Hongtu Zheng

Higher FOXP3-TSDR demethylation rates in adjacent normal tissues in patients with colon cancer were associated with worse survival.

BackgroundThe influence of natural regulatory T cells (nTregs) on the patients with colon cancer is unclear. Demethylated status of the Treg-specific demethylated region (TSDR) of the FOXP3 gene was reported to be a potential biomarker for the identification of nTregs.MethodsThe demethylation rate of the TSDR (TSDR-DMR) was calculated by using methylation-specific quantitative polymerase chain reaction (MS-qPCR) assay. The expression of TSDR-DMR and FOXP3 mRNA was investigated in various colorectal cancer cell lines. A total of 130 colon carcinoma samples were utilized to study the DMR at tumor sites (DMRT) and adjacent normal tissue (DMRN). The correlations between DMRs and clinicopathological variables of patients with colon cancer were studied.ResultsThe TSDR-DMRs varied dramatically among nTregs (97.920 ± 0.466%) and iTregs (3.917 ± 0.750%). Significantly, DMRT (3.296 ± 0.213%) was higher than DMRN (1.605 ± 0.146%) (n = 130, p = 0.000). Higher DMRN levels were found in female patients (p = 0.001) and those with distant metastases (p = 0.017), and were also associated with worse recurrence-free survival in non-stage IV patients (low vs. high, p = 0.022). However, further Cox multivariate analysis revealed that the FOXP3-TSDR status does not have prognostic value.ConclusionMS-qPCR assays of FOXP3-TSDR can efficiently distinguish nTregs from non-nTregs. Abnormal recruitment of nTregs occurs in the local tumor microenvironment. Infiltration of tissue-resident nTregs may have a negative role in anti-tumor effects in patients with colon cancer; however, this role is limited and complicated.

Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict chemotherapy outcomes and prognosis in patients with colorectal cancer and synchronous liver metastasis

BackgroundRecent evidence indicates that inflammatory parameters could be useful to predict metastasis from colorectal cancer. However, their roles in predicting chemotherapy response and prognosis in patients with synchronous colorectal liver metastasis (CLM) are unknown.MethodsThe clinical data and baseline laboratory parameters of 55 patients with synchronous CLM were retrospectively reviewed. All patients underwent palliative resection of the primary tumor and oxaliplatin-based chemotherapy. Two indices of systemic inflammation were reviewed—neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—preoperatively and before the second cycle of chemotherapy. Associations between prognostic variables and tumor response, progression, and survival were investigated.ResultsNLR < 4 and PLR < 150 were correlated with better disease control (p = 0.024 and 0.026, respectively). In univariate analysis, elevated NLR and PLR were significant prognostic factors for poor overall survival (OS) and progression-free survival (PFS). In multivariate analysis, PLR (p = 0.027), age (p = 0.018), resection of liver metastases (p = 0.017), and lactate dehydrogenase level (p = 0.011) were independent predictors of PFS, while resection of liver metastases was the only independent predictor of OS (p = 0.002). In addition, when patients were divided into groups according to changes in NLR and/or PLR, reduced NLR and PLR were associated with improved disease control (p = 0.038 and 0.025, respectively). Normalization of NLR also was associated with improved PFS.ConclusionsNLR and PLR are potentially useful clinical biomarkers to predict chemotherapy response in patients with synchronous CLM. PLR also may be useful to predict PFS in these patients.

Lymph node count after preoperative radiotherapy is an independently prognostic factor for pathologically lymph node-negative patients with rectal cancer

AbstractRecent studies indicated that preoperative radiotherapy significantly reduces the lymph nodes (LNs) harvest from patients with rectal cancer. This may weaken the prognostic value of current standard of LNs retrieval (≥12 LNs). This study investigates the prognostic impact of the LN counts on pathologically LN-negative (ypN0) after preoperative radiotherapy for patients with rectal cancer.Surveillance, Epidemiology and End Results (SEER) registered nonmetastatic rectal cancer patients diagnosed between 1998 and 2005 were included in this study. Optimal cutoff value for number of LNs retrieved was determined by X-tile program. Log-rank tests were adopted to compare the rectal cause specific survival (RCSS) for ypN0 patients using separated cutoff value of LN counting from 2 to 20. Correlation between LN count and tumor regression was investigated in an additional 221 patients from Fudan University Shanghai Cancer Center (FUSCC).The results showed that there were fewer number of LNs examined in patients with preoperative radiotherapy than those without (8.9 vs 10.9, P < 0.001). X-tile program identified the difference in survival was most significant (maximum of &khgr;2 log-rank values) for the number 4. And 5-year RCSS increased accordingly with the cutoff values ranging from 4 to 15, which were confirmed as optimal cutoff and validated as independent prognostic factors in multivariate regression analysis (&khgr;2 = 50.65, P < 0.001). Patients in FUSCC set were found to have fewer LNs retrieval in group of good tumor regression than in that of poor one (P = 0.01).These results confirmed the reduced number of LN retrieval in patients with rectal cancer treated with preop-RT. LN count is still an independently prognostic factor for ypN0 rectal cancer.

Pathological features and survival outcomes of young patients with operable colon cancer: Are they homogeneous?

Objective To compare the pathological features and survival outcomes at different age subgroups of young patients with colon cancer. Methods Using Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 2,861 young patients with colon cancer diagnosed between 1988 and 2005 treated with surgery. Patients were divided into four groups: group 1 (below 25 years), group 2 (26–30 years), group 3 (31–35 years) and group 4 (36–40 years). Five-year cancer specific survival data were obtained. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors. Results There were significant different among four groups in pathological grading, histological type, AJCC stage, current standard (≥12 lymph nodes retrieval), mean number of lymph nodes examined and positive lymph nodes (p<0.001). The 5-year cause specific survival was 71.0% in group 1, 75.1% in group 2, 80.6% in group 3 and 82.5% in group 4, which had significant difference in both univariate (P = 0.002) and multivariate analysis (P = 0.041). Conclusions Young patients with colon cancer at age 18–40 years are essentially a heterogeneous group. Patients at age 31–35, 36–40 subgroups have more favorable clinicopathologic characteristics and better cancer specific survival than below 30 years.

CapOX as neoadjuvant chemotherapy for locally advanced operable colon cancer patients: A prospective single-arm phase II trial

Objective The aim of this prospective, single-arm phase II trial was to confirm the safety and efficacy of neoadjuvant chemotherapy (NAC) using oxaliplatin plus capecitabine (CapOX) for patients with operable locally advanced colon cancer (CC). Methods Patients with computed tomography-defined T4 or lymph node-positive CCs were enrolled. After radiological staging, patients were treated with at least 2 cycles of NAC consisting of 130 mg/m2 oxaliplatin on d 1, plus 1,000 mg/m2 capecitabine twice daily for 14 d every 3 weeks, followed by surgery, and then with the rest cycles of adjuvant chemotherapy. Radiological response was evaluated after 2 cycles of NAC. Tumor response, treatment toxicity, and surgical complications were recorded. The pathological response to therapy was evaluated according to the tumor regression grade (TRG) score. The primary endpoint was pathologic tumor response. This trial is registered in ClinicalTrials.gov (No: NCT02415829). Results Forty-seven patients were enrolled in the study. Forty-two patients completed the planned treatments. The total radiological response rate was 68% (32/47), including complete and partial response rates of 2% (1/47) and 66% (31/47), respectively. Stable disease was observed in 32% (15/47) and progressive disease was observed in none. Complete pathologic response, major regression, and at least moderate regression were achieved in 1 (2%), 2 (4%), and 29 (62%) patients, respectively. Four patients developed grade 3 treatment toxicities. One patient with wound infection occurred after operation (1/47, 2%). There was no treatment-related death. Conclusions Our results suggest that NAC with CapOX is an effective and safe treatment option for patients with locally advanced CCs.

Rectovaginal fistula after low anterior resection in Chinese patients with colorectal cancer

Rectovaginal fistula is a postoperative complication of low anterior resection. We investigated the incidence of rectovaginal fistula (RVF) after low anterior resection, its risk factors and its optimal treatment. We analyzed data from 1,493 female patients who underwent low anterior resection for colorectal cancer between January 2006 and March 2016. We calculated the incidence of RVF and performed univariate and multivariate logistic regression analyses to identify risk factors. Twenty-four patients experienced RVF, giving an incidence of 1.61%. Univariate analysis revealed a short distance between the tumor and the anal verge (p < 0.001), longer surgery duration (p = 0.009), unsatisfactory anastomosis (p < 0.001), and greater intraoperative blood loss (p = 0.002) to be risk factors for RVF. Multivariate analysis showed that only distance between the tumor and the anal verge and unsatisfactory anastomosis were risk factors for RVF. Sixteen patients (66.7%) healed within a range of 30-1,225 days (median, 210 days). Twenty-one patients underwent surgery for diverting stoma; of those, 15 of them (71.4%) recovering after ostomy. These results indicate the primary risk factors for RVF are unsatisfactory anastomosis and short distance between the tumor and the anal verge. Most cases of RVF can be healed using a diverting stoma alone, without the need for additional surgery.Rectovaginal fistula is a postoperative complication of low anterior resection. We investigated the incidence of rectovaginal fistula (RVF) after low anterior resection, its risk factors and its optimal treatment. We analyzed data from 1,493 female patients who underwent low anterior resection for colorectal cancer between January 2006 and March 2016. We calculated the incidence of RVF and performed univariate and multivariate logistic regression analyses to identify risk factors. Twenty-four patients experienced RVF, giving an incidence of 1.61%. Univariate analysis revealed a short distance between the tumor and the anal verge (p < 0.001), longer surgery duration (p = 0.009), unsatisfactory anastomosis (p < 0.001), and greater intraoperative blood loss (p = 0.002) to be risk factors for RVF. Multivariate analysis showed that only distance between the tumor and the anal verge and unsatisfactory anastomosis were risk factors for RVF. Sixteen patients (66.7%) healed within a range of 30-1,225 days (median, 210 days). Twenty-one patients underwent surgery for diverting stoma; of those, 15 of them (71.4%) recovering after ostomy. These results indicate the primary risk factors for RVF are unsatisfactory anastomosis and short distance between the tumor and the anal verge. Most cases of RVF can be healed using a diverting stoma alone, without the need for additional surgery.

Silencing of long non-coding RNA SBDSP1 suppresses tumor growth and invasion in colorectal cancer

Long non-coding RNAs (lncRNAs) play critical roles in tumor development and progression. This study was undertaken to examine the expression and biological functions of a novel lncRNA SBDSP1 in colorectal cancer (CRC). Quantitative real-time PCR analysis was used to measure the expression of SBDSP1 in CRC tissues and cell lines. Knockdown of SBDSP1 via short hairpin RNA technology was performed to determine the roles of SBDSP1 in CRC cell growth, colony formation, cell cycle progression, migration, and invasion. The effect of SBDSP1 knockdown on tumorigenesis of CRC cells was investigated in a subcutaneous tumor mouse model. Western blot analysis was done to examine the involvement of signaling pathways in the action of SBDSP1. Notably, SBDSP1 was overexpressed in CRC tissues and cells relative to corresponding normal controls. Moreover, SBDSP1 expression was significantly greater in CRCs with nodal metastasis than in primary tumors (P=0.0259). Downregulation of SBDSP1 significantly inhibited cell proliferation, colony formation, migration, and invasion in SW480 and HCT116 cells, which was accompanied by suppression of Akt, ERK1/2, and STAT3 phosphorylation. SBDSP1-depleted cells showed a G0/G1 cell cycle arrest and deregulation of p21 and cyclin D1. In vivo studies confirmed that SBDSP1 downregulation retarded the growth of HCT116 xenogaft tumors. Altogether, SBDSP1 plays an essential role in CRC cell growth, invasion, and tumorigenesis, largely through inactivation of multiple signaling pathways. Therefore, targeting SBDSP1 may have therapeutic benefits in the treatment of CRC.

Risk factors of synchronous inguinal lymph nodes metastasis for lower rectal cancer involving the anal canal.

Purpose The aim of the study is to identify the risk factors of synchronous ILN metastasis for lower rectal cancer involving the anal canal. Methods Patients with lower rectal cancer who underwent radical resection at the Fudan University Shanghai Cancer Center were retrospectively analyzed. The synchronous ILN metastasis was defined as the metastasis occurring within 6 months after the diagnosis of rectal cancer. Patients’ gender, age, tumor diameter, dentate line invasion, differentiation level, histological type, depth of invasion, perirectal LN metastasis, lymphovascular invasion or perineural invasion were analyzed in the study. The correlation between synchronous ILN involvement and clinicopathological features were analyzed with Chi-square test/fisher’s exact test. Variables with p<0.05 in univariate analysis were then analyzed in a multivariate logistic model. Odds ratio (OR) along with 95% confidence intervals (95% CI) were calculated. Results A total of 325 patients (182 men and 143 women) with lower rectal cancer met the criteria and were enrolled in the study. Among them, 20 patients (6.2%) had synchronous ILN metastasis. Both univariate and multivariate analysis showed the invasion of the dentate line had a strong correlation with synchronous ILN metastasis with the odds ratio (OR) of 23.558 [95% confidence interval (CI) 6.380–86.982] (p<0.001). The presence of lymphovascular invasion also showed a significant correlation synchronous ILN metastasis with odds ratio (OR) of 5.260 [95% confidence interval (CI) 1.818–15.212] (p = 0.002). Conclusions The invasion of dentate line and lymphovascular invasion are two independent risk factors of inguinal lymph node metastasis for lower rectal cancer involving the anal canal.

Temporary Diverting Stoma Improves Recovery of Anastomotic Leakage after Anterior Resection for Rectal Cancer

Temporary diverting stoma might be a protective factor for the prevention of anastomotic leakage (AL) after anterior resection. Its role in leakage recovery is unknown. This study aimed to evaluate the effect of temporary diverting stoma on anastomotic leakage severity and recovery. We analyzed 323 patients who underwent anterior resection for rectal cancer and developed anastomotic leakage, in which 44 had temporary diverting stoma. Association between diverting stoma and occurrence of anastomotic leakage, recovery time, length of hospital stay, overall costs, local and distant relapse-free survival were further studied. In non-severe AL group, temporary diverting stoma improved leakage recovery by 4 days (mean: 20.7 days vs. 16.1 days, p = 0.031), especially in patients who did not receive neoadjuvant treatment (mean time: 20.9 days vs. 14.4 days, p = 0.016). However, it did not delay the occurrence of anastomotic leakage. Moreover, no significant difference was found in the overall length of hospital stay and costs among patients with versus without a diverting stoma. In severe AL group, however, no difference was detected. The advantage of shortened leakage recovery did not reduce the local and distant relapse-free survival. In conclusion, our findings indicated the recovery benefit from diverting stoma in patients with anterior resection.

A study of peritoneal metastatic xenograft model of colorectal cancer in the treatment of hyperthermic intraperitoneal chemotherapy with Raltitrexed

Peritoneal metastasis of colorectal cancer is one of the most incident and fateful diseases among relapse cases. It shows a certain resistance to systemic chemotherapy. The perfusion system in clinic is complex and hard to be used in fundamental researches. This study aims at evaluating the effect of an improved hyperthermic intraperitoneal chemotherapy with Raltitrexed used in tumor-bearing mice with peritoneal metastatic colorectal carcinoma. The results showed that no severe adverse effect was observed. All control animals developed extensive peritoneal and mesenteric metastatic nodes. Tumor sites in the treatment groups were reduced significantly. The administration dose of Raltitrexed influenced concentration in systemic blood and peritoneal tissues. Temperature promoted the intracellular absorption of Raltitrexed significantly. Our findings reveal that hyperthermic intraperitoneal chemotherapy is an efficient therapy in treating peritoneal metastatic carcinoma in nude mice. It can effectively reduce the extension of carcinoma cells from macro and micro examination. The combination of hyperthermia and Raltitrexed resulted in an improved therapeutic effect on animal models.