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.

Beneficiaries of radical surgery among clinical complete responders to neoadjuvant chemoradiotherapy in rectal cancer.

This study aimed to identify patients who benefit from radical surgery among those with rectal cancer who achieved clinical complete response (cCR). Patients with locally advanced rectal cancer (LARC; stage II/III) who achieved cCR after neoadjuvant chemoradiotherapy (nCRT) were included (n = 212). Univariate/multivariate Cox analysis was performed to validate predictors for distant metastasis-free survival (DMFS). A decision tree was generated using recursive partitioning analysis (RPA) to categorize patients into different risk stratifications. Total mesorectal excision (TME) was compared with the watch-and-wait (W&W) strategy in each risk group. Two molecular predicators of CEA and CA19-9 were selected to establish the RPA-based risk stratification, categorizing LARC patients into low-risk (n = 139; CA19-9 < 35 U/mL and CEA < 5 ng/mL) and high-risk (n = 73; CA19-9 ≥ 35 U/mL or CEA ≥5 ng/mL) groups. Superior 5-y DMFS was observed in the low-risk group vs. the high-risk group (92.9% vs. 76.2%, P = .002). Low-risk LARC patients who underwent TME had significantly improved 5-y DMFS compared with their counterparts receiving the W&W strategy (95.9% vs. 84.3%; P = .028). No significant survival difference was observed in high-risk patients receiving the 2 treatment modalities (77.9% vs. 94.1%; P = .143). LARC patients with cCR who had both baseline CA19-9 < 35 U/mL and CEA < 5 ng/mL may benefit from radical surgery.

Neoadjuvant chemoradiotherapy for patients with unresectable radically locally advanced colon cancer: a potential improvement to overall survival and decrease to multivisceral resection.

BACKGROUND: The management of unresectable locally advanced colon cancer (LACC) remains controversial, as resection is not feasible. The goal of this study was to evaluate the treatment outcomes and toxicity of neoadjuvant chemoradiotherapy (NACRT) followed with surgery and adjuvant chemotherapy in patients with unresectable radically LACC. METHODS: We included patients who were diagnosed at our institution, 2010-2018. The neoadjuvant regimen consisted of radiotherapy and capecitabine/ 5-fluorouracil-based chemotherapy. RESULTS: One hundred patients were identified. The median follow-up time was 32 months. The R0 resection rate, adjusted nonmultivisceral resection rate and bladder preservation rate were 83.0, 43.0 and 83.3%, respectively. The pCR and clinical-downstaging rates were 18, and 81.0%%, respectively. The 3-year PFS and OS rates for all patients were 68.6 and 82.1%, respectively. Seventeen patients developed grade 3-4 myelosuppression, which was the most common adverse event observed after NACRT. Tumor perforation occurred in 3 patients during NACRT. The incidence of grade 3-4 surgery-related complications was 7.0%. Postoperative anastomotic leakage was observed in 3 patients. CONCLUSIONS: NACRT followed by surgery was feasible and safe for selected patients with LACC, and can be used as a conversion treatment to achieve satisfactory downstaging, long-term survival and quality of life, with acceptable toxicities.

Histopathological growth patterns correlate with the immunoscore in colorectal cancer liver metastasis patients after hepatectomy.

Various scoring systems have been proposed to predict the postoperative prognosis of colorectal liver metastasis (CRLM), including the clinical risk score (CRS), the immunoscore and so on. Recently, histopathological growth patterns (HGPs) have been recognized. However, the correlation between HGPs and the immunoscore, and their prognostic values in patients with CRLM after liver resection remain undetermined. In this study, HGPs were retrospectively evaluated in H&E-stained slides from 166 CRLM patients. The immunoscore was calculated according to the densities of immunostained CD3 + and CD8 + cells. A risk score combining HGPs, the immunoscore and the CRS was defined and divided patients into the low-, medium- and high-risk group. Our results showed that the densities of CD3 + and CD8 + cells were higher in the desmoplastic HGP (dHGP) group than in the non-dHGP group, and the proportion of high immunoscores was also higher in the dHGP group (51.9% vs. 33.0%, respectively, P = 0.020). Patients with the dHGP had significantly longer relapse-free survival (RFS) and overall survival (OS) than those with the non-HGP. The low-risk group showed significantly higher 2-year RFS and 5-year OS rates than the other two groups (RFS: 76.2%, 43.7% and 33.1%, respectively; P < 0.001; OS: 89.7%, 54.4% and 33.3%, respectively; P < 0.001). In conclusion, the dHGP correlates with relatively high immunoscores, predicting a favorable prognosis independent of the immunoscore and CRS. A novel risk score combining HGPs, the immunoscore and the CRS may be used for the stratification of CRLM patients' survival.

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.

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.

Reduced expression of p21-activated protein kinase 1 correlates with poor histological differentiation in pancreatic cancer.

BACKGROUND: P21-activated protein kinase 1 (PAK1), a main downstream effector of small Rho GTPases, is overexpressed in many malignancies. PAK1 overexpression is associated with poor prognosis in some tumor types, including breast cancer, gastric cancer, and colorectal cancer. However, the expression and clinical relevance of PAK1 expression in human pancreatic cancer remains unknown. METHODS: The present study investigated the clinical and prognostic significance of PAK1 expression in pancreatic carcinoma. We examined and scored the expression of PAK1 by immunohistochemistry in 72 primary pancreatic carcinoma samples and 20 liver metastatic samples. The relationships between PAK1 and clinicopathological parameters and prognosis in primary and metastatic pancreatic cancer were analyzed. RESULTS: Among the total 92 cases, primary pancreatic cancer samples had a significantly higher rate (38/72, 52.8%) of high PAK1 expression than liver metastatic samples (5/20, 25.0%) (P=0.028). Among the 72 primary pancreatic cancer patients, high PAK1 expression was associated with younger age (P=0.038) and moderately or well differentiated tumor (P=0.007). Moreover, a positive relationship was found between high PAK1 expression and overall survival (OS) (P<0.005). Patients with high PAK1 expression had a better OS than those with low PAK1 expression. Univariate and multivariate analysis by Cox regression including PAK1 and other prognostic pathological markers demonstrated high PAK1 immunostaining as a prognostic factor for survival in pancreatic cancer patients (P<0.005). CONCLUSIONS: We report for the first time that PAK1 is a novel prognostic marker for pathologically confirmed human pancreatic cancer. Reduced expression of PAK1 correlates with poor histological differentiation in pancreatic cancer.

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.

Is early surveillance with CT scan necessary in patients with stage II/III colorectal cancer: a retrospective study.

BACKGROUND AND OBJECTIVES: This analysis aims to evaluate the value of early surveillance within 6 months after resection for stage II/III colorectal cancer (CRC). METHODS: Patients with stage II/III CRC who received surgery with curative intent for CRC were included. CT scans of the chest, abdomen, and pelvis performed within 6 months after surgery were evaluated. RESULTS: Among 150 patients included in the study, 10 patients (1 occurred in stage II disease and 9 occurred in stage III) were diagnosed as recurrence within 6 months after surgery. The proportion of patients diagnosed as recurrence was significantly higher in stage III disease than in stage II disease (P = 0.01). The likelihood of recurrence within 6 months was associated with the extent of lymph node metastases (r = 0.205, P = 0.012). Three patients with recurrent disease underwent salvage resection with curative intent. CONCLUSIONS: Early surveillance with CT scan within 6 months after curative resection may not be necessary for stage II disease. Although, the strategy may be helpful for stage III disease considering the high incidence of salvage surgery for recurrence disease, the early detection of recurrence could not be translated into survival benefit.

[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.

Glucocorticoid receptor gene polymorphisms and glucocorticoid resistance in inflammatory bowel disease: a meta-analysis.

BACKGROUND: Studies investigating the associations between glucocorticoid receptor gene polymorphisms and glucocorticoid resistance in inflammatory bowel disease report conflicting results. AIMS: We conducted a meta-analysis to assess the possible association between the three most commonly investigated glucocorticoid receptor gene (ER22/23EK, N363S, and BclI) polymorphisms and glucocorticoid resistance in inflammatory bowel disease. METHODS: Articles evaluating the effect of ER22/23EK, N363S, and BclI gene polymorphism on glucocorticoid resistance in inflammatory bowel disease were identified from 1950 to February 2012. After extraction of relevant data, meta-analyses were performed to assess the association between glucocorticoid receptor gene polymorphisms and glucocorticoid resistance in inflammatory bowel disease. RESULTS: A total of five eligible studies with 942 cases were included. Our analysis showed that ER22/23EK polymorphisms were not associated with glucocorticoid resistance in inflammatory bowel disease [GG versus GA + AA: odds ratio (OR) = 0.58, 95 % confidence interval (CI) 0.16-2.08]. In N363S polymorphisms, AG + GG allele showed no significant effect on glucocorticoid resistance in inflammatory bowel disease compared with AA allele (OR = 1.19, 95 % CI 0.33-4.30). In BclI polymorphisms, there was also no association of CG + GG allele with glucocorticoid resistance (CC versus CG + GG: OR = 1.22, 95 % CI 0.70-2.13). For Crohn's disease (CD) and ulcerative colitis (UC), no statistically significant associations between these three single-nucleotide polymorphisms (SNPs) and glucocorticoid resistance were found. The shape of the funnel plot did not detect publication bias. CONCLUSIONS: The current meta-analysis found no evidence that glucocorticoid receptor gene polymorphisms (ER22/23EK, N363S, and BclI) are associated with glucocorticoid resistance in inflammatory bowel disease treatment. However, this meta-analysis is underpowered for relatively large effect sizes in some SNPs. More well-designed cohort studies should be conducted to fully characterize such an association.

Comprehensive profiling of 1015 patients' exomes reveals genomic-clinical associations in colorectal cancer.

The genetic basis of colorectal cancer (CRC) and its clinical associations remain poorly understood due to limited samples or targeted genes in current studies. Here, we perform ultradeep whole-exome sequencing on 1015 patients with CRC as part of the ChangKang Project. We identify 46 high-confident significantly mutated genes, 8 of which mutate in 14.9% of patients: LYST, DAPK1, CR2, KIF16B, NPIPB15, SYTL2, ZNF91, and KIAA0586. With an unsupervised clustering algorithm, we propose a subtyping strategy that classisfies CRC patients into four genomic subtypes with distinct clinical characteristics, including hypermutated, chromosome instability with high risk, chromosome instability with low risk, and genome stability. Analysis of immunogenicity uncover the association of immunogenicity reduction with genomic subtypes and poor prognosis in CRC. Moreover, we find that mitochondrial DNA copy number is an independent factor for predicting the survival outcome of CRCs. Overall, our results provide CRC-related molecular features for clinical practice and a valuable resource for translational research.

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.

Assessment of defecation function after sphincter-saving resection for mid to low rectal cancer: A cross-sectional study.

PURPOSE: Patients with mid-to low-rectal cancer can have various dysfunctions of defecation after sphincter-saving resection. Defecation dysfunction can manifest as incontinence, urgency, or frequent bowel movements, and is called low anterior resection syndrome (LARS). This study aimed to examine LARS score and objective anorectal function indices in Chinese patients receiving sphincter-saving surgery for mid-to low-rectal cancer. METHOD: This was a single-center cross-sectional study of patients undergoing sphincter-saving resection for low- or mid-rectal cancer and had restoration of trans-anal defecation for at least 1 month seen between January 2019 and June 2020. Patients completed a questionnaire regarding clinical characteristics, and Low Anterior Resection Syndrome (LARS) score and high-resolution anorectal manometry (HR-ARM) were used to assess defecation function. Multivariable analysis was used to identify variables significantly associated with defecation dysfunction. RESULTS: 146 patients completed and returned the questionnaires. 25 healthy adults also participated as control group for the anorectal manometry. Approximately 76% of patients developed LARS after surgery, of which 35.6% had major LARS. In these patients, anorectal manometry indices including initial rectal sensory capacity and rectal fecal sensory capacity, were significantly lower than normal. Logistic regression analysis showed that preoperative chemo-radiotherapy and the tumor inferior margins being close to the dentate line, especially 2-5 cm, were independent risk factors for defecation dysfunction after surgery. CONCLUSIONS: Defecation dysfunction is a frequent occurrence after sphincter-saving resection for mid- and low-rectal cancer. Preoperative chemo-radiotherapy and a shorter tumor inferior margins distance to the dentate line are independent factors for defecation dysfunction.

The watch-and-wait strategy versus surgical resection for rectal cancer patients with a clinical complete response after neoadjuvant chemoradiotherapy.

BACKGROUND: The watch-and-wait strategy offers a non-invasive therapeutic alternative for rectal cancer patients who have achieved a clinical complete response (cCR) after chemoradiotherapy. This study aimed to investigate the long-term clinical outcomes of this strategy in comparation to surgical resection. METHODS: Stage II/III rectal adenocarcinoma patients who received neoadjuvant chemoradiotherapy and achieved a cCR were selected from the databases of three centers. cCR was evaluated by findings from digital rectal examination, colonoscopy, and radiographic images. Patients in whom the watch-and-wait strategy was adopted were matched with patients who underwent radical resection through 1:1 propensity score matching analyses. Survival was calculated and compared in the two groups using the Kaplan-Meier method with the log rank test. RESULTS: A total of 117 patients in whom the watch-and-wait strategy was adopted were matched with 354 patients who underwent radical resection. After matching, there were 94 patients in each group, and no significant differences in term of age, sex, T stage, N stage or tumor location were observed between the two groups. The median follow-up time was 38.2 months. Patients in whom the watch-and-wait strategy was adopted exhibited a higher rate of local recurrences (14.9% vs. 1.1%), but most (85.7%) were salvageable. Three-year non-regrowth local recurrence-free survival was comparable between the two groups (98% vs. 98%, P = 0.506), but the watch-and-wait group presented an obvious advantage in terms of sphincter preservation, especially in patients with a tumor located within 3 cm of the anal verge (89.7% vs. 41.2%, P < 0.001). Three-year distant metastasis-free survival (88% in the watch-and-wait group vs. 89% in the surgical group, P = 0.874), 3-year disease-specific survival (99% vs. 96%, P = 0.643) and overall survival (99% vs. 96%, P = 0.905) were also comparable between the two groups, although a higher rate (35.7%) of distant metastases was observed in patients who exhibited local regrowth in the watch-and-wait group. CONCLUSION: The watch-and-wait strategy was safe, with similar survival outcomes but a superior sphincter preservation rate as compared to surgery in rectal cancer patients achieving a cCR after neoadjuvant chemoradiotherapy, and could be offered as a promising conservative alternative to invasive radical surgery.

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.

Length of lymphangiogenesis in the rectal tissues distal to rectal cancer.

To investigate the length of lymphangiogenesis in the rectal tissue distal to a rectal cancer and its effect on the resection margins of the rectum, 63 specimens of normal rectal tissue distal to the tumor were collected from the surgical resections of ten rectal cancer patients. The specimens were taken at 0.5-cm intervals between the distal end of tumor and the distal surgical margin. The mean amount of collected tissue in each patient was 6.3. The expression of VEGFR-3 and Prox1 was measured in the specimens using real-time quantitative reverse transcription polymerase chain reaction. VEGFR-3 and Prox1 were expressed in all harvested tissues. There was a reduction of expression of VEGFR-3 (nine cases) and Prox1 (ten cases) from tissue adjacent to the rectal tumor to the distal resection margin of the rectum. A downward slope of the expression levels of VEGFR-3 and Prox1 in all cases was found at less than 3.0 cm distal to the tumor. The median VEGFR-3 expression level in the tissues within 1.5 cm adjacent to the rectal cancer was higher than in those tissues beyond 1.5 cm (P = 0.024). The median Prox1 expression level in the tissues within 1.0 cm distal to the rectal cancer was higher than in those tissues beyond 1.0 cm (P = 0.003). Lymphangiogenesis may facilitate the mural spread of cancer cells. The length of development of new lymphatics in the rectal wall distal to a rectal cancer may be less than 3.0 cm. Resection of a rectal cancer should routinely include 3.0 cm distal to the tumor to ensure adequate excision of tissue subject to lymphangiogenesis and potential mural spread of the tumor.

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.