早期胃癌临床诊治的若干问题

胃癌是全球范围内死亡率最高的恶性肿瘤之一,而胃癌的早期发现和规范化治疗是改善胃癌患者的重要手段。随着医疗技术的发展,早期胃癌的检出率逐年提高,并且手术方式逐渐从传统开腹根治术向内镜切除和腹腔镜手术过渡。本课题组通过多年系列研究,联合国内外最新发现对早期胃癌临床生物学特征、分期系统评估和综合治疗方案等方面进行深入研究,为指导早期胃癌临床诊治提供科学依据。     

Correlation between microsatellite instability‐high phenotype and occult lymph node metastasis in gastric carcinoma

The aim of this study is to investigate the association of microsatellite instability (MSI) status with nodal status in gastric carcinoma (GC). MSI status was investigated in 623 consecutively resected GCs. To detect occult lymph node (LN) metastasis, immunohistochemistry (IHC) using antibodies against pan‐cytokeratin was performed in 391 node‐negative cases by initial histologic examination. MSI‐high (MSI‐H) phenotype was found in 68 GC cases (10.9%) and was significantly associated with increased patient age, antral location, intestinal type, absence of venous/perineural invasion, and expanding growth type (p < 0.05). When the nodal status was evaluated, the number of metastatic LNs of MSI‐H tumors tended to be lower than that of microsatellite stable/MSI‐low (MSS/L) tumors (1.49 ± 3.15 vs 4.37 ± 9.81; p = 0.052), but the MSI‐H phenotype was associated with the presence of lymphatic invasion (p = 0.036) and IHC‐positive occult LN metastasis (p = 0.007). By multivariate analysis, MSI‐H phenotype was significantly associated with IHC‐positive occult LN metastasis (Odds ratio, 2.654; p = 0.044). MSI status and occult LN metastasis were not prognostic factors by survival analysis. Our findings suggest that the relationship between MSI status and regional LN metastasis may have some clinical and biologic implications to be elucidated.     

结直肠癌中Keratin 17的表达及其临床预后价值

目的 分析角蛋白17(Keratin 17,KRT17)在结直肠癌(colorectal cancer,CRC)中的表达及其临床预后价值.方法 采用生物信息学方法分析KRT17在CRC数据库中的表达及预后价值;进一步,采用免疫组织化学技术检测KRT17蛋白在95对CRC临床样本组织中的表达水平,并分析其表达与患者临床病...     

Genetic Polymorphisms of Matrix Metalloproteinases and Clinical Outcomes in Colorectal Cancer Patients

Background: Colorectal cancer metastasis is a multistep process involving degradation of extracellular matrix components by proteolytic enzymes. Among them, matrix metalloproteinases (MMPs) are the principal degrading enzymes and their expressions/activities are also correlated with survival. Much research has showed the associations between genetic polymorphisms in MMPs and risk of colorectal cancer; however, their prognostic significance has not been well determined.Methods: We selected and genotyped 4 cancer-associated single nucleotide polymorphisms (SNPs) in a cohort of 282 colorectal cancer patients. The associations of these SNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis.Results: The relative risks of developing distant metastasis after curative surgery were higher in individuals with minor homozygote AA genotype than in those with GG/GA genotypes at MMP2 rs243866 (P = 0.012). Survival tree analysis also identified a higher-order genetic interaction profile consisting of MMP2 rs243866 and MMP2 rs2285053 that was significantly associated with distant metastasis-free survival (P_trend = 0.016). After adjusting for possible confounders, the genetic interaction profile remained significant (P_trend = 0.050).Conclusions: These results suggest that genetic variations in the MMP2 might be potential predictors of distant metastasis-free survival after curative surgery.     

Microsatellite instability status does not predict total lymph node or negative lymph node retrieval in stage III colon cancer

The relationship between higher total lymph node resection number in colorectal cancer resection specimens and improved overall survival is well known. Recent studies describe an association between a high rate of microsatellite instability and a high total lymph node count in colorectal cancer. Higher lymph node retrieval may potentially explain the improved survival seen in cancers with microsatellite instability. We investigate whether these associations can be validated in a cohort of American Joint Committee on Cancer stage III colon cancers. Medical records from 200 cases of stage III colon cancer resection specimens were reviewed, and sufficient tissue was available for 168. Expression of DNA mismatch repair proteins was determined by immunohistochemistry, and microsatellite status, by polymerase chain reaction. The mean total lymph node count in cases with microsatellite instability versus microsatellite stable tumors (15.9 versus 16.9; P = .664) and the mean number of negative lymph nodes in each respective category (12.2 versus 13.6; P = .522) were not significantly different. There was no difference between microsatellite stable cases and cases with microsatellite instability when total lymph node counts (P = .953) or negative lymph node counts (P = .381) were analyzed with respect to percentage of cases above and below the medians. This cohort of stage III colon cancers does not support a significant relationship between microsatellite status and a higher retrieval of total or negative lymph nodes. Although microsatellite instability is associated with improved overall survival in our cohort (P = .026), the reason for this does not appear to be related to higher numbers of retrieved lymph nodes.     

Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer

Colorectal cancer (CRC) is a worldwide health problem. Glucose-regulated protein 94 (GRP94) is known as an important endoplasmic reticulum-stress response protein that shows correlation with aggressive cancer behavior. However, the role of GRP94 in CRC is still unclear. Our results showed that silencing GRP94 (GRP94-KD) reduced cell proliferation, invasion and migration of CRC cells and suppressed tumorigenesis in the xenograft mouse model. Rescue assay showed that ETV1 overexpression reversed the effect of GRP94 on cell proliferation and migration. In the molecular mechanism, we found that knockdown of GRP94 inhibited the level of MAPK pathway, including ERK/p-ERK, JNK/p-JNK, and p38/p-p38 signals. Cyclooxygenase-2 and epithelial-mesenchymal transformation biomarkers, such as N-cadherin, vimentin, and β-catenin were suppressed in GRP94 knockdown cells. Treatment of specific inhibitors of MAPK pathway showed that ERK/p-ERK, and p38/p-p38 inhibitors significantly influenced ETV1 expression as compared to JNK/p-JNK inhibitor. Our results indicated that silencing GRP94 repressed the ability of EMT process, cancer cell proliferation, metastasis, and CRC tumorigenesis. Therefore, GRP94 may play an important role in CRC by regulating ETV1 and MAPK pathway.     

Collagen Triple Helix Repeat Containing-1 (CTHRC1) Expression in Oral Squamous Cell Carcinoma (OSCC): Prognostic Value and Clinico-Pathological Implications

BACKGROUND: Collagen Triple Helix Repeat Containing 1 (CTHRC1) is a protein often found to be over-expressed in various types of human cancers. However, correlation between CTHRC1 expression level with clinico-pathological characteristics and prognosis in oral cancer remains unclear. Therefore, this study aimed to determine mRNA and protein expression of CTHRC1 in oral squamous cell carcinoma (OSCC) and to evaluate the clinical and prognostic impact of CTHRC1 in OSCC.METHODS: In this study, mRNA and protein expression of CTHRC1 in OSCCs were determined by quantitative PCR and immunohistochemistry, respectively. The association between CTHRC1 and clinico-pathological parameters were evaluated by univariate and multivariate binary logistic regression analyses. Correlation between CTHRC1 protein expressions with survival were analysed using Kaplan-Meier and Cox regression models.RESULTS: Current study demonstrated CTHRC1 was significantly overexpressed at the mRNA level in OSCC. Univariate analyses indicated a high-expression of CTHRC1 that was significantly associated with advanced stage pTNM staging, tumour size ≥ 4 cm and positive lymph node metastasis (LNM). However, only positive LNM remained significant after adjusting with other confounder factors in multivariate logistic regression analyses. Kaplan-Meier survival analyses and Cox model demonstrated that patients with high-expression of CTHRC1 protein were associated with poor prognosis and is an independent prognostic factor in OSCC.CONCLUSION: This study indicated that over-expression of CTHRC1 potentially as an independent predictor for positive LNM and poor prognosis in OSCC.     

Expression of tumor necrosis factor receptor-associated protein 1 and its clinical significance in kidney cancer

Objective: To investigate the expression and clinical significance of TRAP1 (tumor necrosis factor receptor-associated protein 1) in kidney cancer. Methods: TRAP1 expression was detected in kidney cancer and normal kidney tissues by qRT-PCR and immunohistochemistry (IHC), respectively. Then, the correlation of TRAP1 expression with clinicopathological characters and patients’ prognosis was evaluated in kidney cancer. Results: IHC results revealed that the high-expression rates of TRAP1 in kidney cancer tissues and normal kidney tissues were 51.3% (41/80), 23.3% (7/30), and the difference was statistically significant (P=0.01). Also, TRAP1 mRNA level in kidney cancer was found to be significantly greater compared with those in normal kidney by qRT-PCR. In addition, TRAP1 expression in kidney cancer significantly correlated with lymph node metastasis and clinical stage (P<0.05). Kaplan-Meier survival analysis indicated that the mean survival time of patients with TRAP1 low-expression was significantly higher (56 months) than those patients with TRAP1 high-expression (47 months). Meanwhile, Kaplan-Meier and Cox survival analysis indicated that TRAP1, lymph node metastasis and clinical stage were correlated with patients’ prognosis. Conclusion: TRAP1 is highly expressed in kidney cancer and correlates with patients prognosis, which may be served as a potential marker for the diagnosis and treatment of kidney cancer.     

17q allele loss is associated with lymph node metastasis in locally aggressive human colorectal cancer

A consecutive series of 87 colorectal tumours were studied for loss of a polymorphic probe on chromosome 17q and of the 64 informative cases, 13 (20 per cent) showed loss of heterozygosity (LOH). Examples of LOH were found in carcinomas of all stages and in a large non-invasive adenoma. There was no correlation between 17q LOH and patient age, sex, standard clinicopathological variables (differentiation and nature of tumour margin), DNA ploidy, or tumour site, nor was 17q LOH associated with 17p LOH defined at four loci adjacent to p53. However, comparison of Dukes' B and C carcinomas revealed that tumours which had metastasized to regional lymph nodes at the time of primary surgery were significantly more likely to have lost this 17q allele. Clinical follow-up of this cohort of patients showed no significant difference in survival between patients whose tumours had lost or retained 17q. Thus, we conclude that 17q allele loss is associated with lymph node metastasis in locally aggressive colorectal tumours but probably not with blood-borne metastasis.     

KiSS-1 Expression in Human Breast Cancer

The KiSS-1 gene encodes a 145 amino acid residue peptide that is further processed to a final peptide, metastin, a ligand to a G-coupled orphan receptor (OT7T175/AXOR12). KiSS-1 has been identified as a putative human metastasis suppressor gene in melanomas and in breast cancer cell lines. This study aimed to determine the expression and distribution of KiSS-1 and its receptor in human breast cancer tissues and to identify a possible link between expression levels and patient prognosis. Frozen sections from breast cancer primary tumours (matched tumour 124 and background 33) were immuno-stained with KiSS-1 antibody. RNA was reverse transcribed and analyzed by Q-PCR (standardized using β-actin, and normalized with cytokeratin-19 levels). Levels of expression of KiSS-1 were higher in tumour compared to background tissues (3124±1262 vs 2397±1181) and significantly increased in node positive tumours compared to node negative (3637±1719 vs 2653±1994, P = 0.02). KiSS-1 expression was also increased with increasing grade and TNM status. There were no such trends with the KiSS-1 receptor. Expression of KiSS-1 was higher in patients who had died from breast cancer than those who had remained healthy (4631±3024 vs 2280±1403) whereas expression of the receptor was reduced (480±162 vs 195±134). Immunohistochemical staining showed increased expression of KiSS-1 in tumour sections. Insertion of the KiSS-1 gene into the human breast cancer cell line MDA-MB-231, resulted in cells that were significantly more motile and invasive in behaviour, with reduced adhesion to matrix, using respective assays. In conclusion, KiSS-1 expression is increased in human breast cancer, particularly in patients with aggressive tumours and with mortality. Over-expression of KiSS-1 in breast cancer cells result in more aggressive phenotype. Together, it suggests that KiSS-1 plays a role beyond the initial metastasis repressor in this cancer type.     

Depressed-type of early colon cancer with extensive lymph node metastasis

Early colorectal cancer (ECC) is defined as invasive tumor limited to the colonic and rectal mucosa or submucosa, regardless of the presence or absence of lymph node metastasis. The incidence of lymph node metastasis in ECC ranges from 0 to 15.4%, and risk factors include depth of submucosal invasion, growth patterns (polypoid or non-polypoid), histologic subclassification, and lymphatic invasion. Of non-polypoid growth patterns, the depressed types of colorectal cancer have higher malignant potential than polypoid types, even for small sizes. Unfortunately, this type is also difficult to detect on colonoscopic examination. In this report, we describe a case of depressed type ECC with extensive lymph node metastasis without regional lymph node involvement.     

Predicting lymph node status in patients with early gastric carcinoma using double contrast-enhanced ultrasonography

Introduction

Double contrast-enhanced ultrasonography (DCUS) is a new method we used in predicting lymph node metastasis (LNM) in patients with early gastric cancer.

Material and methods

Seventy-six patients with early gastric cancer diagnosed by gastroscope and confirmed by pathology after operation were examined using DCUS preoperatively. Group N1 included 15 patients with LNM and group N0 61 patients without LNM.

Results

In group N1, 13 patients (87%) had marked hyperenhancement during early arterial phase using DCUS, and 2 patients (13%) were unmarked as hyperenhancement. In group N0, 24 patients (39%) had marked hyperenhancement during early arterial phase using DCUS, and 37 patients (61%) had unmarked hyperenhancement. The sensitivity and specificity of marked hyperenhancement in predicting LNM in patients with early gastric cancer was 86.7% and 60.7% respectively, and the Youden’s index was 0.474. The κ value of this method was 0.89.

Conclusions

Double contrast-enhanced ultrasonography is a new valuable method to evaluate LNM at an early stage of gastric cancer and prognosis of early gastric cancer preoperatively.     

120例结直肠癌手术前后血清CEA RIA测定的临床观察

为了解结直肠癌患者血清中CEA的水平与该疾病的关系 ,采用RIA法对 12 0例结直肠癌患者手术前后的血清进行了CEA检测 ,同时检测了 2 4名正常人作为对照。结果显示 :正常组CEA为 9.84± 2 .4 4ng/mL ,术前患病组CEA为 38.85± 19.2 1ng/mL ,其中结肠癌组为 37.4 3± 18.5 8ng/mL ,直肠癌组为 39.72± 2 0 .6 7ng/mL ,正常组与患病组比较P <0 .0 1,结肠癌组与直肠癌组比较P >0 .0 5。术后 2个月内对 4 4例术前CEA阳性者进行监测 ,37例CEA降至 11.2 1± 3.6 5ng/mL ,7例因手术无法根治 ,CEA为 5 0 .6 3± 2 4 .38ng/mL。术后长达 6年随访监测有 4 1例复发 ,CEA水平为 4 3.12± 2 7.15ng/mL ,4 1例复发患者中 3年内复发率占 87.80 %。结论 :CEA水平检测对结直肠癌患者术前诊断 ,术后疗效评估及监测肿瘤复发与转移是一种简便易行的有效手段。     

中性粒细胞—淋巴细胞比预测早期胃癌淋巴结转移的临床价值

目的分析中性粒细胞—淋巴细胞比(NLR)预测早期胃癌(EGC)淋巴结转移的临床价值,以期为EGC治疗方案的制订提供参考。方法回顾性分析在我院行胃癌根治术并经术后病理确诊为EGC的134例患者的临床资料,根据淋巴结是否转移分为阳性组和阴性组。收集EGC患者术前1周血液学指标并计算血小板—淋巴细胞比(PLR)和NLR;收集患者基本信息及术后病理信息,行单因素和多因素Logistic回归分析;通过受试者工作特征(ROC)曲线分析NLR预测EGC伴淋巴结转移阳性的诊断价值;分析术前NLR与患者一般资料及临床病理之间的相关性;Pearson相关性检验分析NLR与肿瘤大小的相关性;Kaplan-Meier(K-M)曲线及Log-rankχ2检验比较高NLR组和低NLR组患者术后生存状况。结果单因素分析结果显示,浸润深度、分化程度、肿瘤大小、PLR、NLR与淋巴结转移相关(P<0.05)。多因素Logistic回归分析结果显示,肿瘤大小≥2cm、浸润深度为黏膜下层、分化程度为低分化、NLR≥1.965是淋巴结转移的独立危险因素(P<0.05)。根据ROC曲线,NLR截断值为2.295,术前NLR预测淋巴结转移的灵敏性和特异性分别为82.6%和77.5%。根据截断值将所有患者分为低NLR组(NLR<2.295)90例和高NLR组(NLR≥2.295)44例,2组患者一般资料及临床病理相关因素分析结果显示,术前NLR与年龄、肿瘤大小、肿瘤大体类型显著相关(P<0.05)。术前NLR与肿瘤大小呈正相关(r=0.645,P<0.001)。术前高NLR组患者术后5年生存率明显低于低NLR组患者(P<0.05)。结论术前NLR对EGC患者发生淋巴结转移具有较高的预测价值,且对EGC患者预后的评估具有一定的临床参考价值。     

Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancer

We examined the phenotype and function of CD4+ T cells expressing the semaphorin III receptor neuropilin-1 (Nrp1) in human lymph nodes and peripheral blood. In lymph nodes, Nrp1 identified a small regulatory CD4+ CD25(high) T-cell subpopulation (Nrp1+ Treg) that expressed higher levels of Forkhead box P3 (Foxp3) message and protein than Nrp1- Treg, and various molecular markers of activated Treg, i.e. CD45RO, human leucocyte antigen (HLA)-DR and glucocorticoid-induced tumour necrosis factor receptor (GITR). Similarly to conventional Treg, Nrp1+ Treg proliferated poorly in vitro, and exerted contact-dependent in vitro suppression of T-cell proliferation and cytokine secretion. However, Nrp1+ Treg were more efficient than Nrp1- Treg at inducing suppression. Nrp1 was also expressed on a small subpopulation of CD25(int) and CD25- CD4+ T cells that expressed more Foxp3, CD45RO, HLA-DR and GITR than their Nrp1- counterparts. In contrast, in peripheral blood Nrp1 identified a minor CD4+ T-cell subset that did not display the phenotypic features of Treg lacking Foxp3 expression and marginally expressing CD25. Hence, the function of Nrp1+ CD4+ T cells seemingly depends on their anatomical location. In a previous report, we proposed that Treg may curb the anti-tumour T-cell response in cervical cancer. We show here that Treg and Nrp1+ Treg levels dropped in the tumour-draining lymph nodes of patients with cervical cancer following preoperative chemoradiotherapy in a direct relationship with the reduction of tumour mass, suggesting that suppressor cell elimination facilitated the generation of T cells mediating the destruction of the neoplastic cells left behind after cytotoxic therapy.     

Metastasis-associated colon cancer-1 is a novel prognostic marker for cervical cancer

Aims: To investigate metastasis associated in colon cancer 1 (MACC1) expression in cervical cancer. Methods: One hundred and four paraffin-embedded cervical cancer specimens were immunohistochemically analyzed for MACC1 expression. The expression of MACC1 in 8 pairs of cervical cancer and adjacent normal cervical tissues were detected by Real-time PCR. Results: MACC1 expression was upregulated in cervical cancer tissues compared with adjacent normal cervical tissues. Patients with higher MACC1 expression had shorter overall survival time, whereas those with lower ASAP1 expression survived longer (P = 0.029). Moreover, high expression of MACC1 was correlated with FIGO stage (P = 0.039) and lymph nodes metastasis (P = 0.003) of this disease. Multivariate analysis revealed that MACC1 was an independent prognostic factor (P = 0.043) for the overall survival of cervical cancer patients. Conclusion: Our study suggests that MACC1 may contribute to tumor development and progression in cervical cancer, and that MACC1 could be a useful marker for the prognosis of cervical cancer.     

Clinicopathologic Characteristics and Prognosis of Advanced Gastric Cancer Simulating Early Gastric Cancer

Background

Although the clinicopathologic features and prognosis of Borrmann type advanced gastric cancer has been well characterized, those of advanced gastric cancer simulating early gastric cancer (AGC simulating EGC) still remains unclear.

Methods

We reviewed 1985 gastric cancer patients who had undergone gastrectomy at our hospital to determine the clinicopathologic characteristics, susceptible sites for lymph node metastasis, and prognosis of AGC simulating EGC in comparison with Borrmann type advanced gastric cancer.

Results

Among 102 patients with AGC simulating EGC, 100 patients (98%) had tumors with depressed type appearance. The frequencies of serosal invasion, lymph node metastasis, lymphatic vessel invasion, blood vessel invasion, and liver metastasis were significantly lower in AGC simulating EGC than in Borrmann type tumors. The prognosis of AGC simulating EGC was significantly better than that of the Borrmann type tumors. Multivariate analysis indicated that the gross appearance was an independent prognostic factor. In patients with AGC simulating EGC which invaded to the the muscularis propria (MP), most lymph node metastasis was restricted with the perigastric lymph nodes (1st-titer lymph nodes) and lymph node metastasis to 2nd-titer lymph nodes was only observed at station 8a.

Conclusion

AGC simulating EGC is less advanced in comparison with Borrmann type advanced gastric cancer. Based on the results of susceptible sites for lymph node metastasis in the current study, limited lymph node dissection could be indicated for AGC simulating EGC whose depth of invasion is MP.     

Altered Activity and Expression of Cytosolic Peptidases in Colorectal Cancer

Background and Objective: The role of peptidases in carcinogenic processes and their potential usefulness as tumor markers in colorectal cancer (CRC) have been classically attributed to cell-surface enzymes. The objective of the present study was to analyze the activity and mRNA expression of three cytosolic peptidases in the CRC and to correlate the obtained results with classic histopathological parameters for tumor prognosis and survival.Methods: The activity and mRNA levels of puromycin-sensitive aminopeptidase (PSA), aminopeptidase B (APB) and pyroglutamyl-peptidase I (PGI) were measured by fluorimetric and quantitative RT-PCR methods in colorectal mucosa and tumor tissues and plasma samples from CRC patients (n=81).Results: 1) PSA and APB activity was higher in adenomas and carcinomas than in the uninvolved mucosa. 2) mRNA levels of PSA and PGI was lower in tumors. 3) PGI activity in CRC tissue correlated negatively with histological grade, tumor size and 5-year overall suvival of CRC patients. 4) Higher plasmatic APB activity was independently associated with better 5-year overall survival.Conclusions: Data suggest that cytosolic peptidases may be involved in colorectal carcinogenesis and point to the determination of this enzymes as a valuable method in the determination of CRC prognosis.     

High-level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients

Fleischmann A, Rocha C, Saxer‐Sekulic N, Zlobec I, Sauter G & Thalmann G N
(2011) Histopathology 58 , 781–789
High‐level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients Aims: To test the prognostic significance of cyclin D1 in nodal‐positive prostate cancer. Methods and results: Nuclear and cytoplasmic cyclin D1 expression was evaluated in 119 nodal‐positive prostate cancer patients undergoing radical prostatectomy and extended lymphadenectomy. Cyclin D1 was correlated with various tumour features and biochemical recurrence‐free survival (bRFS), disease‐specific survival (DSS) and overall survival (OS). In the metastases, high‐level cytoplasmic cyclin D1 expression independently predicted poor outcome (5‐year bRFS, 12.5% versus 26.4%, P = 0.006; 5‐year DSS, 56.3% versus 80.7%, P = 0.007; 5‐year OS, 56.3% versus 78.7%, P = 0.011). These patients had a 2.62‐fold elevated risk of dying from prostate cancer as compared with patients with low‐level cytoplasmic cyclin D1 expression (P = 0.024). All other subcellular compartments of cyclin D1 expression in primary tumours and metastases were prognostically non‐significant. Conclusions: The subcellular location of cyclin D1 expression in prostate cancer is linked to specific clinical courses. Survival stratification according to biomarker expression in metastases indicates an important role for tumour sampling from these tissues.