Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases.

BACKGROUND: The Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of colorectal cancer liver metastases (CRCLM) has not been reported. METHODS: Liver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse-free survival (RFS) and overall survival (OS) was analyzed with Kaplan-Meier curves and Cox multivariate models, and confirmed via an internal validation. Receiver operating characteristic (ROC) curves were plotted to compare the prognostic values of the Immunoscore and the clinical risk score (CRS) system. RESULTS: CRCLM patients with high Immunoscores (> 2) had significantly longer RFS [median RFS (95% confidence interval; 95% CI) 21.4 (7.8-35.1) vs. 8.7 (6.8-10.5) months, P < 0.001] and OS [median OS (95% CI): not reached vs. 28.7 (23.2-34.2) months, P < 0.001] than those with low Immunoscores (≤ 2). After stratification by CRS, the Immunoscore retained a statistically significant prognostic value for OS. The areas under the ROC curves (AUROCs) of the Immunoscore and the CRS system for RFS were 0.711 [95% CI 0.642-0.781] and 0.675[95% CI 0.601-0.749] (P = 0.492), whereas the AUROC of the Immunoscore system for OS was larger than that of the CRS system [0.759 (95% CI 0.699-0.818) vs. 0.660 (95% CI 0.592-0.727); P = 0.029]. CONCLUSIONS: The Immunoscore of liver metastases can be applied to predict the prognosis of CRCLM patients following liver resection.

Primary tumor location as a predictor of the benefit of palliative resection for colorectal cancer with unresectable metastasis.

BACKGROUND: It is still under debate that whether stage IV colorectal cancer patients with unresectable metastasis can benefit from primary tumor resection, especially for asymptomatic colorectal cancer patients. Retrospective studies have shown controversial results concerning the benefit from surgery. This retrospective study aims to evaluate whether the site of primary tumor is a predictor of palliative resection in asymptomatic stage IV colorectal cancer patients. METHODS: One hundred ninety-four patients with unresectable metastatic colorectal cancer were selected from Sun Yat-sen University Cancer Center Database in the period between January 2007 and December 2013. All information was carefully reviewed and collected, including the treatment, age, sex, carcinoembryonic antigen, site of tumor, histology, cancer antigen 199, number of liver metastases, and largest diameter of liver metastasis. The univariate and multivariate analyses were used to detect the relationship between primary tumor resection and overall survival of unresectable stage IV colorectal cancer patients. RESULTS: One hundred twenty-five received palliative resection, and 69 received only chemotherapy. Multivariate analysis indicated that primary tumor site was one of the independent factors (RR 0.569, P = 0.007) that influenced overall survival. For left-side colon cancer patients, primary tumor resection prolonged the median overall survival time for 8 months (palliative resection vs. no palliative resection: 22 vs. 14 months, P = 0.009); however, for right-side colon cancer patients, palliative resection showed no benefit (12 vs. 10 months, P = 0.910). CONCLUSIONS: This study showed that left-side colon cancer patients might benefit from the primary tumor resection in terms of overall survival. This result should be further explored in a prospective study.

Surgery with versus without preoperative concurrent chemoradiotherapy for mid/low rectal cancer: an interim analysis of a prospective, randomized trial.

INTRODUCTION: Multimodality therapy, including preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), has effectively reduced local recurrence rates of rectal cancer over the past decade. However, the benefits and risks of the addition of neoadjuvant CRT to surgery need to be evaluated. This study was to compare the efficacy of TME with versus without preoperative concurrent chemoradiotherapy (CCRT) involving XELOX regimen (oxaliplatin plus capecitabine) in Chinese patients with stages II and III mid/low rectal adenocarcinoma. METHODS: We randomly assigned patients to the TME group (TME without preoperative CCRT) or CCRT + TME group (TME with preoperative CCRT). The primary endpoint was disease-free survival (DFS); the secondary endpoints were overall survival (OS), local and distant recurrence, tumor response to CRT, toxicity, sphincter preservation, and surgical complications. An interim analysis of the potential inferiority of DFS in the CCRT + TME group was planned when the first 180 patients had been followed up for at least 6 months. RESULTS: A total of 94 patients in the TME group and 90 patients in the CCRT + TME group were able to be evaluated. The 3-year DFS and OS rates were 86.3 % and 91.5 % in the whole cohort, respectively. The 3-year DFS rates of the TME and CCRT + TME groups were 85.7% and 87.9 % (P = 0.766), respectively, and the 3-year OS rates were 90.7 % and 92.3 % (P = 0.855), respectively. The functional sphincter preservation rates of the TME and CCRT + TME groups were 71.3 % and 70.0 % (P = 0.849), respectively. In the TME group, 16 (17.0 %) patients were proven to have pTNM stage I disease after surgery. In the CCRT + TME group, 32 (35.6 %) patients achieved a pathologic complete response (pCR). CONCLUSIONS: Preliminary results indicated no significant differences in the DFS, OS, or functional sphincter preservation rates between the TME and CCRT + TME groups. However, preoperative CCRT with XELOX yielded a high pCR rate. Newer techniques are needed to improve the staging accuracy, and further investigation is warranted. CLINICAL TRIAL REGISTRATION NUMBER: Chi CTR-TRC-08000122.

Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial.

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

[Expression of molecular markers detected by immunohistochemistry and risk of lymph node metastasis in stage T1 and T2 colorecrectal cancers].

OBJECTIVE: To study the molecular risk factors of lymph node metastasis in stage T1 and T2 colorectal cancers by tissue microarray and immunohistochemistry techniques. METHODS: Two hundred and three patients with stage T1 and T2 colorectal carcinoma who underwent radical surgery from 1999 to 2010 in our department were included in this study. Their clinicopathological data were retrospectively analyzed. Expression of the following 14 molecular markers were selected and assayed by tissue microarray and immunohistochemistry: VEGFR-3, HER2, CD44v6, CXCR4, TIMP-1, EGFR, IGF-1R, IGF-2, IGFBP-1, ECAD, MMP-9, RKIP, CD133, MSI. Chi-squared test and logistic regression were used to evaluate the variables as potential risk factors for lymph node metastasis. RESULTS: The positive expression rates of biomarkers were as following: VEGFR-3 (44.3%), EGFR (30.5%), HER-2 (28.1%), IGF-1R (63.5%), IGF-2 (44.8%), IGFBP-1 (70.9%), ECAD (45.8%), CD44v6 (51.2%), MMP-9 (44.3%), TIMP-1 (41.4%), RKIP (45.3%), CXCR4 (40.9%), and CD133 (49.8%). The positive rate of MSI expression was 22.2%. Both univariate and multivariate analyses showed that VEGFR-3, HER-2, and TIMP-1 were significant predictors of lymph node metastasis. Univariate analysis showed that CD44v6 and CXCR4 were significant significant predictors of lymph node metastasis. CONCLUSIONS: VEGFR-3, HER2 and TIMP-1 are independent factors for lymph node metastasis in stage T1 and T2 colorectal cancers.

Impact of ERß and CD44 expression on the prognosis of patients with stage II colon cancer.

The correlation of ERß/CD44 expression and progression of patients with stage II of colon cancer were explored in this work. A total of 220 paraffin-embedded specimens with stage II colon cancer from 1995 to 2003 were included for assessing ERß and CD44 by immunohistochemistry in normal mucosa and tumor tissues. Kaplen-Meier method, log-rank test, and the Cox proportional hazards regression model were used to analyze the overall survival data. ROC curve was used to describe the capacity of variables in prognosis prediction. Jackknife method was used to perform cross validation of predictions. The survival rates were significantly different between the patients with high expression and low expression of CD44-tumor tissues (61 % vs. 90 %, p < 0.0001) and between the patients with high expression and low expression of ERß-tumor tissue (99 % vs. 36 %, p < 0.0001), respectively. In addition, the interaction between expression of ERß and CD44 was found that the impact of CD44 to the overall survive appeared only when expression of ERß was low; and the high expression of ERß-tumor could be regarded as a protective factor for overall survival. This study suggest that low expression of ERß-tumor and high expression of CD44-tumor are risk factors for overall survival in patients with stage II colon cancer.

Different effects of ERß and TROP2 expression in Chinese patients with early-stage colon cancer.

Estrogen receptor beta (ERß) and TROP2 expressed in colon carcinoma and might play an important role there. We explored the relationship of ERß and TROP2 expression with the prognosis of early-stage colon cancer. ERß and TROP2 levels were assessed by immunohistochemistry in normal mucosa and tumoral tissues from 220 Chinese patients with T(3)N(0)M(0) (stage IIa) and T(4)N(0)M(0) (stage IIb) colon cancer in the Cancer Center, Sun Yat-sen University, who underwent curative surgical resection between 1995 and 2003. The Cox proportional hazards regression model was applied to analyze the overall survival (OS) data, and the ROC curve, Kaplan-Meier estimate, log rank test, and Jackknife method were used to show the effect of ERß and TROP2 expression at different stages of cancer. The 5-year survival rates were not significantly different between the patients with stage IIa and stage IIb colon cancer (83 vs. 80 %, respectively). The high expression of ERß was related to decreasing OS in stage IIa and stage IIb colon cancer, while the high expression of TROP2 was related to decreasing OS in stage IIb colon cancer. The expression of ERß and TROP2 has tumor-suppressive and tumor-promoting effect in stage IIa and stage IIb colon cancer, respectively.

High dose chemoradiotherapy increases chance of organ preservation with satisfactory functional outcome for rectal cancer.

BACKGROUND: High dose chemoradiotherapy offers a curative chance for patients with rectal cancer that are unfit or unwilling to undergo surgical resection, yet its long-term survival and functional outcomes have been rarely investigated. METHODS: Patients with non-metastatic rectal adenocarcinoma who received pelvic radiation for curative intent from April 2006 to July 2017 were retrospectively investigated. Survival rates were analyzed using the Kaplan-Meier method. Quality of life and functional outcomes were evaluated using the EORTC quality of life questionnaire. RESULTS: A total of 57 patients were included, with a median age of 59.0 (range, 29-84) years. The numbers of patients who were diagnosed as stage I, II and III were 5 (8.8%), 16 (28.1%) and 36 (63.2%), respectively. 53 (93.0%) patients had tumor located within 5 cm from the anal verge. All patients received fluorouracil-based concurrent chemoradiotherapy with a median radiation dose of 80 (range, 60-86) Gy. All kinds of grade 3-4 adverse events occurred in 18 (31.6%) patients. 42 (73.7%) patients achieved a clinical complete response after chemoradiotherapy. After a median follow-up of 43.5 (range 14.9-163.2) months, 12 (21.1%) patients had local progression and 11 (19.3%) developed distant metastasis. The 3-year local recurrence-free survival and distant metastasis-free survival were 77.3% (95% CI, 65.7-88.8%) and 79.2% (95% CI, 68.2-90.2%), while the 3-year progression-free survival, cancer-specific survival, overall survival were 61.9% (95% CI, 48.8-75.0%), 93.1% (95% CI, 85.8-100.0%) and 91.4% (95% CI, 83.6-99.2%), respectively. For patients who had tumor located within 3 cm from the anal verge, the sphincter preservation rate was 85.3% at last follow-up. Long-term adverse events mainly were anal blood loss. 21 patients completed the quality-of-life questionnaire and had a score of the global health status of 78.57 ± 17.59. Of them, 95.2% reported no urinary incontinence and 85.7% reported no fecal incontinence. CONCLUSIONS: High dose chemoradiation demonstrated promising survival outcomes with acceptable short-term and long-term side effects, and satisfying long-term functional outcomes and quality of life. It could be considered as a non-invasive alternative for rectal cancer patients who refuse surgery.

Factors associated with adherence to colonoscopy among individuals who were positive in the preliminary screening for colorectal neoplasms.

OBJECTIVES: This study aimed to investigate the potential factors associated with adherence to colonoscopy among participants who were preliminarily screened positive in a community-based colorectal cancer screening program in China. METHODS: This study analyzed data from 1219 out of 6971 community residents who were identified as positive cases by the well-validated high-risk factor questionnaire (HRFQ) or fecal immunochemical test (FIT) in the preliminary screening stage for colorectal neoplasms. Patients showing adherence to colonoscopy were defined as those who received positive results in a preliminary screening for colorectal neoplasms and later received a colonoscopy examination as required. The associations of social-demographic factors, lifestyle behaviors, history of diabetes, body mass index (BMI), and risk factors in the HRFQ with adherence to colonoscopy were evaluated using logistic regression models. RESULTS: Among 1219 participants who preliminarily screened positive, the top five risk factors reported by the participants were chronic constipation (25.9%), hematochezia (23.5%), family history of CRC in first-degree relatives (22.1%), chronic diarrhea (21.8%), and history of polyps (16.6%). Around 14.2% of participants who preliminarily screened positive reported three or more risk factors, and the proportion was 26.2% among participants who were positive according to both HRFQ and FIT. Among all participants who were preliminarily screened positive, the multivariable results showed that those who were married (OR = 1.58, 95% CI: 1.12, 2.25, p = 0.01), had chronic diarrhea (OR = 1.34, 95% CI: 1.00, 1.78, p = 0.047), and had a positive FIT (OR = 1.60, 95% CI: 1.21, 2.10, p < 0.001 for patients who were negative according to HRFQ but positive according to FIT; OR = 2.12, 95% CI: 1.33, 2.78, p = 0.002 for patients who were positive for both HRFQ and FIT) were more likely to adhere to colonoscopy, while participants with a history of cancer (OR: 0.50, 95% CI: 0.31, 0.79, p = 0.003) were less likely to adhere to colonoscopy. The results among participants who were tested positive according to only HRFQ were similar to those among all participants who were tested positive according to HRFQ or FIT. However, among participants who were tested positive according to only FIT, we only found that those who were married (OR = 2.52, 95% CI: 1.08, 5.90, p = 0.033) had a higher odds of adhering to colonoscopy, while those with a history of diabetes (OR = 0.35, 95% CI: 0.13, 0.96, p = 0.042) were less likely to adhere to colonoscopy. CONCLUSION: Our findings provide evidence supporting the development of tailored interventional strategies that aim to improve adherence to colonoscopy for individuals with a high risk of colorectal neoplasms. Both barriers and facilitators associated with adherence to colonoscopy should be considered in supportive systems and health policies. However, further well-designed prospective studies are warranted to confirm our findings.

Expression of COX-2, MMP-2 and VEGF in stage II and III colorectal cancer and the clinical significance.

OBJECTIVES: To investigate the expression of COX-2, MMP-2 and VEGF in colorectal cancer and the clinical/pathological significance. METHODS: Stage II and III colorectal cancer patients (149 cases) that received radical resection between May 2003 and November 2008 and who had complete clinical and pathological data, were recruited in this study. Expression of COX-2, MMP-2 and VEGF were detected by immunohistochemistry. RESULTS: The positive rate of COX-2, MMP-2, and VEGF expression was 60.4%, 50.3% and 69.1%, respectively. COX-2 correlated with stage, lymph node metastasis, postoperative recurrence and metastasis, and survival rate; MMP-2 correlated with intestinal wall invasion, stage, number of lymph node metastasis, postoperative recurrence and metastasis, and survival rate; VEGF correlated with preoperative serum levels of CEA and CA199, postoperative recurrence and metastasis, and survival rate; the positive rate of COX-2, MMP-2 and VEGF co-expression was 32.9%, which correlated with stage, number of lymph node metastasis, preoperative serum level of CEA, postoperative recurrence and metastasis, and survival rate. CONCLUSION: The expression of COX-2, MMP-2 and VEGF in colorectal cancer plays a synergistic promoting effect on the malignant biological behavior of tumors, which could be used as a marker to determine the malignant progression, invasion and metastasis, and prognosis of the tumor.

[Expression of matrix metalloproteinase 1 in tissue of colon carcinoma and its clinical prognostic significance].

OBJECTIVE: To explore the expression patterns of matrix metalloproteinase1 (MMP-1) in colon carcinoma and evaluate its clinical significance. METHODS: The expression of MMP-1 was detected by SP immunohistochemical method. The tissue microarray samples of 620 colon carcinoma patients were collected and the clinical data reviewed. RESULTS: The positive expression rate of MMP-1 in cancer tissue was higher than that of normal tissue [72.5% (421/581) vs 30.8% (179/581), P = 0.0001]. And the difference was statistically significant (P = 0.0001). The positive rate in stages I and II [77.6% (235/303)] were higher than stages III and IV [66.9% (186/278), P = 0.0040], the former two stages showed a poor prognosis while the latter two stages a fair prognosis. The results of COX regression showed that a lower expression of MMP-1 (HR: 1.042, 95%CI: 0.770 - 1.410, P = 0.0001), tumor type (HR: 0.966, 95%CI: 0.571 - 1.633, P = 0.0150), local infiltration (HR: 0.576, 95%CI: 0.413 - 0.805, P = 0.0010) and infiltration of bowel wall (HR: 0.337, 95%CI: 0.197 - 0.575, P = 0.0001) were significant predictors of colon carcinoma. CONCLUSION: As an independent prognostic factor of colon carcinoma, the expression of MMP-1 in cancer tissue has different prognostic implications according to various stages.

Programmed death-ligand 1 expression in the tumour stroma of colorectal liver oligometastases and its association with prognosis after liver resection.

BACKGROUND: The clinical value of programmed death-ligand 1 (PD-L1) expression in colorectal liver oligometastases (CLOs) remains undefined. This study aimed to detect PD-L1 in the microenvironment of CLOs and determine its association with patient prognosis. METHODS: We collected 126 liver-resection specimens from CLO patients who underwent curative liver resection between June 1999 and December 2016. Immunohistochemistry (IHC) was performed to assess PD-L1 expression in paraffin-embedded specimens. Overall survival (OS) and recurrence-free survival (RFS) were analysed using the Kaplan-Meier method and log-rank test. RESULTS: PD-L1 was mainly expressed in the stroma of liver oligometastases. Patients with high PD-L1 expression had a higher proportion of clinical-risk scores (CRSs) of 2-4 (67.7% vs 40.4%; P = 0.004). With a median 58-month follow-up, patients with high PD-L1 expression had a significantly lower 3-year OS rate (65.5% vs 92.7%; P = 0.001) and 3-year RFS rate (34.7% vs 83.8%; P < 0.001) than patients with low PD-L1 expression. Multivariate Cox analysis demonstrated that high PD-L1 expression (hazard ratio [HR] = 3.581; 95% confidence interval [CI] 2.301-9.972; P = 0.015), CRS 2-4 (HR = 6.960; 95% CI 1.135-42.689; P = 0.036) and increased preoperative CA19-9 (HR = 2.843; 95% CI 1.229-6.576; P = 0.015) were independent risk factors for OS. High PD-L1 expression (HR = 4.815; 95% CI 2.139-10.837; P < 0.001) and lymph-node metastasis (HR = 2.115; 95% CI 1.041-4.297; P = 0.038) were independent risk factors for RFS. CONCLUSION: This study found that PD-L1 was commonly expressed in the tumour stroma of CLOs and high PD-L1 expression was associated with poor prognosis.

CMTM6 and PD-L1 coexpression is associated with an active immune microenvironment and a favorable prognosis in colorectal cancer.

BACKGROUND: CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6), a programmed death-ligand 1 (PD-L1) regulator, is widely expressed in various tumors and regulates the immune microenvironment. However, its prognostic value remains controversial, and the roles of CMTM6 in colorectal cancer (CRC) are still unknown. In this study, we aimed to elaborate the expression patterns of CMTM6 and PD-L1 in CRC and investigate their relationship with the infiltration of T cells and the prognosis of patients with CRC. METHODS: Analysis of CMTM6 mRNA levels, gene ontology enrichment analysis and single-sample gene set enrichment analysis were performed in a The Cancer Genome Atlas colon cancer cohort. The expression of CMTM6 and PD-L1 and the infiltration of T cells in tumor tissues from our cohort containing 156 patients with CRC receiving adjuvant chemotherapy and 77 patients with CRC without chemotherapy were examined by immunohistochemistry assay. RESULTS: CMTM6 expression was upregulated in CRC compared with normal colon tissues, and CMTM6 levels were lower in advanced tumors than in early-stage tumors. High expression of CMTM6 correlated with lower pT stage and more CD4+/CD8+ tumor-infiltrating lymphocytes (TILs) and predicted a favorable prognosis in CRC. PD-L1 was expressed in CRC tissues at a low level, and PD-L1 positivity in tumor stroma (PD-L1(TS)), but not PD-L1 positivity in cancer cells (PD-L1(CC)), was associated with an increased density of CD4+ TILs and a favorable prognosis. The coexpression status of CMTM6 and PD-L1(TS) divided patients with CRC into three groups with low, moderate and high risks of progression and death, and patients with CMTM6High/PD-L1(TS)+ status had the longest survival. Moreover, the prognostic value of CMTM6/PD-L1 expression was more significant in patients with CRC treated with adjuvant chemotherapy than in those not treated with chemotherapy. CONCLUSION: CMTM6 has a critical impact on the immune microenvironment and can be used as an independent prognostic factor for CRC. The coexpression status of CMTM6 and PD-L1 can be used as a new classification to stratify the risk of progression and death for patients with CRC, especially for patients receiving adjuvant chemotherapy. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatment for CRC in the future.

Neoadjuvant chemoradiotherapy in patients with unresectable locally advanced sigmoid colon cancer: clinical feasibility and outcome.

BACKGROUND: Patients with locally advanced sigmoid colon cancer (LASCC) have limited treatment options and a dismal prognosis with poor quality of life. This retrospective study aimed to further evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by surgery as treatment for select patients with unresectable LASCC. METHODS: We studied patients with unresectable LASCC who received NACRT between November 2010 and April 2019. The NACRT regimen consisted of intensity modulated radiotherapy (IMRT) of 50 Gy to the gross tumor and positive lymphoma node and 45 Gy to the clinical target volume. Capecitabine­based chemotherapy was administered every 2 (mFOLFOX6) or 3 weeks (CAPEOX). Surgery was scheduled 6-8 weeks after radiotherapy. RESULTS: Seventy­two patients were enrolled in this study. Patients had a regular follow-up (median, 41.1 months; range, 8.3-116.5 months). Seventy­one patients completed NACRT, and sixty-five completed surgery. Resection with microscopically negative margins (R0 resection) was achieved in 64 patients (88.9%). Pathologic complete response was observed in 15 patients (23.1%), and multivisceral resection was necessary in 38 patients (58.3%). The cumulative probability of 3-year overall survival (OS) and progression-free survival (PFS) were 75.8 and 70.7%, respectively. CONCLUSIONS: For patients with unresectable LASCC, neoadjuvant chemoradiotherapy is feasible, surgery can be performed safely and may result in increased survival and organ preservation rates.

Primary tumor immune score fails to predict the prognosis of colorectal cancer liver metastases after hepatectomy in Chinese populations.

BACKGROUND: Increasing evidence suggests that the immune score is significantly associated with cancer prognosis. However, the prognostic role of primary tumor immune score in colorectal cancer liver metastases (CRLM) after hepatectomy in Chinese patients has not been reported. The present study is designed to investigate whether the immune score of primary tumor can predict the postoperative survival of liver metastases in Chinese patients. METHODS: A total of 131 patients diagnosed with CRLM were included, and the corresponding primary tumor and liver metastasis specimens were acquired. An immune score ranging from 0 to 4 was established based on the counts and densities of CD3+ and CD8+ T cells in the core tumor (CT) and the invasive margin (IM). Relapse-free survival (RFS) and overall survival (OS) were analyzed by Kaplan-Meier curves to assess the prognostic role of primary tumor immune score. Furthermore, we conducted a comprehensive search of the Gene Expression Omnibus (GEO) and selected stage IV colorectal cancer (CRC) patients with liver metastasis to compare the tumor-infiltrating T cell profiles of the primary tumor and liver metastases by CIBERSORT. RESULTS: Patients with high immune scores in the primary tumor has no significantly better RFS and OS after hepatectomy than those with low immune scores [median RFS (95% CI): 19.13 (10.07-28.20) vs. 27.13 (15.97-38.29) months, P=0.604; median OS (95% CI): 64.37 (35.96-92.78) vs. 40.07 (32.54-47.59) months, P=0.652]. Data collected from the GEO indicates that the proportion of CD8+ T cells and total T cells in the primary tumor and liver metastatic lesion are also not significantly correlated (CD8+ T cells: r2 =0.030, P=0.468; total T cells: r2 =0.165, P=0.076). CONCLUSIONS: The immune score of the primary tumor fails to predict the prognosis of CRLM after hepatectomy in Chinese patients.

Prognostic impact of ERß and MMP7 expression on overall survival in colon cancer.

Estrogen receptor beta (ERß) is the most highly expressed protein in patients with colon cancer. Matrix metalloproteinase 7 (MMP7) is consistently expressed throughout cancer progression. We have previously shown that endocrine therapy can inhibit MMP7 expression in colon cancer cells. In this study, we aim to identify the prognostic effects and correlation of ERß and MMP7 in the context of colon cancer. ERß and MMP7 levels were assessed by immunohistochemistry in normal mucosa and tumoral tissues from 423 patients with stage I-III colon cancer. The Cox proportional hazards regression model was applied to analyze the lifetime data, including overall survival (OS) and cause-specific survival (CSS). The 5-year survival rate was significantly higher in patients with high expression of nuclear ERß than in patients with low expression (84.3% vs. 63.9%, respectively, p < 0.05). High expression of MMP7 was related to decreased OS (72% vs. 90%, respectively, p = 0.008) and 5-year survival (86.6% vs. 88.8%, respectively, p = 0.005) compared to patients with low expression of MMP7. In the subset of patients with high expression levels of tumoral nuclear ERß, high expression of MMP7 was related to OS and CSS among colon cancer patients with high expression of ERß. In conclusion, our results suggest that low expression of ERß was a risk factor in colon cancer, and high expression of MMP7 was an independent prognostic factor of ERß-positive patients with colon cancer.

Elevated preoperative neutrophil to lymphocyte ratio predicts risk of recurrence following curative resection for stage IIA colon cancer.

BACKGROUND AND OBJECTIVES: Adjuvant chemotherapy for stage II colon cancer remains controversial but may be considered for patients with high-risk features. Recent studies have shown that elevated neutrophil to lymphocyte ratio (NLR) is a worse prognostic factor and a predictor of response to chemotherapy in patients with advanced colorectal cancer. The purpose of this study was to evaluate whether NLR predicts risk of recurrence in patients with stage IIA colon cancer undergoing curative resection without adjuvant chemotherapy. METHODS: We retrospectively reviewed 141 consecutive patients with stage IIA colon cancer treated with curative surgery alone from 2002 to 2006. NLR, as well as demographics, clinical, histopathologic, and laboratory data were analyzed. Univariate and multivariate analyses were conducted to identify prognostic factors associated with recurrent-free survival (RFS). RESULTS: Cox's regression analysis demonstrated that elevated NLR (>4) (hazard ratio, 4.88; P < 0.01) and less lymph node sampling (<15 lymph nodes; hazard ratio, 3.80; P < 0.05) were adverse prognostic factors for RFS. The 5-year RFS was 91.4% (95% CI, 88.6-94.2%) for patients with normal NLR and 63.8% (51.1-76.3%) for patients with elevated NLR. The 5-year RFS for patients with 0, 1, and 2 of the identified risk factors was 95.1%, 87.4%, and 33.3%, respectively (P < 0.001). CONCLUSIONS: Elevated preoperative NLR is an independent predictor of worse RFS for patients with stage IIA colon cancer and a potential biomarker to identify candidates for adjuvant chemotherapy.

Phase III randomized, placebo-controlled, double-blind study of monosialotetrahexosylganglioside for the prevention of oxaliplatin-induced peripheral neurotoxicity in stage II/III colorectal cancer.

BACKGROUND: Monosialotetrahexosylganglioside (GM1) is a neuroprotective glycosphingolipid that repairs nerves. Oxaliplatin-based chemotherapy is neurotoxic. This study assessed the efficacy of GM1 for preventing oxaliplatin-induced peripheral neurotoxicity (OIPN) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy. METHODS: In total, 196 patients with stage II/III CRC undergoing adjuvant chemotherapy with mFOLFOX6 were randomly assigned to intravenous GM1 or a placebo. The primary endpoint was the rate of grade 2 or worse cumulative neurotoxicity (NCI-CTCAE). The secondary endpoints were chronic cumulative neurotoxicity (EORTC QLQ-CIPN20), time to grade 2 neurotoxicity (NCI-CTCAE or the oxaliplatin-specific neuropathy scale), acute neurotoxicity (analog scale), rates of dose reduction or withdrawal due to OIPN, 3-year disease-free survival (DFS) and adverse events. RESULTS: There were no significant differences between the arms in the rate of NCI-CTCAE grade 2 or worse neurotoxicity (GM1: 33.7% vs placebo: 31.6%; P = .76) or neuropathy measured by the EORTC QLQ-CIPN20 or time to grade 2 neurotoxicity using NCI-CTCAE and the oxaliplatin-specific neuropathy scale. GM1 substantially decreased participant-reported acute neurotoxicity (sensitivity to cold items [P < .01], discomfort swallowing cold liquids [P < .01], throat discomfort [P < .01], muscle cramps [P < .01]). The rates of dose reduction or withdrawal were not significantly different between the arms (P = .08). The 3-year DFS rates were 85% and 83% in the GM1 and placebo arms, respectively (P = .19). There were no differences in toxicity between the arms. CONCLUSION: Patients receiving GM1 were less troubled by the symptoms of acute neuropathy. However, we do not support the use of GM1 to prevent cumulative neurotoxicity. (ClinicalTrials.gov number, NCT02251977).