VEGF-RII influences the prognosis of pancreatic cancer

OBJECTIVE: To evaluate whether the vascular endothelial growth factor (VEGF) pathway can be used as a target for effective treatment of pancreatic cancer. SUMMARY BACKGROUND DATA: VEGF and its receptors (VEGF-RI and -RII) are the predominant regulators of tumor neoangiogenesis, a key element for tumor growth and progression. However, VEGF receptor expression has been thought to be limited to endothelial cells, limiting the possibility of targeting it for therapy of pancreatic cancer. METHODS: Protein localization and mRNA were studied in pancreatic cancer specimens, normal pancreas, human pancreatic cancer cell lines, and an endothelial cell line. Cell proliferation was determined by [ H] thymidine uptake. Both VEGF receptors were genetically eliminated by antisense technology. The same approach was used in a murine model of pancreatic cancer in a therapeutic approach. RESULTS: VEGF-RI mRNA and VEGF-RII mRNA were expressed in 17 and 15 of 24 pancreatic cancer samples, respectively. VEGF receptors were found not only in blood vessels but also in pancreatic cancer cells. VEGF-RII expression correlated with poor tumor differentiation and was associated with poorer survival, while VEGF-RI expression did not correlate. VEGF treatment led to extensive growth stimulation in six of seven pancreatic cancer cell lines, which was completely inhibited by antisense treatment against VEGF-RII. Liposome-mediated gene transfer in nude mice with pancreatic tumors markedly reduced local tumor growth and decreased metastatic tumor spread. CONCLUSIONS: The VEGF/VEGF-RII pathway regulates angiogenesis and local tumor growth and spread in pancreatic cancer. Genetic targeting of VEGF-RII blocks local growth and metastatic spread of pancreatic cancer cells in vivo and therefore offers a potential new therapeutic option for patients with this disease.     

影响胰腺癌预后的因素分析

目的　探讨影响胰腺癌预后的决定因素。 方法　应用流式细胞仪检测胰腺癌ＤＮＡ倍体６２ 例,采用免疫组织化学法检测ｐ２１ 、ｐ５３ 在胰腺癌中的表达,应用Ｃｏｘ 比例风险模型对其预后因素进行分析。 结果　本组共有６２ 例经手术和病理学检查证实的胰腺癌病人,其中胰腺癌患者二倍体２５ 例,四倍体１１ 例,预后较好,平均生存期分别为２８ 个月和３０ 个月,非四倍体异倍体者２６ 例平均生存期仅为５ 个月。胰腺癌组织ｐ２１ 阳性率为８９％ ,ｐ５３ 阳性率为５１％ 。二者表达均与临床分期密切相关;单因素分析发现,ＤＮＡ倍体、后腹膜浸润、手术方式、肝转移、临床分期、ｐ２１ 表达、十二指肠浸润等与预后密切相关,多因素分析中仅ＤＮＡ倍体和临床分期是独立预后决定因素。 结论　ＤＮＡ倍体和临床分期是胰腺癌独立预后的决定因素     

人巨噬细胞金属弹性蛋白酶基因真核表达载体的构建及其鉴定

目的　构建一个包含人巨噬细胞金属弹性蛋白酶 (HME)基因全部功能区的重组真核表达载体pcDNA3 .1(-) /HME ,为进一步研究人巨噬细胞金属弹性蛋白酶对体内肿瘤血管生成的影响奠定基础。方法　用Trizol试剂法从经体外纯化培养的人巨噬细胞中提取总RNA ,经逆转录 聚合酶链式反应 (RT PCR)扩增目的片段 ,PCR产物及真核表达载体分别双酶切后进行连接 ,并转化入大肠杆菌DH5α扩增以获得重组载体。结果　RT PCR获得预期大小的特异性DNA片段 ,经双酶切鉴定及测序证实已将人巨噬细胞金属弹性蛋白酶基因cDNA片段正确插入真核表达载体中。结论　成功获得pcDNA3 .1(-) /HME重组真核表达载体。     

276例胰腺癌临床预后因素分析

目的 探讨影响胰腺癌预后的因素.方法 回顾性分析1995年9月至2005年8月收治的276例胰腺癌患者的临床资料,采用Cox比例风险模型分析可能影响胰头癌、胰体尾癌预后的独立因素,用Kaplan-Meier方法描述不同位置胰腺癌的中位生存时间,并进行Log-rank和Breslow检验.结果 Cox比例风险模型发现包块直径、肠系膜上血管浸润情况和治疗方式是胰头癌预后的独立影响因素;年龄、淋巴结肿大和治疗方式是胰体尾癌预后的独立影响因素.根治术后胰头癌和胰体尾癌患者的中位生存时间分别为460 d和480 d,显著高于姑息治疗或放弃治疗患者的240 d和200 d.在肿瘤位置对生存时间的影响中,全胰癌患者总体中位生存时间为117 d,明显低于胰头癌的330 d和胰体尾癌的300 d.结论 根治性手术是目前改善胰腺癌预后最好的方法.包块直径＞4 cm、肠系膜上血管浸润的胰头癌预后较差;年龄≤60岁和淋巴结肿大的胰体尾癌预后较差.胰头癌与胰体尾癌的预后相近,全胰癌是胰腺癌中极为晚期的状态,预后极差.     

Human T-cell leukemia virus type 1 infection worsens prognosis of hepatitis C virus-related living donor liver transplantation

Severe and life-threatening donor-transmitted human T-cell leukemia virus type 1 (HTLV-1) infections after solid organ transplantation have been reported. However, in HTLV-1-infected recipients, graft and patient survival were not fully evaluated. A total of 140 patients underwent living donor liver transplantation (LDLT). Of these, 47 of 126 adult recipients showed indications of hepatitis C virus (HCV)-related liver disease. The HTLV-1 prevalence rate was 10 of 140 recipients (7.14%) and three of 140 donors (0.02%). In HCV-related LDLT, graft and patient survival was worsened by HTLV-1 infection in recipients (seven cases). The 1-, 3-, and 5-year survival rates in the HCV/HTLV-1-co-infected group were 67%, 32%, and 15%, respectively, and the corresponding rates in the HCV-mono-infected group were 80%, 67%, and 67%, respectively. Only the 5-year survival rates were statistically significant (P=0.04, log-rank method). HTLV-1 infection in recipients is also an important factor in predicting survival in HTLV-1 endemic areas.     

肿瘤相关巨噬细胞在晚期胰腺癌组织中的浸润及其与预后的关系

目的 探讨肿瘤相关巨噬细胞(TAM)在胰腺癌组织中的浸润及对胰腺癌患者生存和预后的影响.方法 应用免疫组织化学方法 检测胰腺癌及胰腺良性病变组织中TAM的特异性标志物CD68,了解TAM在胰腺癌组织和胰腺良性病变中的浸润密度,比较TAM高密度组与低密度组胰腺癌患者的生存差异,并对影响预后的多个临床病理因素进行单因素及多因素分析.结果 在200倍高倍光学显微镜下计数,86例胰腺癌组织标本中TAM平均密度为29.6/HP,25例胰腺良性病变组织标本中TAM平均密度为14.2/HP.在胰腺癌组织中TAM浸润密度较良性病变组织中明显为高(P＜0.01).胰腺癌患者中TAM低密度组的中位生存时间为(16.7±3.4)个月,1年累积生存率为73.8%;TAM高密度组的中位生存时间为(9.4±2.6)个月,1年累积生存率为20.1%.TAM低密度浸润胰腺癌患者1年生存率较TAM高密度患者为高(P＜0.01).在胰腺癌患者中,低分化癌TAM浸润较明显.多因素分析显示,组织学分级及TAM浸润的密度是影响晚期胰腺癌生存的独立的预后因子.结论 晚期胰腺癌组织中有明显的TAM浸润,TAM高密度浸润状态提示预后不良.     

Medial collateral ligament healing in macrophage metalloelastase (MMP-12)-deficient mice.

Medial collateral ligament (MCL) injuries heal by a wound repair scar response controlled by a complex cellular and cytokine environment. Many enzymes participate in wound repair, particularly the matrix metalloproteinases. We hypothesize macrophage metalloelastase (MME/MMP-12) deficiency results in impaired healing of MCL injury. One hundred fifty MME-deficient and 150 WT (MME+/+) mice underwent knee MCL transection with the opposite knee as a sham operated control. Mice were sacrificed at 3, 7, 28, 42, and 56 days. At each of the five time points, 15 mice were utilized for biological and 15 were utilized for biomechanical testing. Outcome measures were the presence of macrophages to represent the inflammatory phase of wound healing, collagen synthesis to assay for matrix repair, and biomechanical testing for repair strength. Immunohistochemistry demonstrated significantly fewer macrophages in cut MCLs from MME-deficient mice versus wild-type (WT) mice at 3, 7, 28, and 42 days (all p相似文献   

S100基因家族在胰腺癌早期诊断和预后方面的研究进展

肿瘤的发生发展受多种基因调控。近几年发现S100基因家族与胰腺癌关系密切,该家族基因编码一种钙离子结合调节蛋白,通过与钙离子结合在肿瘤发生发展中发挥重要作用。     

巨噬细胞炎症蛋白-1α对胃癌血管生成及预后的影响

为探讨胃癌组织微血管计数 (MVC)和巨噬细胞炎症蛋白 1α(MIP 1α)之间及其与胃癌侵袭转移和预后的关系 ,笔者采用免疫组化染色检测 60例胃癌病理标本MVC计数和MIP 1α半定量表达情况及其与肿瘤临床病理参数和预后的关系。结果示MIP 1α的阳性表达与MVC呈密切正相关 (P<0 .0 1) ,胃癌MVC高计数组及MIP 1α高表达组生存率明显低于低计数组和低表达组 (均P <0 .0 1)。提示胃癌MIP 1α表达与胃癌血管生成及预后密切相关 ,检测MIP 1α可能有助于确定术后治疗方案及判断预后。     

Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma

OBJECTIVE: To determine molecular mechanisms involved in angiogenesis of hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Tumor angiogenesis is believed to derive from the balance between angiogenic stimulators and inhibitors. It has been suggested that the switch to the angiogenic phenotype requires both upregulation of the first and downregulation of the second. However, its molecular basis in vivo remains obscure. In this study the authors analyze the participation of two factors in angiogenesis of HCC- human macrophage metalloelastase (HME), a matrix metalloproteinase responsible for the generation of angiostatin, a potent angiogenesis inhibitor, and vascular endothelial growth factor (VEGF), the most potent endogenous angiogenic factor. METHODS: Tumorous and contiguous nontumorous tissues from 25 patients with HCC who underwent curative partial hepatectomy were subjected to Northern blot analysis to detect HME and VEGF messenger RNA (mRNA) expression. Western blot analysis was used to detected angiostatin. Tumor vascularity was evaluated using hepatic angiography. RESULTS: Eleven of the 15 cases expressing the HME gene showed hypovascular tumors, whereas hypervascular tumors were seen in 9 of the 10 HME-negative cases. The median of HME mRNA expression (tumorous/nontumorous ratio) was 6.5 (range 0-264.5) in the hypovascular group and 0 (range 0-3.2) in the hypervascular group. A stepwise logistic analysis revealed that HME and VEGF mRNA expression were two independent variables significantly affecting the vascularity of HCC tumors. CONCLUSION: HME gene expression is significantly associated with hypovascular tumors; moreover, angiogenesis in HCC is not determined by a single factor, but depends on the net balance between HME and VEGF gene expressions.     

Effect of tumor size and lymph node status on the prognosis of pancreatic cancer

Between 1982 and 1987 186 patients with a carcinoma of the pancreas underwent surgery. In 69 patients (37%) a resective surgical procedure was performed. In these patients, lymph node staging was conducted intraoperatively. The operative mortality of the resection was 4.3%. The median survival of the resected patients with papillary carcinoma was 21 months and of the patients with ductal pancreatic carcinoma 7 months. A correlation between survival time and frequency as well as localization of the lymph node attack could be established. Only patients in the TNM stage I of a ductal carcinoma appeared to have profited significantly from the resection compared to the palliative procedure.     

Decreased immunostaining for macrophage scavenger receptor is associated with poor prognosis of prostate cancer

OBJECTIVE

The aim of this study is to evaluate the expression of the macrophage scavenger receptor (MSR) in prostate needle biopsy specimens as a possible prognostic factor for prostate cancer. As MSR reportedly has a role in recognizing foreign pathogenic substances, MSR‐positive inflammatory cells are often detected in solid tumours, and there is a correlation between the relative risk of prostate cancer and polymorphism of the MSR gene.

PATIENTS AND METHODS

MSR was evaluated by immunostaining in needle biopsies of the prostate from 135 patients who were confirmed to have prostate cancer. Among these men, 70 were treated by radical prostatectomy or by radiotherapy as definitive therapy; the other 65 were treated by hormonal therapy because of advanced disease or age. Needle‐biopsy specimens were sectioned at 5 µm and immunostained with a monoclonal antibody against MSR. Six microscopic (×400) fields around the cancer foci were selected in each case for analysis.

RESULTS

The median number of MSR‐positive cells (MSR count) in each case was 24. There was an inverse correlation between the MSR count and Gleason score and clinical stage. The MSR count was lower in patients with biochemical (prostate‐specific antigen, PSA) failure than that in those with no PSA failure (P < 0.001). In all patients, the recurrence‐free survival (RFS) rate was significantly higher in those with a high MSR count (≥24) than that in those with low MSR count (<24, P < 0.001). Moreover, for patients treated by definitive or hormonal therapy, the RFS rates in those with a higher MSR count were higher than in those with a lower MSR count (P < 0.001 and 0.014, respectively). Cox multivariate analysis showed that the MSR count was a prognostic factor for prostate cancer in addition to extraprostatic extension and Gleason score (P = 0.002, 0.038 and 0.011, respectively).

CONCLUSION

The results of immunostaining of MSR in needle‐biopsy specimens is a prognostic factor for prostate cancer.     

Intraoperative blood loss is not a predictor of prognosis for pancreatic cancer

Purpose

The relationship between intraoperative blood loss (IBL) and prognosis has been reported for some types of cancer, but not for pancreatic cancer, which has one of the highest mortality rates of any cancer. We conducted this study to analyze the relationship between IBL and clinical outcome for patients undergoing radical surgery for pancreatic cancer.

Methods

The subjects of this study were 144 patients who underwent curative pancreatectomy for invasive pancreatic cancer between 2002 and 2014. Clinicopathological characteristics were recorded and prognostic factors were identified by univariate and multivariate analyses.

Results

Large IBL was significantly associated with advanced tumor stage, a long operation time, a large tumor, portal vein resection, and blood transfusion. According to univariate analysis, IBL was also significantly associated with overall survival (OS) and relapse-free survival (RFS); however, it was not an independent prognostic factor for OS and RFS in multivariate analysis. According to multivariate analysis, lymph node metastasis and R-status were independent prognostic factors for OS and RFS. A subgroup analysis of patients who received no blood transfusion showed similar results.

Conclusion

Minimizing IBL is very important; however, the present study found that positive lymph node metastasis and R-status were stronger independent prognostic factors for pancreatic cancer.

     

以规范化手术及综合治疗为策略改善胰腺癌预后

胰腺癌恶性程度高,预后极差.提高早期诊断率,做好术前可切除性评估,使有手术条件患者积极手术是目前改善胰腺癌患者预后最为关键的因素.手术时应注意标准化、规范化操作,提高R0切除的比率,并且注意对手术标本切缘标记.术后辅助化放疗对预防肿瘤局部复发及远处转移有积极作用.多科协作、综合治疗有助于提高患者生活质量,改善预后.

Abstract：

Pancreatic adenocarcinoma is a highly malignant tumor and its prognosis is poor. The key factors for cure and prolonged survival are early detection, adequate evaluation of resectability and surgical resection with microscopic tumor clearance. Surgeons should pay attention to standardize operative procedures to increase the R0 resection rate. Whipple specimens should be inked and examined carefully. Postoperative adjuvant radiotherapy and chemotherapy are beneficial in the prevention of local tumor recurrence and distant metastasis. Inter-disciplinary cooperation and multimodality treatment are helpful to improve the prognosis and quality of life of patients with pancreatic cancer.     

肿瘤标志物对胰腺癌诊断及预后评估作用的研究进展

胰腺癌是目前常见的恶性肿瘤,其发病率与致死率近乎持平。如何提高胰腺癌早期确诊率和胰腺癌的治疗效果是急需解决的问题。肿瘤标志物对胰腺癌患者的筛选、治疗效果评估和监测术后复发的作用正在不断扩大。笔者通过回顾胰腺癌血清和胰液等体液中的肿瘤标志物的研究进展及存在的问题,重点探讨肿瘤标志物对胰腺癌诊断及预后评估的作用。     

Preoperative neutrophili-to-lymphocyte ratio is useful for stratifying the prognosis of tumor markers-negative pancreatic cancer patients

BackgroundElevated levels of preoperative tumor markers (TMs), including carcinoembryonic antigen and carbohydrate antigen 19–9 are risk factors for the survival of patients with pancreatic cancer (PC). However, TMs are not always applicable in various conditions. This study aimed to investigate the prognostic value of systemic inflammatory marker (SIM) in such patients.MethodsSeventy-seven patients who underwent curative surgery for PC with negative TMs were included in this study. Various SIMs for each patient were examined to determine the most reliable one. Using the most superior SIM, the patients were divided into two groups and their characteristics and postoperative results were compared.ResultsThe NLR was superior to other SIMs. Despite no significant intergroup differences were observed between the groups, the overall survival (OS) rate was significantly higher in the low NLR group than in the high NLR group (5-year OS rate: 81.2% vs. 24.2%, p < 0.001).ConclusionThe NLR is a simple and reliable prognostic marker in TM-negative PC patients.