Prognostic significance of DNA ploidy in patients with stage II colorectal cancer

DNA ploidy status associated with colorectal cancer has been investigated widely in recent years. But the relationship between DNA analysis and prognosis has not been confirmed.[1(3] Some investigations showed that DNA aneuploid status was associated with lymph node involvement and poor differentiation, and thus may predict a poor clinical outcome in patients with colorectal cancer. These observations suggest that DNA ploidy abnormality may influence the development and progression of colo…     

Prognostic significance of mesenteric tumor nodules in patients with stage III colorectal cancer

BACKGROUND: Tumor nodules are occasionally found in adjacent mesentery of colorectal cancer specimens and are felt to reflect a worse prognosis. The clinical significance of mesenteric tumor nodules was investigated. METHODS: A review of 786 patients with stage III colorectal cancer referred between 1995 and 1999 was undertaken. TNM staging was standardized by considering mesenteric nodules separately and not assigning them to T or N categories. Survival analyses were performed. RESULTS: Mesenteric tumor nodules were found in 116 (14.8%) patients: 48 (41.4%) with colon cancer and 68 (58.6%) rectal cancer. Mean age at surgery was 63 years. Adjuvant chemotherapy was given to 84.8% of colon cancer patients. Two (2.9%) rectal cancer patients received neoadjuvant chemoradiation, and 63 (92.6%) received adjuvant therapy (chemotherapy and/or radiation). In the cohort with mesenteric nodules, the median time to progression was 23.1 months, the median 5-year disease-free survival was 35%, and the median overall survival (OS) was 47.9 months, with 44% OS at 5 years. In the 19 (16.4%) patients with mesenteric nodules and no lymph nodes the 5-year OS was 60% (SEER stage II 5-year survival 82.5%), whereas in 97 patients who were lymph node-positive the 5-year OS was 40% (SEER 5-year survival stage IIIc 44.3%; stage IV 8.1%). CONCLUSIONS: In comparison to SEER survival data, the presence of mesenteric nodules appears to worsen the prognosis of any T/N0 disease to that of overall stage III disease. Mesenteric nodules with any T/N+ disease had prognosis similar to that of stage IIIC disease, but the prognosis was better than M1 disease. .     

The association of preoperative serum tumour markers with Dukes' stage and survival in colorectal cancer.

The tumour markers carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), TPS, CA 19-9, CA 50 and CA 242 were analysed in serum from 203 potentially curable colorectal cancer patients. The levels of all markers increased with increasing tumour stage, and all markers correlated with survival. Multivariate analyses indicated that the Dukes stage had the best prognostic explanatory power, followed by TPA. In the subset of 166 potentially cured patients, the prognostic information by the markers was substantially reduced. We conclude that preoperative serum tumour marker measurements have the potential to aid therapy selection, but also that their clinical usefulness is not immediately apparent.     

MicroRNA-21靶向PDCD4对胃癌细胞增殖及凋亡的影响

目的探讨MicroRNA-21对胃癌细胞中PDCD4表达、细胞增殖与凋亡的影响。方法将MGC-803人胃癌细胞分为5组,分别为空白对照组(不转染)、阴性对照组(转染不相关siRNA)、mir 21组(转染miRNA-21质粒)、mir 21 Inhibitor组(转染miRNA-21抑制物)、PDCD4 siRNA组(转染PDCD4 siRNA)。分别于转染后36、48、72小时收集细胞,采用实时定量PCR及细胞爬片免疫组织化学检测细胞中PDCD4基因及蛋白水平,运用MTS法检测细胞增殖情况,流式细胞仪检测细胞凋亡。结果与空白、阴性对照组比较,mir 21组PDCD4表达量下降,细胞增殖能力增强(均P<0.05);mir 21 Inhibitor组PDCD4表达量增多(P<0.05),细胞增殖受到抑制(P<0.01),细胞总凋亡比例增高(P<0.05);PDCD4 siRNA组PDCD4表达几乎完全被抑制,细胞增殖能力增强(均P<0.01),36小时时细胞总凋亡比例减少(P<0.05)。而阴性和空白对照组比较,细胞PDCD4表达量、细胞增殖与凋亡都无明显差异(P>0.05)。结论 MicroRNA-21能靶向调控PDCD4,抑制胃癌细胞MicroRNA-21的表达后可上调PDCD4表达,发挥抑制细胞增殖并诱导细胞凋亡的作用。     

Loss of p27 expression predicts poor prognosis in patients with Dukes' B stage or proximal colorectal cancer.

p27 is a cyclin-dependent kinase inhibitor which regulates progression of cells from G1 into S phase in a cell cycle. Loss of the negative regulator may contribute to oncogenesis and tumor progression. The aim of this study was to examine p27 expression in normal mucosa, primary and metastatic tumors from patients with colorectal adenocarcinomas and to analyze association of p27 with patient survival and clinicopathological variables. p27 expression was estimated by immunohistochemistry in 178 primary colorectal cancers, 34 lymph node metastases and 48 normal mucosa samples from patients with colorectal adenocarcinoma. Associations of p27 with patient survival, clinicopathological characteristics and expression of p53, p73 and DCC were analyzed. Loss of p27 was found in 51% of primary tumors, 68% of metastases and 56% of normal samples. The intensity of p27 staining was similar in the matched primary tumor, metastasis and normal mucosa. In patients with Dukes' B or with proximal tumors, the loss of p27 predicted poorer prognosis (p = 0.03 and p = 0.05, respectively). However, there were no significant differences in the patients with other individual Dukes' stage or distal tumors. No relationships were found between p27 and patients' gender, age, tumor location, growth pattern and expression of p53, p73 and DCC (p > 0.05). The data suggest that loss of p27 was associated with poor prognosis in patients with Dukes' B tumor or those with proximal tumor. p27 might be a useful marker to identify the more progressive tumors in these groups.     

Prognostic significance of peritoneal lavage cytology in patients with colorectal cancer

Background

The clinical significance of peritoneal lavage cytology for patients with gastric cancer is recognized, whereas that for patients with colorectal cancer remains controversial. The present study used a nationwide registry to clarify the prognostic significance of peritoneal lavage cytology in patients with colorectal cancer.

Methods

We retrospectively analyzed factors associated with recurrence and survival in patients with T3–T4 colorectal cancer without distant metastasis taken from the nationwide registry of the Japanese Society for Cancer of the Colon and Rectum between 1984 and 1999.

Results

Among 34,554 patients in this study, not all of whom received peritoneal lavage cytology, 35 had positive peritoneal lavage cytology. Gender (P = 0.0004), tumor location (P < 0.0001), histological grade (P < 0.0001), depth of tumor invasion (P < 0.0001), lymph node metastasis (P < 0.0001) and peritoneal cytology (P = 0.015) were risk factors for peritoneal recurrence. Multivariate analysis revealed that tumor location (P < 0.0001), histological grade (P < 0.0001), depth of tumor invasion (P < 0.0001) and lymph node metastasis (P < 0.0001) were independent risk factors for peritoneal metastasis. Gender (P < 0.0001), tumor location (P < 0.0001), age (P < 0.0001), histological grade (P < 0.0001), depth of tumor invasion (P < 0.0001), lymph node metastasis (P < 0.0001) and peritoneal cytology (P = 0.0004) were independent prognostic factors according to the Cox proportional hazards model.

Conclusion

Positive peritoneal lavage cytology was associated with poorer survival in patients with stage II and III colorectal cancer. Positive cytology might be a good indicator of candidates for intensive adjuvant chemotherapy. The benefit of intensive adjuvant chemotherapy for such patients should be validated in prospective trials.     

Aldose reductase inhibition suppresses colon cancer cell viability by modulating microRNA-21 mediated programmed cell death 4 (PDCD4) expression

Inhibition of polyol pathway enzyme aldose reductase (AR) has been shown to prevent colon cancer cells growth in culture and in nude mice xenografts. However, the role of AR in the mediation of growth factor-induced colon cancer cells growth is not well understood. In this study, we have investigated how AR inhibition prevents tumour growth via regulation of microRNA (miR)-21-mediated programmed cell death 4 (PDCD4) expression in colon cancer cells in in vitro and in vivo. Treatment of colon cancer cells (HT29, SW480 and Caco-2) with epidermal growth factor (EGF) caused increased expression of miR-21 and inhibition of AR prevented it. Further, AR inhibition also increased PDCD4, a putative target of miR-21 in human colon cancer cells. Inhibition of AR also prevented EGF-induced phosphorylation of PDCD4. Treatment of HT29 cells with AR inhibitor, fidarestat, prevented the EGF-induced phosphorylation of mammalian target of rapamycin (mTOR), regulatory associated protein of mTOR (Raptor), eukaryotic initiation factor 4E (eIF4E), p70 S6 kinase (S6K) and eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and increased the phosphorylation of 5’ adenosine monophosphate-activated protein kinase (AMPK). Similarly, in nude mice xenograft tissues, PDCD4 and 4E-BP1 levels were significantly higher in AR inhibitor-treated mice compared to controls. Collectively, these results indicate that AR inhibition prevents growth factor-induced colon cancer growth by down-regulating miR-21 expression and increasing PDCD4 levels through the reactive oxygen species (ROS)/AMPK/mTOR/AP1/4E-BP1 pathway.     

Prognostic value of programmed death‐ligand 1 expression in patients with stage III colorectal cancer

The programmed death‐1/programmed death‐ligand 1 (PD‐L1) pathway is a negative feedback pathway that suppresses the activity of T cells. Previous studies reported that high PD‐L1 expression on tumor cells (TC) was associated with poor survival in patients with colorectal cancer; however, the prognostic evaluation of these studies was limited because they included patients at various disease stages. The purpose of the present study was to evaluate the relationship between PD‐L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Two hundred and thirty‐five patients were included in the analysis. PD‐L1 expression on TC and tumor‐infiltrating mononuclear cells (TIMC) was evaluated by immunohistochemistry. The median follow‐up of thisi study was 52.9 months. A total of 8.1% of stage III colorectal cancer showed high PD‐L1 expression on TC and 15.3% showed high PD‐L1 expression on TIMC. Patients with high PD‐L1 expression on TC had significantly shorter disease‐free survival (DFS) than patients with low expression (hazard ratio [HR] 2.36; 95% confidence interval [CI], 1.21–4.62; P = 0.012). In addition, patients with high PD‐L1 expression on TIMC were associated with longer DFS than patients with low expression (HR 0.40; 95% CI, 0.16–0.98; P = 0.046). These findings suggest that PD‐L1 expression status may be a new predictor of recurrence for stage III colorectal cancer patients and highlight the necessity of evaluating PD‐L1 expression on TC and TIMC separately in the tumor microenvironment.     

miR-192与ZEB2在结直肠癌中的表达及其临床意义

背景与目的：微小RNA(microRNA,miRNA)是一类具有重要调控作用的非编码小分子RNA,在多种疾病的发生、发展中起重要作用。本研究通过检测结直肠癌(colorectal cancer,CRC)组织中miR-192及E盒结合锌指蛋白2(zinc finger E-box binding homeobox 2,ZEB2) mRNA、蛋白表达,分析miR-192的异常表达与CRC的临床病理特征的关系及与ZEB2的相关性。方法：选择CRC组织和癌旁组织(距肿瘤边缘≥5 cm)各30例,结直肠腺瘤组织25例,正常结直肠组织15例。实时定量PCR(quantitative real-time polymerase chainreation,qRT-PCR)法检测上述各组中miR-192及ZEB2 mRNA表达;蛋白质印迹法(Western blot)检测ZEB2蛋白表达;对CRC组织中miR-192与临床病理特征关系及前者与ZEB2的相关性进行分析。结果：CRC组miR-192表达明显下调,ZEB2 mRNA和蛋白表达明显上调,分别与癌旁组、结直肠腺瘤组及正常组相比,差异均有统计学意义(P<0.05);miR-192的表达下调与CRC的淋巴结转移(P=0.021)和远处转移(P=0.023)相关。在CRC组织中,miR-192与ZEB2蛋白的表达呈显著的负相关关系(r=-0.365,P<0.05)。结论：miR-192在CRC组织中的表达下调与肿瘤的转移有关,且可能通过ZEB2参与CRC的发生、发展过程。     

Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer

Background: We demonstrated that circulating tumor cell (CTC) number at baseline and follow-up is an independent prognostic factor in metastatic colorectal cancer (mCRC). This analysis was undertaken to explore whether patient and treatment characteristics impact the prognostic value of CTCs.Patients and methods: CTCs were enumerated with immunomagnetic separation from the blood of 430 patients with mCRC at baseline and on therapy. Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of ≥3 or <3 CTCs/7.5 ml, respectively. Subgroups were analyzed by line of treatment, liver involvement, receipt of oxaliplatin, irinotecan, or bevacizumab, age, and Eastern Cooperative Oncology Group performance status (ECOG PS).Results: Seventy-one percent of deaths have occurred. Median follow-up for living patients is 25.8 months. For all patients, progression-free survival (PFS) and overall survival (OS) for unfavorable compared with favorable baseline CTCs is shorter (4.4 versus 7.8 m, P = 0.004 for PFS; 9.4 versus 20.6 m, P < 0.0001 for OS). In all patient subgroups, unfavorable baseline CTC was associated with inferior OS (P < 0.001). In patients receiving first- or second-line therapy (P = 0.003), irinotecan (P = 0.0001), having liver involvement (P = 0.002), ≥65 years (P = 0.0007), and ECOG PS of zero (P = 0.04), unfavorable baseline CTC was associated with inferior PFS.Conclusion: Baseline CTC count is an important prognostic factor within specific subgroups defined by treatment or patient characteristics.     

哈萨克族食管癌组织中microRNA-21的表达及其意义

目的：探讨哈萨克族食管癌组织中microRNA-21（miRNA-21）的表达及其意义。方法收集72例哈萨克族食管癌患者临床样本,采用实时定量PCR检测食管癌组织、周围正常食管组织miRNA-21表达水平;以患者性别、年龄、临床分期、肿瘤部位、分化程度、淋巴结转移、病情是否恶化等作为观察指标,分析miRNA-21与临床资料的关系。再以肿瘤中位生存期作为观察指标,筛选出影响哈萨克族食管癌患者预后的危险因素。结果食管癌组织miRNA-21相对表达量为（7.57±0.14）,周围正常食管组织相对表达量为（1.37±0.08）,食管癌组织相对表达量高于正常组织（P﹤0.05）。72例食管癌患者分为miRNA-21高表达组42例和低表达组30例,miRNA-21表达与临床分期、淋巴结转移、肿瘤进展有关,即淋巴结转移、肿瘤进展及肿瘤临床分期越晚,肿瘤miRNA-21表达也越高（P﹤0.05）;miRNA-21高表达组5年生存率为20.7%,低表达组5年生存率为38.6%,两组5年生存率比较差异具有统计学意义（χ2=4.715,P=0.005）;多因素分析显示,临床分期、肿瘤进展、miRNA-21表达水平是影响哈萨克族食管癌患者预后的独立危险因素（P﹤0.05）。结论 miRNA-21在食管癌组织表达水平高于正常组织,且miRNA-21表达越高,患者预后越差,miRNA-21可以作为哈萨克族食管癌诊断及预后评价的指标之一。