Pan-cancer analysis of Sushi domain-containing protein 4 (SUSD4) and validated in colorectal cancer.

Sushi domain-containing protein 4 (SUSD4) is a complement regulatory protein whose primary function is to inhibit the complement system, and it is involved in immune regulation. The role of SUSD4 in cancer progression has largely remained elusive. SUSD4 was studied across a variety of cancer types in this study. According to the results, there is an association between the expression level of SUSD4 and prognosis in multiple types of cancer. Further analysis demonstrated that SUSD4 expression level was related to immune cell infiltration, immune-related genes, tumor heterogeneity, and multiple cancer pathways. Additionally, we validated the function of SUSD4 in colorectal cancer cell lines and found that knockdown of SUSD4 inhibited cell growth and impacted the JAK/STAT pathway. By characterizing drug sensitivity in organoids, we found that the expression of SUSD4 showed a positive correlation trend with IC50 of Selumetinib, YK-4-279, and Piperlongumine. In conclusion, SUSD4 is a valuable prognostic indicator for diverse types of cancer, and it has the potential to be a target for cancer therapy.

Perineural and lymphovascular invasion predicts for poor prognosis in locally advanced rectal cancer after neoadjuvant chemoradiotherapy and surgery.

Background: Perineural invasion (PNI) and lymphovascular invasion (LVI) are associated with poor prognosis in colorectal cancer, but their clinical significance is still controversial for patients with locally advanced rectal cancer (LARC) who had received neoadjuvant chemoradiotherapy (nCRT) and surgical resection. The aim of this study was to confirm the correlation between PNI and/or LVI and clinical prognosis and to further confirm whether PNI and/or LVI can be used as potential prognostic indicators of adjuvant chemotherapy after nCRT and surgery in LARC. Methods: From February 2002 to December 2012, a total of 181 patients with LARC who had received nCRT and surgical resection were retrospectively reviewed. Overall survival (OS) and disease-free survival (DFS) were determined by the Kaplan-Meier method, log-rank test, and Cox proportional hazard regression model. Results: The median follow-up time was 48 months (range, 3 to 162 months). All the PNI-positive and/or LVI-positive patients showed adverse DFS and OS (P<0.001). In multivariate analysis, PNI and LVI were independent prognostic factors for DFS. PNI, rather than LVI, was also an independent prognostic factor for OS. In a subgroup analysis, PNI-positive, rather than LVI-positive, may benefit from adjuvant chemotherapy. Conclusion: For patients with LARC undergoing nCRT and surgery, PNI-positive and/or LVI positive were associated with poorer DFS and OS. And PNI-positive, rather than LVI-positive, may benefit from adjuvant chemotherapy.

Knockdown of MON1B Exerts Anti-Tumor Effects in Colon Cancer In Vitro.

BACKGROUND Colon cancer is one of the most common cancers in the world. We performed the present study to determine the molecular mechanism of MON1B in colon cancer cells. MATERIAL AND METHODS Colon cancer tissues and adjacent normal tissues were collected from 34 colon cancer patients. MON1B-silenced LoVo colon cancer cells were constructed. RT-qPCR and Western blot analysis were used to detect mRNA and protein levels, respectively, of colon cancer tissues and cells. Cell counting kit-8 (CCK-8), wound healing, and Transwell assays were used to detect viability, migration, and invasion, respectively, of colon cancer cells. RESULTS The mRNA and protein levels of MON1B were higher in colon cancer tissues and human colon cancer cell lines (HT-29, SW480, COLO205, LoVo). Cell proliferation, migration, and invasion abilities were all inhibited when MON1B was silenced in LoVo colon cancer cells. Both the mRNA and protein levels of tissue inhibitor of metalloproteinase (TIMP)-2 and iκB were increased, while that of matrix metalloproteinases (MMP)-2, MMP-9, metastasis-associated genes (MTA)-1, nuclear factor-kappa B (NF-κB), and chemokine receptor type (CXCR)-4 was decreased when MON1B was silenced. CONCLUSIONS MON1B interference exerted anti-tumor effect in colon cancer in vitro.

Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy.

BACKGROUND Increasing evidence suggests that cancer-associated inflammation is associated with poorer outcomes. The neutrophil-to-lymphocyte ratio (NLR), considered as a systemic inflammation marker, is thought to predict prognoses in colorectal cancer. In this study, we explored the association between the NLR and prognoses following neoadjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC). MATERIAL AND METHODS From February 2002 to December 2012, a group of 202 patients diagnosed with LARC and receiving neoadjuvant CRT followed by radical surgery was included in our retrospective study. The associations between the pre-CRT NLR and clinicopathological characteristics, as well as the predictive value of pre-CRT NLR against survival outcomes, were analyzed. RESULTS The average NLR was 2.7±1.5 (median 2.4, range 0.6-12.8). There were 63 (31.2%) patients with NLR ≥3.0, and 139 (68.8%) patients with NLR <3.0. Correlation analyses showed that no clinicopathological characteristics except age were associated with NLR. We did not find an association between NLR and survival outcomes. In multivariate Cox model analyses, the R1/R2 resection, lymph node ratio ≥0.1, and perineural/lymphovascular invasion were independently associated with worse disease-free survival and overall survival. CONCLUSIONS In our cohort, the NLR did not correlate with survival outcomes in LARC patients undergoing neoadjuvant CRT. The prognostic value of NLR should be validated in large-scale prospective studies.

Factors Predicting Difficulty of Laparoscopic Low Anterior Resection for Rectal Cancer with Total Mesorectal Excision and Double Stapling Technique.

BACKGROUND: Laparoscopic sphincter-preserving low anterior resection for rectal cancer is a surgery demanding great skill. Immense efforts have been devoted to identifying factors that can predict operative difficulty, but the results are inconsistent. OBJECTIVE: Our study was conducted to screen patients' factors to build models for predicting the operative difficulty using well controlled data. METHOD: We retrospectively reviewed records of 199 consecutive patients who had rectal cancers 5-8 cm from the anal verge. All underwent laparoscopic sphincter-preserving low anterior resections with total mesorectal excision (TME) and double stapling technique (DST). Data of 155 patients from one surgeon were utilized to build models to predict standardized endpoints (operative time, blood loss) and postoperative morbidity. Data of 44 patients from other surgeons were used to test the predictability of the built models. RESULTS: Our results showed prior abdominal surgery, preoperative chemoradiotherapy, tumor distance to anal verge, interspinous distance, and BMI were predictors for the standardized operative times. Gender and tumor maximum diameter were related to the standardized blood loss. Temporary diversion and tumor diameter were predictors for postoperative morbidity. The model constructed for the operative time demonstrated excellent predictability for patients from different surgeons. CONCLUSIONS: With a well-controlled patient population, we have built a predictable model to estimate operative difficulty. The standardized operative time will make it possible to significantly increase sample size and build more reliable models to predict operative difficulty for clinical use.

Increased expression of FERM domain-containing 4A protein is closely associated with the development of rectal cancer.

The aim of the present study was to detect the expression levels of FERM domain-containing 4A (FRMD4A) in rectal cancer tissues and peripheral blood and to investigate the correlation between FRMD4A and cancer development. A total of 78 consecutive patients were enrolled in this study. Thirty healthy individuals were used as the control group. The expression of FRMD4A in rectal cancer and the corresponding normal adjacent tissues was detected by immunohistochemistry and western blotting. The expression of FRMD4A mRNA in peripheral blood was detected by reverse transcription-quantitative polymerase chain reaction. The expression of FRMD4A in rectal cancer tissues was found to be negatively correlated with the degree of differentiation, depth of invasion and Dukes' stage. A negative correlation was identified between FRMD4A and epithelial cadherin expression. The expression of FRMD4A in the peripheral blood of patients with rectal cancer was significantly increased compared with that in the control group (P<0.05). Expression of FRMD4A in the peripheral blood in the patients with lymph node metastasis was significantly increased compared with that in the patients without lymph node metastasis (P<0.05). These results indicate that the expression of FRMD4A is significantly increased in rectal cancer tissues and the peripheral blood of patients with rectal cancer, and the expression levels of FRMD4A are closely associated with differentiation, invasion of rectal cancer and Dukes' stage. In conclusion, the findings of the present study suggest that FRMD4A may be used as a target for the diagnosis and treatment of rectal cancer.

[Expression difference of DNA mismatch repair gene hMLH1 and hMSH2 between schistosomiasis-associated colorectal cancer and sporadic colorectal cancer].

OBJECTIVE: To investigate the expression difference of DNA mismatch repair gene hMLH1 and hMSH2 between schistosomiasis-associated colorectal cancer and sporadic colorectal cancer. METHOD: Clinical and pathological data of colorectal cancer patients receiving operations in Zhejiang Cancer Hospital between January 2008 and December 2010 were retrospectively analyzed. Patients were divided into schistosomiasis group(n=80) and sporadic group (n=258) according to the preoperative history and pathologic results. Pathological specimens were collected and tissue chips were made to analyze the expression of hMLH1 and hMSH2 by immunohistochemistr. RESULTS: Compared with sporadic group, older age [(62.2 ± 9.6) year vs. (57.2 ± 11.7) year, P=0.000)], lower platelet level [(197.0 ± 59.6) × 10(9)/L vs. (217.0 ± 84.3) × 10(9)/L, P=0.02] and lower WBC level [(5.9 ± 1.9) × 10(9)/L vs. (6.6 ± 2.8) × 10(9)/L, P=0.02] were found in schistosomiasis group. Ratio of low differentiation-undifferentiation tumor was significantly higher in schistosomiasis group [44.2% (34/77) vs. 4.9% (12/247), P<0.05]. Lower positive rate of hMLH1 expression [77.5% (62/80) vs. 98.1% (253/258), P=0.000] and hMSH2 expression [75.0% (60/80) vs. 95.3% (246/258), P=0.000] was found in schistosomiasis group compared with sporadic group. Concurrent schistosomiasis was one of the risk factors of hMLH1/hMSH2 deficiency (RR: 0.913, 95% CI: 0.836-0.997, P=0.043), but not an independent factor (RR: 0.951, 95% CI: 0.867-1.043, P=0.286). CONCLUSION: Schistosomiasis is associated with lower positive expression of hMLH1 and hMSH2, which indicates that hMLH1/hMSH2 deficiency may be a potential mechanism of schistosomiasis inducing carcinogenesis of colorectal cancer.

Comparison of perioperative outcomes between laparoscopic and open surgery for mid-low rectal cancer with total mesorectal excision following neoadjuvant chemoradiotherapy.

OBJECTIVE: The objective of our study was to determine the feasibility and safety of laparoscopic total mesorectal excision (TME) for mid-low rectal cancer following neoadjuvant chemoradiotherapy (nCRT). METHODS: We retrospectively reviewed the records of 172 patients with locally advanced rectal cancer who underwent laparoscopic (n = 75) or conventional open (n = 97) surgery with TME following nCRT from June 2009 to October 2015. Perioperative outcomes and related clinical variables were collected and statistically analyzed. RESULTS: Our results showed that patients who underwent laparoscopic surgery had significantly less blood loss and shorter time to pass first flatus and to start a liquid diet compared to those on open surgery. However, other perioperative outcomes, including operative times, postoperative morbidity rates, number of lymph nodes harvested, and sphincter preservation rates, were not significantly different between the two groups. After controlling for surgical approaches, we found that age, gender, tumor stages, and tumor distance to anal verge were significantly correlated with operative times in both groups. Likewise, age, body mass index, tumor T stages, and tumor distance to anal verge were predictors for postoperative morbidity in both groups. CONCLUSIONS: We concluded that laparoscopic TME following nCRT is feasible and safe for patients with mid-low rectal cancer. Furthermore, tumor distance to anal verge and age are two important determinants of both operative times and postoperative morbidity, regardless of surgical option.

Prospective phase II trial of nimotuzumab in combination with radiotherapy and concurrent capecitabine in locally advanced rectal cancer.

PURPOSE: The aim of the study was to evaluate the safety and efficacy of adding concurrent nimotuzumab to preoperative radiotherapy with concurrent capecitabine in locally advanced rectal cancer. METHODS AND MATERIALS: Patients with rectal cancer (clinical stage T3/4 or N+) were scheduled to receive weekly nimotuzumab (400 mg; days -6, 1, 8, 15, 22, and 29). Capecitabine (825 mg/m(2)) was delivered orally twice daily for the duration of radiotherapy. Radiotherapy was administered at 50.4 Gy (45 + 5.4 Gy). The main endpoint was the pathologic complete response (pCR) rate. RESULTS: Twenty-one patients with T3 or T4 disease were enrolled; 66.7 % were nodal-positive; the median distance from the anal verge was 5.5 cm. A pCR was achieved in four patients (19.0 %); 71.4 % patients obtained moderate or good tumor regression (Grade 2 and 3). Downstaging occurred in 15/21 (71.4 %) patients by T stage and 11/14 (78.6 %) by N stage. The actual dose intensities (median/mean, %) were nimotuzumab (100, 100) and capecitabine (100, 99.5). The most frequent Grade 1/2 toxicities were radiation dermatitis (57.1 %), nausea/vomiting (52.4 %), leukocytopenia (47.6 %), diarrhea (47.6 %), and proctitis (38.1 %). Grade 3 diarrhea was observed in 9.5 % of patients and Grade 3 leukocytopenia in 4.8 %. CONCLUSION: These preliminary results indicate that nimotuzumab can be safely combined with radiotherapy plus concurrent capecitabine. The efficacy of this regimen (pCR = 19.0 %) was significantly higher than that observed in previous phase II trials of preoperative radiotherapy with concurrent capecitabine and cetuximab in rectal cancer. Further investigation of concurrent nimotuzumab with radiotherapy plus capecitabine is warranted.

[Prognostic significance of metastatic lymph node ratio in colorectal cancer].

OBJECTIVE: To investigate the prognostic significance of metastatic lymph node ratio in patients with colorectal cancer. METHODS: The clinicopathological data of 303 surgically treated patients with colorectal cancer were retrospectively analyzed. Spearman correlation analysis was used to determine the correlation coefficient. The survival was analyzed using Kaplan-Meier method, and the survival difference was assessed by Log-rank test. Multivariate analysis was performed using Cox proportional hazard regression model in forward stepwise regression. Receiver working characteristic curve was used to compare the accuracy of the metastatic lymph nodes ratio in predicting the death of patients at 5 years postoperatively with that of the number of metastatic lymph nodes. RESULTS: The MLR was not correlated with the total number of dissected lymph nodes (Spearman correlation coefficient: -0.099, P > 0.05), but the positive rate of metastatic lymph nodes did (correlation coefficient: 0.107, P < 0.05). Kaplan-Meier survival analysis revealed that the MLR significantly influenced the postoperative survival time (Log-rank chi(2) = 42.878, P < 0.01), even in the patients with less than 12 resected lymph nodes. The 5-year survival rates for rN0, rN1, rN2 and rN3 were 90.9%, 68.9%, 54.7% and 39.4%, respectively. There was a significant difference between the different stages (P < 0.01). Cox proportional hazard regression model analysis showed that the metastatic lymph node ratio was an independent prognostic factor. (EXP(B) = 7.809, P < 0.01). There was no significant difference between metastatic lymph node ratio and the number of metastatic lymph nodes in predicting the death of patients at 5 years postoperatively based on the area under the receiver working characteristic curve. CONCLUSION: The metastatic lymph node ratio in colorectal cancer patients is not correlated with the total number of dissected lymph nodes. The metastatic lymph node ratio is a major independent prognostic factor for patients with colorectal cancer. The ability of metastatic lymph node ratio in predicting the death of colorectal cancer patients at 5 years postoperatively is the same as that of the number of metastatic lymph nodes.

[Differential expression of guanylin in colorectal cancer].

OBJECTIVE: To investigate the expression of guanylin in colorectal cancer. METHODS: The expression of guanylin was examined by RT-PCR and semiquantitative analysis in 20 cases of colorectal cancer, and its relationship with clinical characteristics was analyzed. RESULTS: The positive expression of guanylin in normal tissue (80%, 16/20) was significantly higher than that in tumor tissue (35%, 7/20) (P<0.01). The same result was found in the semiquantitative analysis of 14 cases with differential expression. Differential expression of guanylin in colorectal cancer was associate with TNM stage (P<0.05), not with sex, Borrmann type and degree of differentiation (all P>0.05). CONCLUSION: There is differential expression of guanylin in colorectal cancer, and this kind of differential expression is associated with tumor TNM stage.