Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.

Coloanal anastomosis is a surgical procedure in which the colon is connected to the anus after rectal resection, and it can be divided into one-stage immediate anastomosis and two-stage (delayed) coloanal anastomosis. Based on relevant literature and team practices, the authors explore the indications, technical essentials, complications, and functional aspects of both immediate and delayed coloanal anastomosis. When performing coloanal anastomosis, it should make rational choices based on the patient′s indications, condition, and actual technical situation of the surgeon. In sphincter-preserving surgery for low rectal cancer, the success of coloanal anastomosis depends on achieving effective reconstruction that ensures oncological safety, anatomical integrity, and func-tional recovery.

Background::Pre-operative assessment with high-resolution magnetic resonance imaging (MRI) is useful for assessing the risk of local recurrence (LR) and survival in rectal cancer. However, few studies have explored the clinical importance of the morphology of the anterior mesorectum, especially in patients with anterior cancer. Hence, the study aimed to investigate the impact of the morphology of the anterior mesorectum on LR in patients with primary rectal cancer.Methods::A retrospective study was performed on 176 patients who underwent neoadjuvant treatment and curative-intent surgery. Patients were divided into two groups according to the morphology of the anterior mesorectum on sagittal MRI: (1) linear type: the anterior mesorectum was thin and linear; and (2) triangular type: the anterior mesorectum was thick and had a unique triangular shape. Clinicopathological and LR data were compared between patients with linear type anterior mesorectal morphology and patients with triangular type anterior mesorectal morphology.Results::Morphometric analysis showed that 90 (51.1%) patients had linear type anterior mesorectal morphology, while 86 (48.9%) had triangular type anterior mesorectal morphology. Compared to triangular type anterior mesorectal morphology, linear type anterior mesorectal morphology was more common in females and was associated with a higher risk of circumferential resection margin involvement measured by MRI (35.6% [32/90] vs. 16.3% [14/86], P = 0.004) and a higher 5-year LR rate (12.2% vs. 3.5%, P = 0.030). In addition, the combination of linear type anterior mesorectal morphology and anterior tumors was confirmed as an independent risk factor for LR (odds ratio = 4.283, P = 0.014). Conclusions::The classification established in this study was a simple way to describe morphological characteristics of the anterior mesorectum. The combination of linear type anterior mesorectal morphology and anterior tumors was an independent risk factor for LR and may act as a tool to assist with LR risk stratification and treatment selection.

Objective:To investigate the prognostic value of gastroepiploic lymph node (GLN) metastasis in transverse colon cancer.Methods:The propensity score matching and retrospective cohort study was conducted. The clinicopathological data of 371 patients with transverse colon cancer who were admitted to Fujian Medical University Union Hospital from November 2010 to November 2017 were collected. There were 202 males and 169 females, aged from 21 to 92 years, with a median age of 58 years. Patients were performed complete mesocolic excision combined with GLN dissection by one group of surgeons. Of the 371 patients with transverse colon cancer, 15 cases had positive GLN metastasis (GLN+), and 356 cases had negative GLN metastasis (GLN-). Observation indicators: (1) the propensity score matching conditions and comparison of baseline data between GLN- patients and GLN+patients with transverse colon cancer after propensity score matching; (2) follow-up and survival of GLN- patients and GLN+patients with transverse colon cancer; (3) influencing factors for prognosis of patients with transverse colon cancer. Patients were followed up by outpatient examination or telephone interview to detect tumor metastasis and survival. Follow-up was conducted once every 3 months within postoperative 2 years, once every 6 months within postoperative 2-5 years and once a year thereafter up to January 2020. The propensity score matching was conducted by 1∶4 matching using the nearest neighbor method. Measurement data with skewed distribution were described as M (range), and comparison between groups was analyzed using the rank sum test. Count data were represented as absolute numbers, and comparison between groups was analyzed using the chi-square test or Fisher exact probability. The Kaplan-Meier method was used to calculate survival rates and draw survival curves, and Log-rank test was used for survival analysis. Univariate and multivariate analyses were performed using the COX proportional hazard regression model. The variables with P<0.10 in the univariate analysis were included for multivariate analysis. Results:(1) The propensity score matching conditions and comparison of baseline data between GLN- patients and GLN+ patients with transverse colon cancer after propensity score matching: 55 of 371 patients had successful matching, including 44 GLN- patients and 11 GLN+ patients. Before propensity score matching, the age, cases in stage 0 or stage 1 of M staging, preoperative carcinoembryonic antigen were 60 years(range, 24-92 years), 328, 22, 4.1 μg/L(range, 0.2-343.7 μg/L) for GLN- patients, respectively, versus 67 years(range, 21-79 years), 11, 4, 5.0 μg/L(range, 0.7-952.4 μg/L) for GLN+ patients, showing significant differences in the above indicators between the two groups ( Z=-1.440, χ2=9.031, Z=-2.086, P<0.05). After propensity score matching, the above indicators were 58 years(range, 45-67 years), 40, 4, 4.0 μg/L(range, 2.0-10.0 μg/L) for GLN- patients, respectively, versus 67 years(range, 59-71 years), 9, 2, 5.0 μg/L(range, 8.0-19.0 μg/L) for GLN+ patients, showing no significant difference between the two groups ( Z=-1.580, χ2=0.105, Z=-0.821, P>0.05). (2) Follow-up and survival of GLN- patients and GLN+ patients with transverse colon cancer: GLN- patients and GLN+ patients with transverse colon cancer were followed-up for 12-92 months and 1-70 months, with a median time of 53 months and 30 months respectively. Three cases of GLN- patients and 2 cases of GLN+patients had postoperative liver metastasis, respectively, showing no significant difference between the two groups ( χ2 =0.344, P>0.05). One case of GLN- patients and 3 cases of GLN+ patients had heterochronous lung metastasis, respectively, showing a significant difference between the two groups ( χ2 =4.870, P<0.05). The 5-year disease progression-free survival rates were 82.3% and 33.9% for GLN- patients and GLN+ patients, respectively, showing a significant difference between the two groups ( χ2 =13.366, P<0.05). (3) Influencing factors for prognosis of patients with transverse colon cancer: results of univariate analysis showed that pT staging, pN staging, M staging and GLN metastasis were related factors for prognosis of patients with transverse colon cancer ( hazard ratio=1.599, 5.107, 4.511, 6.273, 95% confidence interval as 0.467-5.471, 1.867-13.971, 1.385-14.694, 2.052-19.176, P<0.05). Results of multivariate analysis showed that pN staging, M staging and GLN metastasis were independent influencing factors for prognosis of patients with transverse colon cancer ( hazard ratio=6.399, 6.163, 4.024, 95% confidence interval as 2.028-20.189, 1.666-22.800, 1.177-13.752, P<0.05). Conclusion:For the patients with transverse colon cancer, GLN metastasis is associated with high postoperative heterochronous lung metastasis rate and poor prognosis. GLN metastasis is an independent prognostic factor for patients with transverse colon cancer.

BACKGROUND: Postoperative chylous ascites is an infrequent condition after colorectal surgery and is easily treatable. However, its effect on the long-term oncological prognosis is not well established. This study aimed to investigate the short-term and long-term impact of chylous ascites treated with neoadjuvant therapy followed by rectal cancer surgery and to evaluate the incidence of chylous ascites after different surgical approaches. METHODS: A total of 898 locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery between January 2010 and December 2018 were included. The clinicopathological data and outcomes of the patients with chylous ascites were compared with those of the patients without chylous ascites. The primary endpoint was recurrence-free survival (RFS). To balance baseline confounders between groups, propensity score matching (PSM) was performed for each patient with a logistic regression model. RESULTS: Chylous ascites was detected in 3.8% (34/898) of the patients. The incidence of chylous ascites was highest after robotic surgery (6.9%, 6/86), followed by laparoscopic surgery (4.2%, 26/618) and open surgery (1.0%, 2/192, P = 0.021). The patients with chylous ascites had a significantly higher number of lymph nodes harvested (15.6 vs. 12.8, P = 0.009) and a 3-day longer postoperative hospital stay (P = 0.017). The 5-year RFS rate was 64.5% in the chylous ascites group, which was significantly lower than the rate in the no chylous ascites group (79.9%; P = 0.007). The results remained unchanged after PSM was performed. The chylous ascites group showed a nonsignificant trend towards a higher peritoneal metastasis risk (5.9% vs. 1.6%, P = 0.120). Univariate analysis and multivariate analysis confirmed chylous ascites (hazard ratio= 3.038, P < 0.001) as an independent negative prognostic factor for RFS. CONCLUSIONS Considering the higher incidence of chylous ascites after laparoscopic and robotic surgery and its adverse prognosis, we recommend sufficient coagulation of the lymphatic tissue near the vessel origins, especially during minimally invasive surgery.
Chylous Ascites/etiology* ; Humans ; Incidence ; Laparoscopy ; Rectal Neoplasms/surgery* ; Retrospective Studies ; Risk Factors ; Robotic Surgical Procedures/adverse effects*

Objective:To explore and establish an artificial neural network (ANN) model for predicting the efficacy of first-line FOLFOX chemotherapy for metastatic colorectal cancer.Methods:A set of FOLFOX chemotherapy data from a group of patients with metastatic colorectal cancer (mCRC) (GSE104645) was downloaded from the GEO database as a training set. According to the FOLFOX protocol, the efficacy was divided into two groups: the chemo-sensitive group (including complete response and partial response) and the chemo-resistant group (including stable disease and progressive disease), including 31 cases in the sensitive group and 23 in the resistant group. Then, chip data (accessible number: GSE69657) from Fujian Medical University Union Hospital were chosen as a test set. A total of 30 patients were enrolled in the study, including 13 in the sensitive group and 17 in the resistant group. The batch effect correction was performed on the expression values of the two sets of matrices using the R 3.5.1 software Combat package. The gene expression difference of sensitive and resistant group in GSE104645 was analyzed by the GEO2R platform. P<0.05 and the absolute value of log 2FC>0.33 (FC abbreviation of fold change) were used as the threshold value to screen the drug resistance and sensitive genes of the FOLFOX regimen. An ANN was constructed using the multi-layer perceptron (MLP) to perform the FOLFOX regimen on the GSE104645 dataset. The GSE69657 expression matrix and clinical efficacy parameters were then used for retrospective verification. Receiver operating characteristic(ROC) curves were used to evaluate the test results and predictive power. Results:A total of 2, 076 differentially expressed genes in GSE104645 were selected, of which 822 genes were up-regulated and 1, 254 genes were down-regulated in the chemo-resistance group. The down-regulated genes were sensitive genes. GO analysis of the biological processes in which the differentially expressed genes were involved, revealed that they were mainly involved in the regulation of substance metabolism. A total of 39 genes were included in the final model construction. This was a neural network model with two hidden layers. The accuracy of predicting training samples and test samples was 75.7% and 76.5%, respectively, and the area under the ROC curve was 0.875. The chip data set of our department (GSE69657) was set as the test set, and the area under the ROC curve was 0.778.Conclusions:In this study, an artificial neural network model is successfully constructed to predict the efficacy of first-line FOLFOX regimen for metastatic colorectal cancer based on the microarray, and an independent external verification is also conducted. The model has good stability and well prediction efficiency. Besides, the results of this study suggest that the gene functions related to oxaliplatin resistance are mainly enriched in the regulation process of substance metabolism.

Objective:To explore and establish an artificial neural network (ANN) model for predicting the efficacy of first-line FOLFOX chemotherapy for metastatic colorectal cancer.Methods:A set of FOLFOX chemotherapy data from a group of patients with metastatic colorectal cancer (mCRC) (GSE104645) was downloaded from the GEO database as a training set. According to the FOLFOX protocol, the efficacy was divided into two groups: the chemo-sensitive group (including complete response and partial response) and the chemo-resistant group (including stable disease and progressive disease), including 31 cases in the sensitive group and 23 in the resistant group. Then, chip data (accessible number: GSE69657) from Fujian Medical University Union Hospital were chosen as a test set. A total of 30 patients were enrolled in the study, including 13 in the sensitive group and 17 in the resistant group. The batch effect correction was performed on the expression values of the two sets of matrices using the R 3.5.1 software Combat package. The gene expression difference of sensitive and resistant group in GSE104645 was analyzed by the GEO2R platform. P<0.05 and the absolute value of log 2FC>0.33 (FC abbreviation of fold change) were used as the threshold value to screen the drug resistance and sensitive genes of the FOLFOX regimen. An ANN was constructed using the multi-layer perceptron (MLP) to perform the FOLFOX regimen on the GSE104645 dataset. The GSE69657 expression matrix and clinical efficacy parameters were then used for retrospective verification. Receiver operating characteristic(ROC) curves were used to evaluate the test results and predictive power. Results:A total of 2, 076 differentially expressed genes in GSE104645 were selected, of which 822 genes were up-regulated and 1, 254 genes were down-regulated in the chemo-resistance group. The down-regulated genes were sensitive genes. GO analysis of the biological processes in which the differentially expressed genes were involved, revealed that they were mainly involved in the regulation of substance metabolism. A total of 39 genes were included in the final model construction. This was a neural network model with two hidden layers. The accuracy of predicting training samples and test samples was 75.7% and 76.5%, respectively, and the area under the ROC curve was 0.875. The chip data set of our department (GSE69657) was set as the test set, and the area under the ROC curve was 0.778.Conclusions:In this study, an artificial neural network model is successfully constructed to predict the efficacy of first-line FOLFOX regimen for metastatic colorectal cancer based on the microarray, and an independent external verification is also conducted. The model has good stability and well prediction efficiency. Besides, the results of this study suggest that the gene functions related to oxaliplatin resistance are mainly enriched in the regulation process of substance metabolism.

There are three goals of the treatments for rectal cancer, including risk reduction of local recurrence in the pelvic cavity through treatment to the most extent (better down to less than 5%), reduction of acute or chronic complications as soon as possible, and preservation of good sphincter function as well as life quality. As a new concept, rectum preserving surgery following neoadjuvant therapy, remains controversial in its implementation process. There are controversies in the selection criteria, regimens of neoadjuvant therapy, therapy procedures, complications, and evaluation of oncological prognosis and life quality. The authors discuss the above issues in this article based on literatures and our own practical experience, in order to provide references for the promotion of rectum preserving surgery.

Objective:To investigate the feasibility and safety of sphincter-preserving surgery after neoadjuvant chemoradiotherapy (nCRT) with consolidation chemotherapy in the interval period or total neoadjuvant therapy (TNT) for low rectal cancer.Methods:A descriptive case series study was carried out. Clinical data of patients with locally advanced low rectal cancer (LALRC) who achieved complete clinical response (cCR) or nearly cCR (near-cCR) after nCRT at the Department of Colorectal Surgery of Fujian Medical University Union Hospital from May 2015 to February 2019 were retrospectively analyzed. Case inclusion criteria: (1) Low rectal adenocarcinoma within 6 cm from the anal verge. (2) After nCRT, tumor presented markedly regression as mucosal nodule or abnormalities, superficial ulcer, scar or a mucosal erythema (< 2 cm); no regional lymph node metastasis or distant metastasis was found in rectal ultrasonography, pelvic MRI and PET-CT; MRI showed obvious fibrosis in the original tumor site; and post-treatment CEA was normal. (3) The patient and the family members adhered to receive the transanal full-thickness local excision with informed consent. (4) When the residual lesions were difficult to detect after nCRT, patients received the watch and wait (W&W) strategy. Exclusion criteria: (1) Before nCRT, pathological results showed poorly differentiated or signet-ring cell carcinoma; lateral lymph node metastasis was suspected. (2) When the residual lesion size was more than 3 cm after nCRT, it was difficult to perform local excision. The consolidation nCRT group received 3-4 cycles of CAPOX regimen (oxaliplatin and capecitabine) or six cycles of mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) combined with the long-course radiotherapy (intensity-modulated radiation therapy with a total dose of 50.4Gy). Patients with concurrent chemotherapy more than or equal to five cycles of CAPOX or eight cycles of mFOLFOX6 were defined as total neoadjuvant therapy (TNT) group. Local resection was recommended for patients who were near-cCR according to modified MSKCC criteria 8-33 weeks after the end of radiotherapy. Patients with a near-cCR, who were judged as ycN0 according to PET-CT and MRI and were ypT0 after local excision, could enter the W&W strategy. Patients with pathologic stage more advanced than ypT1, and those with positive resection margin, or lymphovascular invasion were recommended for salvage radical surgery after local excision. The ypT1 patients with a negative resection margin and without lymphovascular invasion might receive the W&W management carefully if they refused radicalsurgery to sacrifice the sphincter for low rectal cancer.Results:Of 32 patients, 14 were males and 18 were females with the average age of 59 years old. Twenty-three patients underwent consolidation nCRT, and 9 received TNT. The first evaluation after treatments showed 19 cases with cCR and 13 with near-cCR. Twenty-nine patients received local excision while 3 patients with undetectable lesions received W&W policy. Four cases (12.5%) underwent salvage radical surgery with abdominoperineal resection. After local excision, 3 cases underwent salvage radical surgery immediately, and the final pathologic result was ypT3N0, ypT2N0, and ypT2N0 respectively, of whom 2 cases were in the group of consolidation CRT and 1 was in the TNT group. Of these 3 cases, 1 case with an initial cT3 stage showed a pathologic stage of ypT1 and a negative circumferential resection margin after consolidation nCRT and local excision, however, the final pathologic stage was ypT3 with fragmented tumor deposits in the mesorectum after the salvage radical surgery. Meanwhile 1 patient in the TNT group receiving W&W suffered from intraluminal regrowth after 7.4 months follow-up and underwent salvage abdominoperineal resection. One patient in the consolidation nCRT group died of stroke 42.5 months after local resection. Another patient in the TNT group had cerebral metastasis 10 months after the W&W policy, but no local recurrence was found in the pelvic cavity, then received resection of the metastatic tumors. The average follow-up for all the patients was 23 (5-51) months. The cumulative local regrowth rate was 5.0%. The overall survival rate was 85.7%, and the sphincter-preservation rate was increased from 25.0% (28/32) in the original plan to 87.5% (28/32) actually. The 3-year disease-free survival rate was 89.7%. The 3-year organ-preserving survival rate was 85.7%, and the 3-year stoma-free survival rate was 82.5%. At present, 31 patients still survived.Conclusions:After nCRT with consolidation chemotherapy or TNT for low rectal cancer, patients with cCR, ycN0 according to PET-CT and MRI, and ypT0 after local excision, can consider the W&W strategy. Strict patient selection with a near-cCR for local resection and sphincter-preserving strategy can reduce the local regrowth of cancer, and the short-term outcomes are satisfactory.

Objective:To investigate the feasibility and safety of sphincter-preserving surgery after neoadjuvant chemoradiotherapy (nCRT) with consolidation chemotherapy in the interval period or total neoadjuvant therapy (TNT) for low rectal cancer.Methods:A descriptive case series study was carried out. Clinical data of patients with locally advanced low rectal cancer (LALRC) who achieved complete clinical response (cCR) or nearly cCR (near-cCR) after nCRT at the Department of Colorectal Surgery of Fujian Medical University Union Hospital from May 2015 to February 2019 were retrospectively analyzed. Case inclusion criteria: (1) Low rectal adenocarcinoma within 6 cm from the anal verge. (2) After nCRT, tumor presented markedly regression as mucosal nodule or abnormalities, superficial ulcer, scar or a mucosal erythema (< 2 cm); no regional lymph node metastasis or distant metastasis was found in rectal ultrasonography, pelvic MRI and PET-CT; MRI showed obvious fibrosis in the original tumor site; and post-treatment CEA was normal. (3) The patient and the family members adhered to receive the transanal full-thickness local excision with informed consent. (4) When the residual lesions were difficult to detect after nCRT, patients received the watch and wait (W&W) strategy. Exclusion criteria: (1) Before nCRT, pathological results showed poorly differentiated or signet-ring cell carcinoma; lateral lymph node metastasis was suspected. (2) When the residual lesion size was more than 3 cm after nCRT, it was difficult to perform local excision. The consolidation nCRT group received 3-4 cycles of CAPOX regimen (oxaliplatin and capecitabine) or six cycles of mFOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) combined with the long-course radiotherapy (intensity-modulated radiation therapy with a total dose of 50.4Gy). Patients with concurrent chemotherapy more than or equal to five cycles of CAPOX or eight cycles of mFOLFOX6 were defined as total neoadjuvant therapy (TNT) group. Local resection was recommended for patients who were near-cCR according to modified MSKCC criteria 8-33 weeks after the end of radiotherapy. Patients with a near-cCR, who were judged as ycN0 according to PET-CT and MRI and were ypT0 after local excision, could enter the W&W strategy. Patients with pathologic stage more advanced than ypT1, and those with positive resection margin, or lymphovascular invasion were recommended for salvage radical surgery after local excision. The ypT1 patients with a negative resection margin and without lymphovascular invasion might receive the W&W management carefully if they refused radicalsurgery to sacrifice the sphincter for low rectal cancer.Results:Of 32 patients, 14 were males and 18 were females with the average age of 59 years old. Twenty-three patients underwent consolidation nCRT, and 9 received TNT. The first evaluation after treatments showed 19 cases with cCR and 13 with near-cCR. Twenty-nine patients received local excision while 3 patients with undetectable lesions received W&W policy. Four cases (12.5%) underwent salvage radical surgery with abdominoperineal resection. After local excision, 3 cases underwent salvage radical surgery immediately, and the final pathologic result was ypT3N0, ypT2N0, and ypT2N0 respectively, of whom 2 cases were in the group of consolidation CRT and 1 was in the TNT group. Of these 3 cases, 1 case with an initial cT3 stage showed a pathologic stage of ypT1 and a negative circumferential resection margin after consolidation nCRT and local excision, however, the final pathologic stage was ypT3 with fragmented tumor deposits in the mesorectum after the salvage radical surgery. Meanwhile 1 patient in the TNT group receiving W&W suffered from intraluminal regrowth after 7.4 months follow-up and underwent salvage abdominoperineal resection. One patient in the consolidation nCRT group died of stroke 42.5 months after local resection. Another patient in the TNT group had cerebral metastasis 10 months after the W&W policy, but no local recurrence was found in the pelvic cavity, then received resection of the metastatic tumors. The average follow-up for all the patients was 23 (5-51) months. The cumulative local regrowth rate was 5.0%. The overall survival rate was 85.7%, and the sphincter-preservation rate was increased from 25.0% (28/32) in the original plan to 87.5% (28/32) actually. The 3-year disease-free survival rate was 89.7%. The 3-year organ-preserving survival rate was 85.7%, and the 3-year stoma-free survival rate was 82.5%. At present, 31 patients still survived.Conclusions:After nCRT with consolidation chemotherapy or TNT for low rectal cancer, patients with cCR, ycN0 according to PET-CT and MRI, and ypT0 after local excision, can consider the W&W strategy. Strict patient selection with a near-cCR for local resection and sphincter-preserving strategy can reduce the local regrowth of cancer, and the short-term outcomes are satisfactory.