growth in human colorectal cancer by targeting MAPK inactivator dual-specificity phosphatase 1.

Aberrant expression of long noncoding RNA cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1) has been detected in human colorectal cancer (CRC). This study aimed to investigate the role of CDKN2B-AS1 and the underlying mechanism in human CRC. Gain- and loss-of-function assays were performed to explore the role of CDKN2B-AS1 in the malignant behavior of HCT116 and SW480 CRC cells in vitro and in vivo. RNA pull-down assay was conducted to identify the target of CDKN2B-AS1 in CRC cells. The physical and functional interactions between CDKN2B-AS1 and the target were examined. CDKN2B-AS1 inhibited CRC cell proliferation and migration while promoting apoptosis in vitro via activation of mitogen-activated protein kinase kinases (MEK)/extracellular signal-regulated kinase (ERK)/p38 signaling. CDKN2B-AS1 bound to mitogen-activated protein kinase (MAPK) inactivator dual-specificity phosphatase 1 (DUSP1) in CRC cells. In contrast to CDKN2B-AS1, DUSP1 promoted CRC cell proliferation, suppressed apoptosis and inactivated MEK/ERK/p38 signaling in CRC cells. Furthermore, CDKN2B-AS1 overexpression attenuated DUSP1 expression in normal colonic myofibroblasts and CRC cells. Overexpression of DUSP1 effectively countered the activation of MEK/ERK/p38 signaling induced by CDKN2B-AS1 overexpression or further blocked MEK/ERK/p38 signaling suppressed by CDKN2B-AS1 silencing. In the mouse xenograft model, CDKN2B-AS1 suppressed CRC growth, whereas DUSP1 promoted CRC growth. CDKN2B-AS1 induced cell apoptosis while suppressing EMT (epithelial-mesenchymal transition), whereas DUSP1 suppressed cell apoptosis while inducing EMT in CRC, as evidenced by the alterations in the protein levels of apoptosis and EMT markers in tumor tissue samples. CDKN2B-AS1 regulates CRC cell growth and survival by targeting MAPK inactivator DUSP1.

LINC00200 contributes to the chemoresistance to oxaliplatin of gastric cancer cells via regulating E2F1/RAD51 axis.

The goal of this research was to decipher the biological functions and mechanism of long intergenic non-protein coding RNA 200 (LINC00200) in gastric cancer (GC). In this study, our data confirmed that LINC00200 expression was up-regulated in GC tissues and its high expression was correlated with the poor differentiation of GC tissues and lymph node metastasis of the patients. In vitro experiments indicated that, the overexpression of LINC00200 facilitated the proliferation of GC cells, constrained their apoptosis, and increased the IC50 of oxaliplatin (Oxa), whereas knockdown of LINC00200 exhibited the opposite effects. Additionally, we demonstrated that LINC00200 could bind to E2F transcription factor 1 (E2F1), and the up-regulation of LINC00200 expression enhanced the binding between E2F1 and RAD51 promoter, hence promoting RAD51 transcription, while knockdown of LINC00200 inhibited the transcription of RAD51. In conclusion, LINC00200 may recruit E2F1 to the RAD51 recombinase (RAD51) promoter region, thereby up-regulating the expression of RAD51 and enhancing the chemoresistance of GC cells to Oxa. Our data suggested that LINC00200 could probably be a promising target for treating GC.

Knockdown of Forkhead box A1 suppresses the tumorigenesis and progression of human colon cancer cells through regulating the phosphatase and tensin homolog/Akt pathway.

BACKGROUND: This study aimed to evaluate the role and the underlying mechanisms of Forkhead box A1 (encoded by FOXA1) in colon cancer. METHODS: We analyzed FOXA1 mRNA and protein expression in colon cancer tissues and cell lines. We also silenced FOXA1 expression in HCT116 and SW480 cells to evaluate the effects on cell proliferation, cell cycle, migration, and invasion by using MTT, colony formation, flow cytometry, and the Transwell assay, respectively. RESULTS: FOXA1 immunostaining was higher in colon cancer tissues than adjacent healthy tissues. FOXA1 mRNA and protein expression was significantly increased in human colon cancer cells compared with a normal colonic cell line. FOXA1 expression was also significantly higher in colorectal cancer tissues from TCGA data sets and was associated with worse prognosis in the R2 database. FOXA1 expression was negatively correlated with the extent of its methylation, and its knockdown reduced proliferation, migration, and invasion, and induced G2/M phase arrest in HCT116 and SW480 cells by suppressing the phosphatase and tensin homolog/Akt signaling pathway and inhibiting epithelial-mesenchymal transition. CONCLUSION: FOXA1 may act as an oncogene in colon cancer tumorigenesis and development.

A Comprehensive Repertoire of Transfer RNA-Derived Fragments and Their Regulatory Networks in Colorectal Cancer.

To provide systematic insight into the composition and expression of transfer RNA (tRNA) derivatives transcriptome in colorectal cancer (CRC). tRNA derivatives expression profiles in three pairs of CRC and adjacent normal colon tissues were performed by tRNA-derived small RNA fragments (tRFs) and tRNA halves (tiRNA) sequencing, and microarray data of transcriptomes from CRC and paired controls were retrieved from Gene Expression Omnibus database. The differentially expressed tRFs and tiRNAs and differentially expressed genes between CRC and paired normal samples were screened. The functional regulations between tRF and tiRNA and gene were identified. A total of 60 upregulated and 48 downregulated tRNA derivatives and 7373 upregulated and 12,138 downregulated messenger RNA (mRNA) were identified. The tRF and tiRNA-gene regulatory modules were constructed by analyzing computational tRF and tiRNA-target predictions and inverse expression relationships between tRF and tiRNAs and mRNA. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway annotation showed that the function of targets of tiRNA-Tyr-GTA was mainly enriched in negative regulation of epithelial cell apoptotic process and peroxisome proliferator activated-receptors (PPAR) signaling pathway. Cellular response to monoamine stimulus and inflammatory bowel disease was enriched in function of tiRNA-Val-CAC. Two functions, including negative regulation of c-Jun N-terminal kinase (JNK) cascade and choline metabolism in cancer, were enriched in tRF-Gln-CTG. The function of mesenchymal to epithelial transition was enriched in tRF-Leu-TAG. For the first time to our knowledge, our study provided a landscape of tRNA derivatives expression profiles in CRC. Further tRF and tiRNA-gene regulatory modules construction explored the potential functions related to these tRNA derivatives in the pathogenesis of CRC.

High SPRR1A expression is associated with poor survival in patients with colon cancer.

High expression of small proline-rich protein 1A (SPRR1A) has been shown to be associated with tumor prognosis; however, the association between SPRR1A expression and colon cancer prognosis remains unclear. The present study sought to evaluate the association between SPRR1A expression and the clinicopathological characteristics of colon cancer, and to examine its potential prognostic value. A total of 114 patients with colon cancer were included. SPRR1A expression was evaluated by immunohistochemical staining, and the association between SPRR1A expression and clinicopathological parameters was analyzed. The prognostic value of SPRR1A was analyzed by Cox regression analysis, the Oncomine database and the R2 platform. SPRR1A expression was significantly increased in cancerous tissues compared with that in adjacent non-cancerous tissues. SPPRR1A expression was significantly associated with lymph node invasion. High SPRR1A expression was significantly associated with worse overall and disease-free survival rate. Cox regression analysis revealed that T stage, pathological N stage and high SPRR1A expression remained independent predictors for overall survival rate. The Oncomine database analysis demonstrated that SPRR1A mRNA expression levels were significantly increased in colorectal cancer tissues compared with those in adjacent non-cancerous tissues, and high SPRR1A expression was associated with a significantly worse event- and relapse-free survival time in the R2 platform. The data indicate that SPRR1A may serve as a potential biomarker for the prognosis of colon cancer.

FBXW4 Acts as a Protector of FOLFOX-Based Chemotherapy in Metastatic Colorectal Cancer Identified by Co-Expression Network Analysis.

BACKGROUND: FOLFOX chemotherapy is one of the most commonly used treatments for colorectal cancer (CRC) patients. However, the efficacy and tolerance of FOLFOX therapy varies between patients. The purpose of this study was to explore hub genes associated with primary chemotherapy-resistance and to explore the possible mechanisms involved from non-European patients. METHOD: A weighted gene co-expression network was constructed to identify gene modules associated with chemotherapy resistance in mCRC from China. RESULTS: A Gene Array Chip was used to detect mRNA expression in 11 mCRC patients receiving preoperative FOLFOX chemotherapy. The immune response was associated with chemotherapy-resistance in microarray data. Through the use of WGCNA, we demonstrated that the crucial functions enriched in chemotherapy-resistance modules were cell proliferation, MAPK signaling pathways, and PI3K signaling pathways. Additionally, we identified and validated FBXW4 as a new effective predictor for chemotherapy sensitivity and a prognostic factor for survival of CRC patients by using our own data and GSE69657. Furthermore, a meta-analysis of 15 Gene Expression Omnibus-sourced datasets showed that FBXW4 messenger RNA levels were significantly lower in CRC tissues than in normal colon tissues. An analysis of the data from the R2: Genomics Analysis and Visualization Platform showed that low FBXW4 expression was correlated with a significantly worse event- and relapse-free survival. Gene set enrichment analysis showed that the mechanism of FBXW4-mediated chemotherapy resistance may involve the DNA replication signal pathway and the cell cycle. CONCLUSION: FBXW4 is associated with chemotherapy resistance and prognosis of CRC probably by regulating DNA replication signaling pathways and the cell cycle.

Overexpressed CES2 has prognostic value in CRC and knockdown CES2 reverses L-OHP-resistance in CRC cells by inhibition of the PI3K signaling pathway.

CES-2 (carboxylesterase-2) belongs to the carboxylesterase gene family, which plays crucial roles in lipid mobilization and chemosensitivity to irinotecan. However, its role in chemosensitivity to oxaliplatin (L-OHP) remains unclear. Herein, L-OHP-resistant cells (HCT-116L and RKOL) were established by increasing the concentration of L-OHP. The results showed that CES2 expression was upregulated in L-OHP-resistant tissues and cells lines (both P < 0.01). Low expression of CES2 correlated with a better survival, and the results were further confirmed in the R2 platform: a biologist friendly web-based genomics analysis and visualization application. Downregulation of CES2 suppressed cell proliferation, induced apoptosis and reversed L-OHP resistance by medicating the PI3K signaling pathway in L-OHP-resistant cells. However, both PI3K inhibitor (LY294002) and activator (IGF-1) could not medicate CES2 expression. These findings indicated that CES2 may be utilized as a novel biomarker and therapeutic target for L-OHP resistance in CRC treatment.

Identification of LncRNAs Associated With FOLFOX Chemoresistance in mCRC and Construction of a Predictive Model.

Oxaliplatin, fluorouracil plus leucovorin (FOLFOX) regimen is the first-line chemotherapy of patients with metastatic colorectal cancer (mCRC). However, studies are limited regarding long non-coding RNAs (lncRNAs) associated with FOLFOX chemotherapy response and prognosis. This study aimed to identify lncRNAs associated with FOLFOX chemotherapy response and prognosis in mCRC patients and to construct a predictive model. We analyzed lncRNA expression in 11 mCRC patients treated with FOLFOX chemotherapy before surgery (four sensitive, seven resistant) by Gene Array Chip. The top eight lncRNAs (AC007193.8, CTD-2008N3.1, FLJ36777, RP11-509J21.4, RP3-508I15.20, LOC100130950, RP5-1042K10.13, and LINC00476) for chemotherapy response were identified according to weighted correlation network analysis (WGCNA). A competitive endogenous RNA (ceRNA) network was then constructed. The crucial functions of the eight lncRNAs enriched in chemotherapy resistance were mitogen-activated protein kinase (MAPK) and proteoglycans signaling pathway. Receiver operating characteristic (ROC) analysis demonstrated that the eight lncRNAs were potent predictors for chemotherapy resistance of mCRC patients. To further identify a signature model lncRNA chemotherapy response and prognosis, the validation set consisted of 196 CRC patients from our center was used to validate lncRNAs expression and prognosis by quantitative PCR (qPCR). The expression of the eight lncRNAs expression between CRC cancerous and adjacent non-cancerous tissues was also verified in the validation data set to determine the prognostic value. A generalized linear model was established to predict the probability of chemotherapy resistance and survival. Our findings showed that the eight-lncRNA signature may be a novel biomarker for the prediction of FOLFOX chemotherapy response and prognosis of mCRC patients.

Overexpression of FZD7 is associated with poor survival in patients with colon cancer.

BACKGROUND: Overexpression of Frizzled-7 (FZD7) has been associated with tumor invasion and distant metastases, but little is known about the relationship between FZD7 expression and prognosis in colon cancer. PATIENTS AND METHODS: A total of 114 patients with colon cancer between June 2010 and December 2010 were enrolled in this study. The expression of FZD7 in cancerous and adjacent non-cancerous tissues was determined by immunohistochemistry, and the association between FZD7 expression and patient's clinicopathological characteristics was explored. The correlation between FZD7 expression and prognosis of colon cancer patients was analyzed using the Oncomine database and R2. RESULTS: FZD7 expression levels were significantly higher in colon cancer tissues compared with adjacent non-cancerous tissues (P < 0.001). High expression of FZD7 was significantly associated with metastatic or recurrent disease in colon cancer (P = 0.010). Kaplan-Meier survival analysis demonstrated that colon cancer patients with high expression of FZD7 had a significantly poorer OS (P = 0.013) and DFS (P = 0.010). Cox regression demonstrated that the expression of FZD7 was an independent prognostic factor for DFS (HR = 6.647, P = 0.023). A meta-analysis from the Oncomine database demonstrated that FZD7 mRNA levels were significantly higher in colorectal cancer tissues than in normal colorectal tissues, and FZD7 high expression was associated with a significantly poorer event and relapse-free survival time by analyzing the data from the R2: Genomics Analysis and Visualization Platform. CONCLUSIONS: Overexpression of FZD7 was associated with poor survival in patients with colon cancer. Our data suggest that FZD7 expression could be an effective prognostic biomarker for colon cancer.

[Efficacy analysis of radiotherapy combined with surgery for locally advanced rectal mucinous adenocarcinoma: a retrospective study based on data of Surveillance, Epidemiology, and End results population].

OBJECTIVE: To explore the efficacy of radiotherapy combined with surgery for locally advanced rectal mucinous adenocarcinoma. METHODS: Clinical data of patients with locally advanced rectal mucinous adenocarcinoma (T3-4 and/or N+) diagnosed by postoperative pathology from 1992 to 2013 were retrieved from the US Surveillance, Epidemiology, and End Results (SEER) database. Patients with local excision only, tumor biopsy or combined organ excision and incomplete follow-up information were excluded. All the enrolled patients were divided into three groups according to different treatments, including surgery alone (SA) group, preoperative radiotherapy combined with surgery (RT+S) group and surgery combined with postoperative radiotherapy (S+RT) group. The extracted data included basic data of patients and tumor, treatment status, and follow-up results. The χ² test was used to compare the count data. Kaplan-Meier method was used to draw the survival curve and calculate the survival rate. The survival was analyzed and compared by Log-rank test. The R language 2.8.1 was used to match the patients as 1:1 pairing through the propensity score matching (PSM). The matching variables included gender, age at diagnosis, year at diagnosis, ethnicity, degree of tissue differentiation, TNM stage, depth of invasion, making the baseline data of subgroups comparable. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. RESULTS: A total of 2 149 patients with locally advanced rectal mucinous adenocarcinoma were enrolled in the study, including 1 255 males (58.4%) and 894 females (41.6%). There were 706 patients (32.9%) in the SA group, 772 patients (35.9%) in the RT+S group and 671 patients (31.2%) in the S+RT group. In SA, RT+S and S+RT groups, the median overall survival time was 39, 85, and 74 months respectively; the 5-year overall survival (OS) rate was 38.7%, 56.5%, and 55.2% respectively; the median cancer-specific survival (CSS) time was 86, 127, and 111 months respectively, and the 5-year CSS rate was 53.7%, 62.2% and 60.7% respectively. In comparison among the 3 groups, the 5-year OS rate and CSS rate in the SA group were significantly lower than those in the RT+S group and S+RT group (all P<0.001); the 5-year OS rate and CSS rate between RT+S group and S+RT group were not significantly different (P=0.166 and 0.392,respectively). After the baseline data of subgroups were corrected through PSM, the 5-year OS rate and CSS rate in the SA group (n=375) were significantly lower than those in the RT+S group (n=375)(OS:40.1% vs. 54.5%, P<0.001; CSS:54.3% vs. 63.3%, P=0.023). The 5-year OS rate and CSS rate in the SA group (n=403) were also lower than those in the S+RT group (n=403) (OS:37.4% vs. 54.7%,P<0.001;CSS:51.6% vs. 61.0%,P=0.031). The 5-year OS rate and CSS rate between RT+S group (n=363) and S+RT group (n=363) were not significantly different (OS:51.7% vs. 55.5%, P=0.789; CSS:57.7% vs. 60.5%, P=0.484). Cox multivariate analysis showed that radiotherapy (HR=0.845, 95%CI: 0.790 to 0.903, P=0.001) was an independent prognostic factor for OS of locally advanced rectal mucinous adenocarcinoma; radiotherapy (HR=0.907, 95% CI: 0.835 to 0.985, P=0.021) was also an independent prognostic factor affecting CSS in patients with locally advanced rectal mucinous adenocarcinoma. CONCLUSION: As compared with surgery alone, surgery combined with preoperative or postoperative radiotherapy is beneficial to the long-term survival of patients with locally advanced rectal mucinous adenocarcinoma.

Completely Abdominal Approach Laparoscopic Partial Intersphincteric Resection After Neoadjuvant Chemoradiation for Initial cT3 Juxta-Anal Rectal Cancer.

Purpose: Traditional intersphincteric resection is a technically demanding procedure that required a perineal approach dissection and a handsewn coloanal anastomosis. Our study was to investigate the feasibility and the prognostic factors of completely abdominal approach partial intersphincteric resection (APISR) after neoadjuvant chemoradiotherapy (CRT) for low rectal cancer with initial stage cT3. Methods: A total of 101 consecutive patients with initial stage cT3 juxta-anal rectal cancer who underwent APISR after neoadjuvant CRT between January 2010 and March 2015 were enrolled. Survival rates were estimated and compared using the Kaplan-Meier method and log-rank tests. Cox proportional hazard model was utilized for multivariable analysis for disease-free survival (DFS). The cutoff values of residual tumor size calculated by X-tile were used in the multivariate analysis as well. Results: The median follow-up was 39 months. The local recurrence rate within 3 years was 2.5%. The 3-year DFS rate was 80.2%, and the 3-year overall survival rate was 95.3%. The 3-year DFS in pathological stage 0-III were 96.2%, 94.4%, 85.7%, and 44.7% respectively (Log-rank = 29.791, P < .001). In multivariate analysis, stage ypN1-2 (hazard ratio (HR) = 8.256, 95% confidence interval [CI]: 2.742-24.855, P < .001) and tumor size after CRT more than 2.8 cm (HR = 3.077, 95% CI: 1.036-9.137, P = .043) were the independent factors for worse DFS. Conclusions: Laparoscopic and open APISR after CRT produces satisfactory mid-term oncological outcomes for juxta-anal rectal cancer downstaged from initial cT3 especially in stage ypN0 or with tumor size after CRT <2.8 cm. Hence, stage ypN1-2 and tumor size after CRT more than 2.8 cm are poor prognostic factors that should be estimated for APISR.

Comparative Outcomes of Preoperative Chemoradiotherapy and Selective Postoperative Chemoradiotherapy in Clinical Stage T3N0 Low and Mid Rectal Cancer.

Purpose/aim: Preoperative chemoradiotherapy (pre-CRT) and total mesorectal excision (TME) have become the standard of care for patients with locally advanced rectal cancer (LARC). Nevertheless, it is a controversial issue whether pre-CRT in cT3N0M0 patients would result in potential overtreatment. Materials and methods: In total, 183 clinical stage IIA rectal cancer patients treated with and without pre-CRT between 2011 and 2014 were retrospectively analyzed. Capecitabine/FOLFOX/CAPOX chemotherapy was co-administered with preoperative radiotherapy. Surgical resection with laparoscopic or open TME was conducted 8-12 weeks after completion of the pre-CRT. Postoperative radiotherapy was routinely given to patients with pT4 lesion or circumferential margin (CRM) and/or distal resection margin (DRM) involvement. Results: In total, 108 (59%) patients received pre-CRT and 75 (41%) underwent surgery first. The pre-CRT patients presented with less-advanced pathological T stage tumors compared with the surgery-first patients (p < 0.001). However, the pathological N stage was not significantly different between the two groups (p = 0.065). The 3-year overall survival (OS), disease-free survival (DFS), and 2-year local recurrence (LR) rate were similar in the pre-CRT and surgery-first patients (88.4 versus 88.7%, p = 0.552; 79.6 versus 83.3%, p = 0.797; 2.8 versus 2.7%, p = 0.960, respectively). Cox regression analysis showed that pN stage and CRM/DRM involvement were independently correlated with an unfavorable DFS. Conclusions: In this study, the omission of pre-CRT in cT3N0M0 patients did not translate into a worse oncological outcome. Postoperative radiotherapy should remain a standard option for patients with CRM/DRM involvement and pathological T4 tumors. A generalized indication for pre-CRT in cT3N0 patients is likely to result in overtreatment.

Demethylation and Overexpression of CSF2 are Involved in Immune Response, Chemotherapy Resistance, and Poor Prognosis in Colorectal Cancer.

PURPOSE: This study aimed to evaluate the role of colony-stimulating factor 2 (CSF2) in chemotherapy resistance, prognosis, and immune response and to identify its possible mechanisms underlying drug resistance. METHODS: Drug-resistant cell lines were obtained by successively increasing drug concentration. RNA-Seq was performed to screen hub genes. CSF2 expression was analyzed via immunohistochemistry. Moreover, The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER) dataset, and R2 platform were used to explore the correlations among CSF2 expression, prognosis, and immune response. RESULTS: RNA-Seq indicated that microRNAs in cancer, P53 signaling pathway, and cell cycle were associated with FOLFOX chemotherapy resistance. Protein-protein interaction (PPI), molecular complex detection (MOCDE), and qRT-PCR analysis verified CSF2 as the hub gene in chemotherapy resistance. Moreover, CSF2 expression was lower in the normal tissue than in the cancerous tissue (P<0.05). Higher expression of CSF2 was associated with poor OS and DFS in colon cancer patients (P<0.05). We further found similar results in the Oncomine database and R2 platform (P<0.05). A higher expression of CSF2 in the CRC tissue may be caused by demethylation, which was verified using the TCGA datasets. Moreover, GSEA demonstrated that CSF2 was associated with immune response, which was consistent with results reported using TIMER datasets. CONCLUSION: CSF2 is a novel biomarker and a prognostic factor for the survival of CRC patients affecting the immune response, and an overexpression of CSF2 in CRC patients may be caused by DNA demethylation.

Survival outcome of adjuvant radiotherapy after local excision for T2 early rectal cancer: An analysis based on the surveillance, epidemiology, and end result registry database.

BACKGROUND: Major resection (MR) is recommended for cases with T2 finding after local excision (LE) of early rectal cancer, but the revision procedure is accompanied with high morbidity. We evaluated the oncological safety of LE followed by adjuvant radiotherapy as a rectum-preserving alternative to MR for T2 early rectal cancer. METHODS: A total of 3786 patients with T2N0M0 rectal adenocarcinoma between 1998 and 2013 were included from the SEER database. Survival rates were compared using the Kaplan-Meier method with a log-rank test, and multivariate analyses were performed using Cox proportional regression models. RESULTS: Of these patients included, 429 (11.3%) treated with LE alone (LE group), 3067 (81.0%) treated with MR (MR group), and 290 (7.7%) treated with LE followed by adjuvant radiotherapy (LE + adjuvant RT group). The 5-year cancer specific survival (CSS) rate and 5-year overall survival (OS) rate were significantly lower in LE patients group than those in MR patients group (70.5% vs. 81.8%, P < 0.001; 57.3% vs. 72.3%, P < 0.001). The 5-year CSS rate and 5-year OS rate were similar between LE + adjuvant RT and MR groups (78.4% vs. 81.8%, P = 0.975, and 70.7% vs. 72.3%, P = 0.311, respectively). Multivariate Cox regression revealed that treatment strategies, age and CEA status were independently associated with CSS and OS. After age adjustment, LE was associated with reduced CSS (using MR as a reference, HR, 1.784; P < 0.001) and reduced OS (HR, 1.739; P < 0.001). However, CSS and OS related to LE + adjuvant RT of T2 rectal cancer group weren't be affected (HR, 0.994; P = 0.962 and HR, 0.904; P = 0.302, respectively). CONCLUSIONS: When MR is inappropriate for T2 early rectal cancer patients because of patients refusal or co-morbidities, LE + adjuvant RT can provide acceptable levels of long-term survival.

Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell.

INTRODUCTION: Kallikrein 11 (KLK11) plays a crucial role in drug-resistance to oxaliplatin (L-OHP) in the treatment of metastatic colorectal cancer (mCRC). The study aimed to investigate the role of KLK11 in chemoresistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of KLK11. MATERIALS AND METHODS: Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal adenocarcinoma cell lines by exposing cells to increasing concentrations of L-OHP. MTT, RT-qPCR, and Western blot were used to evaluate the resistance to L-OHP. We then knocked down KLK11 in HCT-8/L-OHP cells to explore the mechanism through which KLK11 reverses L-OHP resistance. The mRNA and protein expression of KLK11 in tissues from mCRC patients were detected by RT-qPCR and immunohistochemistry. RESULTS: The drug resistance index (RI) of HCT-8/L-OHP cell line to L-OHP, 5-Fluorouracil (5-FU), Irinotecan (CPT-11), Vincristine (VCR) and Cis-diamminedichloroplatinum (CDDP) were 10, 5.35, 3.23, 1.28, and 6.64, respectively. Increased expression of multi-drug resistant genes ABCC1, ABCB1, GSTP1 and ERCC1 were detected in HCT-8/L-OHP cell line. Moreover, the activated PI3K/AKT pathway was related to L-OHP-resistance. Knockdown of KLK11 in HCT-8/L-OHP cell reversed L-OHP-resistance by inhibiting cell growth and activating apoptosis via suppressing the PI3K/AKT signaling pathway. Moreover, high expression of KLK11 in chemoresistant-patients was associated with lymph node metastases and histopathology. CONCLUSION: KLK11 was highly expressed in chemoresistant-patients and L-OHP-resistant cell lines. Moreover, L-OHP resistance was associated with activated PI3K/AKT signal pathway. Knockdown of KLK11 can reverse L-OHP resistance by blocking PI3K/AKT signaling pathway.