Yeting Hu

Incidence, Surgical Treatment, and Prognosis of Anorectal Melanoma From 1973 to 2011: A Population-Based SEER Analysis.

AbstractAnorectal melanoma (AM) is a rare type of melanoma that accounts for 0.4% to 1.6% of total malignant melanomas. The incidence of AM increases over time, and it remains highly lethal, with a 5-year survival rate of 6% to 22%. Considering the rare nature of this disease, most studies on AM comprise isolated case reports and single-center trials, which could not provide comprehensive assessment of the disease. Therefore, we conducted a population-based study by using the Surveillance, Epidemiology, and End Results (SEER) program to provide the latest and best available evidence of AM.We extracted all cases of AM registered in the SEER database from 1973 to 2011 (April 2014 release) and calculated age-adjusted incidence. Only cases with active follow-up were included to predict factors associated with prognosis. Survival outcomes were also compared among different types of surgery.We identified 640 AM cases, which consisted of 265 rectal melanoma and 375 anal melanoma. The estimated annual incidence rates of AM per 1 million population were 0.259 in males and 0.407 in females, and it increased with advanced age and over time. Tumor stage and surgical treatment were independent predictors of survival. Results implied that surgery improved the prognosis of patients with local- and regional-stage AM but could not prolong the survival of patients with distant-stage AM. Moreover, the outcome of less extensive excision was not statistically different from that of more extensive excision.This study provides an up-to-date estimation of the incidence and prognosis of AM by using SEER data. The incidence of AM continuously increases over time, despite its rarity. This disease also exhibits poor prognosis. Thus, AM must be further investigated in future studies. We also recommend surgery as the optimal treatment for local- and regional-stage AM patients but not for those with distant metastasis.

BEX1 Promotes Imatinib-Induced Apoptosis by Binding to and Antagonizing BCL-2

An enhanced anti-apoptotic capacity of tumor cells plays an important role in the process of breakpoint cluster region/Abelson tyrosine kinase gene (BCR/ABL)-independent imatinib resistance. We have previously demonstrated that brain expressed X-linked 1 (BEX1) was silenced in secondary imatinib-resistant K562 cells and that re-expression of BEX1 can restore imatinib sensitivity resulting in the induction of apoptosis. However, the mechanism by which BEX1 executes its pro-apoptotic function remains unknown. We identified B-cell lymphoma 2 (BCL-2) as a BEX1-interacting protein using a yeast two-hybrid screen. The interaction between BEX1 and BCL-2 was subsequently confirmed by co-immunoprecipitation assays. Like BCL-2, BEX1 was localized to the mitochondria. The region between 33K and 64Q on BEX1 is important for its localization to the mitochondria and its ability to interact with BCL-2. Additionally, we found that this region is essential for BEX1-regulated imatinib-induced apoptosis. Furthermore, we demonstrated that the interaction between BCL-2 and BEX1 promotes imatinib-induced apoptosis by suppressing the formation of anti-apoptotic BCL-2/BCL-2-associated X protein (BAX) heterodimers. Our results revealed an interaction between BEX1 and BCL-2 and a novel mechanism of imatinib resistance mediated by the BEX1/BCL-2 pathway.

TNM Staging of Colorectal Cancer Should be Reconsidered According to Weighting of the T Stage: Verification Based on a 25-Year Follow-Up

AbstractThe gradient monotonicity of existing tumor, node, metastases staging systems for colorectal cancer is unsatisfactory. Our proposed T-plus staging system strengthens weighting of the T stage. In this study, applicability of the T-plus staging system was verified with data of a Chinese colorectal cancer center.Records of 2080 nonmetastatic, advanced cancer patients undergoing colorectal cancer surgery from 1985 to 2011 were reviewed for T, N stage pathology and follow-up information. Using overall and disease-specific survival data, the 7th edition tumor, node, metastases staging system and the T-plus staging system were compared for stage homogeneity and discrimination and gradient monotonicity.For gradient monotonicity, the T-plus staging system was superior for both colon and rectal cancer. With Kaplan–Meier survival curves, the T-plus staging system discriminated among different stages, and the corresponding survival was inversely associated with the stage. However, for the 7th edition tumor, node, metastases staging system, stage IIIa had a better prognosis than stage II for rectal cancer and stage I for colon cancer. For homogeneity within the same stage and discrimination between different stages, the 2 staging systems were similar for colorectal cancer, but the T-plus system was clearly better for colon cancer.The T-plus staging system provides good gradient monotonicity. For future colorectal cancer staging systems, we propose replacement of lymph node status as the criterion to discriminate colorectal cancer stage II and stage III with greater weighting of the T stage.

Hormone receptor status may impact the survival benefit of surgery in stage iv breast cancer: a population-based study.

Introduction The role of surgery in stage IV breast cancer is controversial. We used the Surveillance, Epidemiology, and End Results database to explore the impact of surgery on the survival of patients with stage IV breast cancer. Methods In total, 10,441 eligible stage IV breast cancer patients from 2004 to 2008 were included. They were divided into four groups as follows: R0 group (patients who underwent primary site and distant metastatic site resection), primary site resection group, metastases resection group, and no resection group. Results The four groups achieved a median survival time (MST) of 51, 43, 31 and 21 months, respectively, P < 0.001. The Cox proportional hazards model showed that the R0 group, primary resection group and metastases resection group had a good survival benefit, with hazard ratios of 0.558 (95% CI, 0.471-0.661), 0.566 (95% CI, 0.557-0.625) and 0.782 (95% CI, 0.693-0.883), respectively. In the hormone receptor (HR)-positive population, the R0 group (MST = 66 m, 5-year OS = 54.1%) gained an additional survival benefit compared with the primary resection group (MST = 52 m; 5-year OS = 44.9%; P < 0.001). The metastases resection group (MST = 38 m; 5-year OS = 31.7%) survived longer than the no resection group (MST = 28 m; 5-year OS = 22.0%; P < 0.001). In the HR-negative population, the R0 group and primary resection group had a similar survival (P = 0.691), and the metastases resection group had a similar outcome to that of the no resection group (P = 0.526). Conclusion Patients who underwent surgery for stage IV breast cancer showed better overall survival than the no resection group. Cytoreductive surgery could provide a survival benefit in HR+ stage IV breast cancer; however, in the HR- population, extreme caution should be exercised when considering surgery.

Sunitinib mesylate inhibits proliferation of human colonic stromal fibroblasts in vitro and in vivo

ObjectiveCancer stromal fibroblasts are important members of the cancer microenvironment. In this study, we determined the effect of sunitinib, a small molecule tyrosine kinase inhibitor, on the primary human colonic fibroblasts.MethodsCell cycle analysis and cell proliferation assays were performed to evaluate the inhibitory effect of sunitinib in vitro. Western-blot analysis was performed to evaluate variations in the levels of phosphorylated platelet-derived growth factor receptor β (PDGFR-β), Akt, and ERK proteins. Co-injection of SW620 cells and colonic fibroblasts in nude mice was employed to test anti-growth efficacy in vivo.ResultsSunitinib was found to effectively inhibit the growth of primary colonic fibroblasts. Low-dose sunitinib blocked the PDGF-BB-induced cell proliferation and PDGFR-β signaling. Co-injection of SW620 cells and colonic fibroblasts in nude mice generated greater tumor volumes than single injection of SW620 cells. Sunitinib treatment inhibited the SW620 cell+colonic fibroblast tumor growth more effectively than treatment of 5-fluorouracil.ConclusionsSunitinib mesylate inhibited the proliferation of primary human colonic fibroblasts through target-inhibited PDGFR signaling in vitro and in vivo.概要研究目的探索小分子酪氨酸激酶抑制剂舒尼替尼(sunitinib)对结肠肿瘤微环境中的肿瘤相关成纤维细胞的作用及其机制。创新要点舒尼替尼通过抑制肿瘤间质成纤维细胞的生长, 间接发挥抗肿瘤效应, 为结肠癌综合治疗的提供新途径。研究方法通过细胞周期分析和细胞增殖测定进行舒尼替尼体外抑制肿瘤细胞的研究。 采用Western-blot检测磷酸化血小板衍生生长因子β 受体(PDGFR-β)、 蛋白激酶B(Akt)及细胞外信号调节蛋白激酶(ERK)的蛋白水平。 通过注射肠腺癌细胞株SW620 和结肠成纤维细胞构建的裸鼠移植瘤模型来研究舒尼替尼的体内抑瘤效果。重要结论舒尼替尼可有效抑制结肠癌来源的原代结肠成纤维细胞生长, 该抑制作用主要通过抑制血小板衍生生长因子(PDGF)信号通路得以实现。

Neuroendocrine Differentiation Is a Prognostic Factor for Stage II Poorly Differentiated Colorectal Cancer

Neuroendocrine differentiation (NED) in colorectal cancer is an indistinct phenomenon and may define a new cancer subtype, especially in the poorly differentiated colorectal cancer (PDCRC). The clinical features of PDCRC with NED remain controversial, thus confusing the implementation of individualized treatment. This study included 171 patients who underwent surgery from 2000 to 2011 and had pathology-confirmed PDCRC. Each sample was examined by immunohistochemistry for the biological markers of NED, synaptophysin (Syn), and chromogranin (CgA). Patients with Syn(+) and/or CgA(+) cells were classified as NED(+); otherwise, they were NED(−). Data were collected for patients who were followed up for at least two years. NED(+) staining was present in 71 (41.5%) patients. The median survival time was 36.9 months. No survival differences existed between the NED(−) and NED(+) groups (P > 0.05). However, stage II NED(+) patients had a significantly worse prognosis than NED(−) patients (P = 0.018). For the NED(+) group, the median survival was 38.56 months, and the 5-year survival was 65%. For the NED(−) group, the median survival was 53.18 months, and the 5-year survival was 90%. NED is a common event in primary PDCRC. For stage II PDCRC, NED(+) indicates a poor prognosis.

ANGPTL1 attenuates colorectal cancer metastasis by up-regulating microRNA-138

BackgroundAngiopoietin-like protein 1 (ANGPTL1) has been reported to suppress migration and invasion in lung and breast cancer, acting as a novel tumor suppressor candidate. Nevertheless, its effects on colorectal cancer (CRC) remain poorly defined. In this study, we aim to demonstrate the biological function of ANGPTL1 in CRC cells.MethodsWe explored ANGPTL1 mRNA expression in human CRC tissues and its association with prognosis. CRC cell lines overexpressing ANGPTL1 or with ANGPTL1 knocked down were constructed and analyzed for changes in proliferation, colony formation, migration and invasion. ANGPTL1-regulated microRNAs were analyzed, and microRNA inhibitor and mimics were used to explore the role of microRNA in ANGPTL1-associated biological function.ResultsANGPTL1 mRNA expression was down-regulated in CRC tissues, and high ANGPTL1 expression predicted better survival in CRC patients. ANGPTL1 overexpression resulted in suppressed migration and invasion in vitro, and it prolonged overall survival in mouse models. By contrast, its down-regulation enhanced migration and invasion of CRC cells. MicroRNA-138 expression was positively correlated with ANGPTL1 mRNA level in CRC tissues and up-regulated by ANGPTL1 in CRC cells. In addition, the microRNA-138 inhibitor or mimics could reverse or promote the ANGPTL1-mediated inhibition of the migratory capacity of CRC cells, respectively.ConclusionsThis study is the first to demonstrate the biological function of ANGPTL1 in CRC cells. ANGPTL1 expression was down-regulated in CRC tissues and inversely correlated with poor survival. ANGPTL1 repressed migration and invasion of CRC cells, and microRNA-138 was involved in this process.

BEX2 promotes tumor proliferation in colorectal cancer

BEX2 has been suggested to promote the tumor growth in breast cancer and glioblastoma, while inhibit the proliferation of glioma cells. Thus, the role of BEX2 in tumor was still in debate. Additionally, the biological functions of BEX2 in colorectal cancer (CRC) have not yet been clarified. Here, we reported that BEX2 was overexpressed in advanced CRC from both the GSE14333 database and fresh CRC tissue specimens, and positively correlated with clinical staging. Knockdown of BEX2 significantly decreased the in vitro proliferation of SW620 colorectal cancer cells, suppressed subcutaneous xenograft growth and enhanced the survival of mice with cecal tumors. These effects were mainly mediated by the JNK/c-Jun pathway. Knockdown of BEX2 inhibited JNK/c-Jun phosphorylation, while BEX2 overexpression activated JNK/c-Jun phosphorylation. Moreover, the administration of the JNK-specific inhibitor SP600125 to SW620 with BEX2 overexpression abolished the effect of BEX2 on SW620 cell proliferation. This study reveals that BEX2 promotes colorectal cancer cell proliferation via the JNK/c-Jun pathway, suggesting BEX2 as a potential candidate target for the treatment of CRC.

Extent of enhancement on multiphase contrast-enhanced CT images is a potential prognostic factor of stage I–III colon cancer

ObjectiveBy evaluating extent of tumour enhancement on preoperative contrast-enhanced MDCT, we aimed to establish an imaging-based model to predict cancer-specific survival in stage I–III colon cancer.MethodsA total of 548 stage I–III colon cancer patients who underwent curative resection from 2007 to 2013 were retrospectively included and divided into primary cohort and validation cohort according to admission time. The attenuation coefficient of each colon cancer was measured on the workstation by drawing the ROI in CT images. The enhancement ratio was calculated using maximum tumour attenuation value in triphasic MDCT scanning divided by the minimum. Patients were divided into low/high-enhancement groups according to the optimal cut-off value derived from time-dependent ROC curve. Kaplan–Meier method and COX regression analysis were adopted to evaluate prognostic value of variables. A nomogram for prognosis was conducted on the basis of a multivariate Cox proportional hazard model.ResultsNo significant differences were observed in age, sex, pTNM stage, perioperative chemoradiotherapy, serum CEA, tumour size, tumour localisation and histologic type between low- and high-enhancement groups. The high-enhancement group had a significantly shorter cancer-specific survival rate (69.5%) than the low-enhancement group (85.9%) (p < 0.001). Subgroup analysis indicated that high-enhancement state was closely associated with increased risk of colon cancer mortality in stage I (p = 0.033), stage II (p = 0.002) and stage III (p = 0.014). Cox regression analysis indicated the extent of enhancement was an independent prognostic factor (HR 2.258, 95% CI 1.476–3.455; p < 0.001).ConclusionsThe extent of tumour enhancement on MDCT can serve as a potential risk factor for stage I–III colon cancer.Key Points• Survival rates of stage I–III colon cancer vary widely even within the same stage.• Prognostic value of the extent of tumour enhancement on MDCT was assessed.• The high-enhancement group had a significantly shorter cancer-specific survival rate.

Neuroendocrine differentiation is predictive of poor survival in patients with stage II colorectal cancer

The diagnosis of neuroendocrine differentiation (NED) is made primarily on the basis of ultrastructure and/or immunohistochemistry (IHC). Synaptophysin (Syn) and chromogranin A (CgA) are two important frequently used NED markers in colorectal cancer (CRC). The association between NED and the prognosis of stage II CRC remains controversial. Administration of adjuvant chemotherapy remains challenging for stage II CRC. Identification of reliable factors that improve the selection of patients with stage II CRC at high risk following surgery is of great importance. A total of 151 cases of patients with stage II CRC who received radical surgery in The Second Affiliated Hospital of Zhejiang University (Hangzhou, China) between January 2002 and March 2011 were assayed for Syn and CgA using IHC, following which patients were classified as NED(+) or NED(−). Survival curves were constructed using the Kaplan-Meier estimator, and the prognostic value was determined using a log-rank test and Coxs regression test. In the 151 cases of stage II CRC examined, the incidence of NED was 34.44%. The overall survival of the NED(+) group was significantly less favorable than that of the NED(−) group (P=0.001). The 5-year survival rate was 68% for NED(+) (n=51) and 90% for NED(−) (n=97). The independent prognostic factors of survival of patients with stage II CRC following multivariate analysis were age ≥65 years (P=0.007) and NED-positivity (P=0.014). NED was revealed to be an independent factor of poor prognosis for patients with stage II CRC, which may offer potential for improved therapy stratification.