Yanwu Sun

A nomogram predicting pathological complete response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer: implications for organ preservation strategies

PURPOSE To determine predictors of pathological complete response (pCR) in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), and develop a predictive nomogram. METHODS A total of 522 locally advanced rectal cancer patients undergoing nCRT and curative resection between 2008 and 2014 were included. Uni- and multivariate analysis was performed to identify predictors of pCR. A nomogram was developed and validated by internal (n=425) and external validation (n=97). RESULTS With a median follow-up of 55 months, pCR was associated with better 5-year overall and disease-free survival, distant control, but similar local control. Logistic regression showed that post-CRT distance from the anal verge (OR =0.840, P = 0.022), post-CRT tumor size (OR = 0.565, P = 0.003), post-CRT circumferential extent of tumor (OR = 0.021, P < 0.001), pre-CRT CEA level (OR = 2.004, P = 0.033), and post-CRT CEA level (OR = 3.767, P = 0.038) were independently associated with pCR. A nomogram was developed with a C-index of 0.81 and 0.75 on internal and external validation, respectively. CONCLUSION pCR was associated with better long-term outcome. A nomogram was successfully developed to predict pCR. It could support decision-making in organ preservation strategies.Purpose To determine predictors of pathological complete response (pCR) in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), and develop a predictive nomogram. Methods A total of 522 locally advanced rectal cancer patients undergoing nCRT and curative resection between 2008 and 2014 were included. Uni- and multivariate analysis was performed to identify predictors of pCR. A nomogram was developed and validated by internal (n=425) and external validation (n=97). Results With a median follow-up of 55 months, pCR was associated with better 5-year overall and disease-free survival, distant control, but similar local control. Logistic regression showed that post-CRT distance from the anal verge (OR =0.840, P = 0.022), post-CRT tumor size (OR = 0.565, P = 0.003), post-CRT circumferential extent of tumor (OR = 0.021, P < 0.001), pre-CRT CEA level (OR = 2.004, P = 0.033), and post-CRT CEA level (OR = 3.767, P = 0.038) were independently associated with pCR. A nomogram was developed with a C-index of 0.81 and 0.75 on internal and external validation, respectively. Conclusion pCR was associated with better long-term outcome. A nomogram was successfully developed to predict pCR. It could support decision-making in organ preservation strategies.

A nomogram to predict distant metastasis after neoadjuvant chemoradiotherapy and radical surgery in patients with locally advanced rectal cancer

To compare distant metastasis (DM) in locally advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (nCRT) and surgery alone, and to develop a predictive nomogram for DM following nCRT.

Knockdown of KLK11 inhibits cell proliferation and increases oxaliplatin sensitivity in human colorectal cancer.

It has been reported that kallikrein 11 (KLK11) is crucially involved in the development and progression of various types of cancer. However, the molecular mechanisms that underlie the involvement of KLK11 in aberrant colorectal cancer (CRC) cell growth remain largely unclear. The aim of the present study was to investigate the role of KLK11 and the effects of KLK11 on oxaliplatin (L-OHP) chemosensitivity by knocking down KLK11 in LOVO and HCT-8 cells. Loss-of-function assays revealed KLK11 inhibition significantly inhibited growth and induced apoptosis of CRC cells in vitro. Notably, further experiments found that knockdown of KLK11 expression increased the L-OHP chemosensitivity of CRC cells. KLK11 inhibition of increased L-OHP-induced apoptosis may be associated with activation of caspase-3 cleavage and the apoptosis signaling pathway. The present results indicated that KLK11 may be an potential target of interest for future research into therapies for CRC.

Knockdown of KLK11 reverses oxaliplatin resistance by inhibiting proliferation and activating apoptosis via suppressing the PI3K/AKT signal pathway in colorectal cancer cell

Introduction Kallikrein 11 (KLK11) plays a crucial role in drug-resistance to oxaliplatin (L-OHP) in the treatment of metastatic colorectal cancer (mCRC). The study aimed to investigate the role of KLK11 in chemoresistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of KLK11. Materials and Methods Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal adenocarcinoma cell lines by exposing cells to increasing concentrations of L-OHP. MTT, RT-qPCR, and Western blot were used to evaluate the resistance to L-OHP. We then knocked down KLK11 in HCT-8/L-OHP cells to explore the mechanism through which KLK11 reverses L-OHP resistance. The mRNA and protein expression of KLK11 in tissues from mCRC patients were detected by RT-qPCR and immunohistochemistry. Results The drug resistance index (RI) of HCT-8/L-OHP cell line to L-OHP, 5-Fluorouracil (5-FU), Irinotecan (CPT-11), Vincristine (VCR) and Cis-diamminedichloroplatinum (CDDP) were 10, 5.35, 3.23, 1.28, and 6.64, respectively. Increased expression of multi-drug resistant genes ABCC1, ABCB1, GSTP1 and ERCC1 were detected in HCT-8/L-OHP cell line. Moreover, the activated PI3K/AKT pathway was related to L-OHP-resistance. Knockdown of KLK11 in HCT-8/L-OHP cell reversed L-OHP-resistance by inhibiting cell growth and activating apoptosis via suppressing the PI3K/AKT signaling pathway. Moreover, high expression of KLK11 in chemoresistant-patients was associated with lymph node metastases and histopathology. Conclusion KLK11 was highly expressed in chemoresistant-patients and L-OHP-resistant cell lines. Moreover, L-OHP resistance was associated with activated PI3K/AKT signal pathway. Knockdown of KLK11 can reverse L-OHP resistance by blocking PI3K/AKT signaling pathway.

Prognostic significance of neoadjuvant rectal score in locally advanced rectal cancer after neoadjuvant chemoradiotherapy and construction of a prediction model.

To evaluate the prognostic significance of neoadjuvant rectal (NAR) score after neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC), and to develop a nomogram predicting disease‐free survival (DFS).

Risk Factors for Early Postoperative Small Bowel Obstruction after Elective Colon Cancer Surgery: An Observational Study of 1,244 Consecutive Patients

Background: Early postoperative small bowel obstruction (EPSBO) is a common complication following colon cancer surgery. EPSBO is associated with increased hospital stays, mortality rates, and healthcare costs. The purpose of this study was to identify risk factors for EPSBO following elective colon cancer surgery. Study Design: We retrospectively reviewed the clinicopathological variables of 1,244 patients with colon cancer who underwent partial colectomy from January 2000 to December 2014. A multivariable logistic regression model was used to identify risk factors for EPSBO. Results: The EPSBO rate was 3.5%. In multivariate analysis, preoperative bowel obstruction (OR 2.378; 95% CI 0.986-5.735, p = 0.054), weight loss >10% of body weight (OR 3.029; 95% CI 1.000-9.178, p = 0.05), albumin level (in g/L; OR 0.966; 95% CI 0.937-0.996, p = 0.024), and surgical duration (in min; OR 1.008; 95% CI 1.003-1.012, p = 0.003) were significant predictors of EPSBO. Conclusion: EPSBO is more likely to develop in the presence of poor systemic conditions (e.g., weight loss >10% of body weight, hypoalbuminemia, and preoperative bowel obstruction) and following operations of longer duration. These predictors may facilitate the stratification of patients at risk for EPSBO following surgery for elective colon cancer.

A scoring system basing pathological parameters to predict regional lymph node metastasis after preoperative chemoradiotherapy for locally advanced rectal cancer: implication for local excision.

Local excision is an alternative to radical surgery that is indicated in patients with locally advanced rectal cancer (LARC) who have a good response to chemoradiotherapy (CRT). Regional lymph node status is a major uncertainty during local excision of LARC following CRT. We retrospectively reviewed clinicopathologic variables for 244 patients with LARC who were treated at our institute between December 2000 and December 2013 in order to identify independent predictors of regional lymph node metastasis. Multivariate analysis of the training sample demonstrated that histopathologic type, tumor size, and the presence of lymphovascular invasion were significant predictors of regional nodal metastasis. These variables were then incorporated into a scoring system in which the total scores were calculated based on the points assigned for each parameter. The area under the curve in the receiver operating characteristic analysis was 0.750, and the cutoff value for the total score to predict regional nodal metastasis was 7.5. The sensitivity of our system was 73.2% and the specificity was 69.4%. The sensitivity was 77.8% and the specificity was 51.2% when the scoring system was applied to the testing sample. Using this system, we could accurately predict regional nodal metastases in LARC patients following CRT, which may be useful for stratifying patients in clinical trials and selecting potential candidates for organ-sparing surgery following CRT for LARC

Selecting stage ypT0-1N0 for locally advanced rectal cancer following preoperative chemoradiotherapy: implications for potential candidates of organ-sparing management.

Local excision or a wait‐and‐see policy may offer the possibility of organ preservation for locally advanced rectal cancer (LARC) after preoperative chemoradiotherapy (CRT). Identifying associated factors of good responders (GR) with stage ypT0–1N0 would probably influence the selection of potential candidates who were theoretically eligible for organ‐sparing management. This study was to establish a scoring system to select stage ypT0–1N0 for LARC following preoperative CRT.

Pirfenidone suppresses TGF‑β1‑induced human intestinal fibroblasts activities by regulating proliferation and apoptosis via the inhibition of the Smad and PI3K/AKT signaling pathway

Intestinal fibroblasts, the main effector cells of intestinal fibrosis, are considered to be a good target for anti-fibrotic therapy. The aim of the present study was to examine the effects of pirfenidone (PFD) on human intestinal fibroblasts (HIFs) stimulated by transforming growth factor (TGF)-β1 and to explore the potential mechanism. Prior to stimulation with TGF-β1 (10 ng/ml), HIFs were treated with or without PFD (1 mg/ml). Cell proliferation was determined by Cell Counting Kit (CCK)-8 and colony formation assays, and cell apoptosis was assessed using flow cytometry and a TUNEL assay. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to evaluate the mRNA and protein expressions of α-smooth muscle actin (α-SMA), collagen I and fibronectin. The protein expression of TGF-β1/mothers against decapentaplegic homolog (Smad) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways was evaluated by western blotting. CCK-8 and colony formation assays demonstrated that PFD significantly inhibited cell proliferation in HIFs stimulated with TGF-β1. Flow cytometry and TUNEL assays revealed that PFD treatment significantly enhanced apoptosis in TGF-β1-stimulated HIFs. In addition, PFD markedly reduced TGF-β1-induced HIF activities, such as myofibroblast differentiation (α-SMA), and collagen production (collagen I and fibronectin). These effects of PFD were mediated by the inhibition of the TGF-β1/Smad and PI3K/AKT signaling pathways. Therefore, the present study demonstrated that PFD reduced TGF-β1-induced fibrogenic activities of HIFs, suggesting that PFD may be a potential therapeutic agent for intestinal fibrosis.

Prognostic Implication of Negative Lymph Node Count in ypN+ Rectal Cancer after Neoadjuvant Chemoradiotherapy and Construction of a Prediction Nomogram

PurposeThis study aimed to investigate the prognostic significance of negative lymph nodes (NLNs) for ypN+ rectal cancer after neoadjuvant chemoradiotherapy (nCRT) and radical surgery and to construct a nomogram predicting disease-free survival (DFS).MethodOne hundred fifty-eight eligible patients were included. X-tile analysis was performed to determine cutoff values of NLNs. Clinicopathological and survival outcomes were compared. A Cox regression analysis was performed to identify prognostic factors of DFS. A nomogram was constructed and validated internally.ResultsX-tile analysis identified cutoff values of 4 and 16 in terms of DFS (χ2 = 8.129, p = 0.017). The 3-year DFS rates for low (≤ 4), middle (5–16), and high (≥ 17) NLNs group was 15.2, 55.5, and 73.1%, respectively (P = 0.017). NLN count (NLNs ≥ 17, HR = 0.400, P = 0.022), IMA nodal metastasis (HR = 1.944, P = 0.025), tumor differentiation (poor/anaplastic, HR = 1.805, P = 0.021), and ypT4 stage (HR = 7.787, P = 0.047) were independent prognostic factors of DFS. A predicting nomogram incorporating the four significant predictors was developed with a C-index of 0.64.ConclusionNLN count was an independent prognostic factor of DFS in patients with ypN+ rectal cancer following nCRT. A nomogram incorporating NLN count, IMA nodal metastasis, tumor differentiation, and ypT stage could stratify rectal cancer patients with different DFS and might be helpful during clinical decision-making.