N2肺癌预后因素分析及手术适应证的探讨

目的 :识别纵隔淋巴结转移 (N2 )的非小细胞肺癌 (non smallcelllungcancer ,NSCLC)患者根治术后的预后不利因素 ,探讨N2 肺癌合理的手术适应证。方法 :回顾1993年 1月 1日～ 2 0 0 0年 1月 3 1日 ,2 12例根治性切除及系统性淋巴结廓清术后病理诊断为N2 肺癌患者的临床资料。应用Ka plan Meier法计算生存率 ,Log rank检验比较不同临床病理因素组间患者的生存差别 ;Cox多因素回归分析 ,判定N2 肺癌预后的不利因素。结果 :本研究 5年生存率为17% ,其中有N2 临床症状、大细胞肺癌和T4患者的预后最差 ,中位生存期不足 12个月。有纵隔淋巴结转移症状 (RR =9 2 ,P <0 0 0 1)、T4肿瘤 (RR =7 15 ,P <0 0 0 1)、淋巴结被膜受侵 (RR =1 72 8,P =0 0 0 8)和多站(≥ 3站 )淋巴结转移 (RR =2 2 94,P =0 0 0 2 )是预后的不利因素。结论 :N2 非小细胞肺癌患者的预后有很大的差别 ,根治切除的适应证应该加以选择。有明显纵隔淋巴结转移症状、大细胞肺癌和T4肿瘤的N2 患者预后极差 ,不宜将外科手术作为首选的治疗方法。     

63例宫颈腺癌临床治疗和预后分析

目的:了解影响宫颈腺癌预后的相关因素,探讨宫颈腺癌比较理想的治疗方法.方法:对天津医科大学附属肿瘤医院1980年1月至2000年1月间收治的63例宫颈腺癌进行分析,占同期宫颈癌的4.65%,并随机选取同期治疗的80例宫颈鳞癌作为对照进行比较.患者平均发病年龄53.7岁,绝经后患者占55.6%.主要症状为阴道不规则出血和/或白带增多.其中Ⅰ期17例,Ⅱ期33例,Ⅲ期13例.20例采用单纯放射治疗,43例采用放射治疗与手术相结合的综合治疗.结果:收治的宫颈腺癌占宫颈癌的比例从80年代的3.5%(38/1087)上升至90年代的7.36%(34/462),其5年总的生存率为56.9%(33/63-5),低于同期宫颈鳞癌5年生存率.单纯放疗组5年生存率50%;手术放疗组5年生存率为60.5%,两组间无统计学差异.行根治性手术的Ⅰ、Ⅱ期患者5年生存率为80%,而行全宫切除的同期患者5年生存率仅为39.3%,但二者差异尚无统计学意义.宫颈肿瘤≥4cm和＜4cm者5年生存率分别为34.3%(12/35)和60.7%(17/28)具有明显差异(P＜0.05).Ⅰ、Ⅱ期5年生存率62%(31/50),而Ⅲ期5年生存率为7.7%(1/13),二者差异显著(P＜0.01).结论:宫颈腺癌的发病比例呈上升趋势,宫颈腺癌的预后与临床分期、肿瘤大小、治疗方式关系密切.以根治性手术为主的综合治疗是宫颈腺癌的主要治疗方法.     

贲门癌切除机械吻合术后的胃食管反流

目的:探讨贲门癌切除食管胃机械吻合术后重建食管与胃食管反流之间的关系.方法:对30例术后患者进行食管胃压力测定,其中16例行24h食管pH监测,12例行内镜检查和病理学检查.结果:测压结果显示:吻合口与吻合口下方的静息压相似,比较差异无显著性(P＞0.05),而吻合口上方静息压增高,平均为3.42mmHg,经比较吻合口上方和吻合口下方差异有显著性(P＜0.05).值得注意的是其压力值(3.42mmHg)远低于正常括约肌的静息压(10～45mmHg),因此其抗反流作用的程度是有限的.本组16例术后食管24h pH监测表明食管的酸暴露时间延长,食管酸暴露时间百分比平均为13.78%,为正常人的11倍,反流次数增加,最长反流时间达43min,说明手术后的胃食管反流是客观存在的.内镜检查和病理检查,83.3%有异常现象及食管炎征象,进一步证实术后患者有不同程度的反流性食管炎.结论:1)贲门癌切除食管胃吻合术后存在胃食管反流.2)反流的发生不因机械吻合或手工吻合而异.3)反流的发生与术后时间长短无关.4)24h食管pH监测是最敏感的观察方法.5)半卧位睡眠是预防反流的有效方法.6)反流的治疗主要应用促动力药和粘膜保护剂.     

流式细胞术测定COX-2、iNOS基因蛋白在食管癌上的表达及意义

 目的　探讨环氧化酶 2 (COX 2 ) ,Ⅱ型一氧化氮合酶 (iNOS)基因蛋白在食管癌上的表达以及与食管癌的分化和淋巴结转移的关系。方法　采用流式细胞术定量检测 6 5例食管鳞状细胞癌上COX 2、iNOS的蛋白表达量 (用荧光指数FI表示 )。结果　COX 2、iNOS在低分化型 (G3)鳞癌上的表达量明显高于分化型 (G1、G2 )鳞癌 (其P值分别为 0 .0 0 0 1、0 .0 385 ) ;二者之间呈明显正相关。这两种基因蛋白的表达强弱均与淋巴结转移无关。结论　COX 2、iNOS的表达强弱与食管癌的分化密切相关 ;COX 2与i NOS在促食管癌的发生发展中有互相协同作用     

Interleukin-12 enhances the sensitivity of human osteosarcoma cells to 4-hydroperoxycyclophosphamide by a mechanism involving the Fas/Fas-ligand pathway.

Cyclophosphamide (CY) and its derivative ifosfamide are alkylating agents used to treat osteosarcoma (OS). The purpose of these studies was to determine whether alkylating agents affect the expression of Fas ligand (FasL) and whether interleukin 12 enhances the sensitivity of human OS cells to alkylating agents. 4-Hydroperoxycyclophosphamide (4-HC), the preactivated CY compound, and 4-hydroperoxydidechlorocloclophosphamide (4-HDC), its nonalkylating analogue, human OS LM6 cells, and a clone of cells derived by transfection with the interleukin 12 gene (LM6-#6) were used for these studies. Incubation of LM6 and LM6-#6 with 10 micro M 4-HC increased the expression of FasL mRNA (2.5- and 3.0-fold, respectively). By contrast, 4-HDC, Adriamycin (ADR), cisplatin (CDP), and methotrexate (MTX) had no effect on FasL mRNA expression. Increased FasL expression after treatment with 4-HC was also demonstrated by immunohistochemistry and flow cytometry. Drug-induced FasL was functional and mediated cell death. We examined the effect of FasL up-regulation by 4-HC on LM6 and LM6-#6 cells. Flow cytometry showed that LM6-#6 cells expressed 2.2-fold more Fas than LM6 cells. Cytotoxicity of 4-HC, 4-HDC, ADR, CDP, and MTX on LM6, LM6-neo, and LM6-#6 were quantified. Colony-forming assay revealed an IC(50) of 2.10 micro M for 4-HC in LM6-neo cells compared with 0.41 micro M in LM6-#6 cells. The IC(50) for 4-HDC, ADR, CDP, and MTX were not significantly different between the two cell lines. We concluded that the increased expression of Fas enhanced LM6-#6 sensitivity to 4-HC. These data indicate that Fas/FasL may be involved in the cytotoxic pathway of CY. Combining biological agents with chemotherapeutic agents that have complementary Fas/FasL pathway actions may offer new therapeutic alternatives.     

Overexpressed eIF4E is functionally active in surgical margins of head and neck cancer patients via activation of the Akt/mammalian target of rapamycin pathway.

PURPOSE: Overexpression of eIF4E in surgical margins of head and neck cancer patients is an independent risk factor for recurrence. We hypothesize that overexpressed eIF4E is functionally active in tumor margins through activation of the Akt/mammalian target of rapamycin (mTOR) pathway EXPERIMENTAL DESIGN: Western blots and/or immunohistochemistry were performed to determine whether phosphorylation of mTOR and activation of its downstream molecules eIF4E-binding protein-1 (4E-BP1) and p70 S6 kinase and the upstream modulator of mTOR, Akt, were expressed in margins overexpressing eIF4E. RESULTS: There was a significant association between phospho-4E-BP1 and eIF4E expression of a margin or a significant difference in phospho-4E-BP1 expression between the eIF4E-positive and -negative margins (P < 0.01). A significant association between eIF4E and phospho-p70 S6 kinase as well as eIF4E and phospho-mTOR was also noted (P < 0.05). Western blot analysis indicated a highly significant difference in the phosphorylation status of 4E-BP1 between tumors and resection margins. A total of 89% of the 4E-BP1-expressing margins expressed more of the phosphorylated (beta, gamma, and delta) isoforms, whereas 81% of the 4E-BP1-expressing tumors expressed more of the unphosphorylated alpha isoform. A similar difference in Akt activation was noted between eIF4E-positive margins and tumors (P < 0.05). CONCLUSIONS: Overexpression of eIF4E is functionally active in tumor margins through activation of the Akt/mTOR signaling pathway. The greater degree of expression of downstream targets and upstream regulators of mTOR in margins compared with the tumors indicates preferential activation of the Akt/mTOR signaling pathway in margins overexpressing eIF4E. Rapamycin analogs can potentially be used as adjuvant therapy for patients with eIF4E-positive margins.     

MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course.

MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P < 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P < 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis.     

The attitudes of cancer patients and their families toward the disclosure of terminal illness.

PURPOSE:To ascertain the attitude of cancer patients and their families toward disclosure of terminal illness to the patient. PATIENTS AND METHODS: We constructed a questionnaire that included demographic and clinical information and delivered it to 758 consecutive individuals (433 cancer patients and 325 families that have a relative with cancer) at seven university hospitals and one national cancer center in Korea. RESULTS: 380 cancer patients and one member from each of 281 families that have a relative with cancer completed the questionnaire. Cancer patients were more likely than family members to believe that patients should be informed of the terminal illness (96.1% v 76.9%; P <.001). Fifty percent of the family members and 78.3% of the patients thought that the doctor in charge should be the one who informs the patient. Additionally, 71.7% of the patients and 43.6% of the family members thought that patients should be informed immediately after the diagnosis. Stepwise multiple logistic regression indicated that the patient group was more likely than the family group to want the patient to be informed of the terminal illness (odds ratio [OR], 9.76; 95% CI, 4.31 to 22.14), by the doctor (OR, 4.00; 95% CI, 2.61 to 6.11), and immediately after the diagnosis (OR, 3.64; 95% CI, 2.45 to 5.41). CONCLUSION: Our findings indicated that most cancer patients want to be informed if their illness is terminal, and physicians should realize that the patient and the family unit may differ in their attitude toward such a disclosure. Our results also reflect the importance of how information is given to the patient.     

Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer.

PURPOSE: The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid cancer, including brain cancer. The present study was designed to prolong survival in mice with intracranial human brain cancer with the weekly i.v. injection of nonviral gene therapy causing RNA interference (RNAi) of EGFR gene expression. EXPERIMENTAL DESIGN: Human U87 gliomas were implanted in the brain of adult scid mice, and weekly i.v. gene therapy was started at day 5 after implantation of 500000 cells. An expression plasmid encoding a short hairpin RNA directed at nucleotides 2529-2557 within the human EGFR mRNA was encapsulated in pegylated immunoliposomes. The pegylated immunoliposome was targeted to brain cancer with 2 receptor-specific monoclonal antibodies (MAb), the murine 83-14 MAb to the human insulin receptor and the rat 8D3 MAb to the mouse transferrin receptor. RESULTS: In cultured glioma cells, the delivery of the RNAi expression plasmid resulted in a 95% suppression of EGFR function, based on measurement of thymidine incorporation or intracellular calcium signaling. Weekly i.v. RNAi gene therapy caused reduced tumor expression of immunoreactive EGFR and an 88% increase in survival time of mice with advanced intracranial brain cancer. CONCLUSIONS: Weekly i.v. nonviral RNAi gene therapy directed against the human EGFR is a new therapeutic approach to silencing oncogenic genes in solid cancers. This is enabled with a nonviral gene transfer technology that delivers liposome-encapsulated plasmid DNA across cellular barriers with receptor-specific targeting ligands.     

Porcine stem cell engraftment and seeding of murine thymus with class II+ cells in mice expressing porcine cytokines: toward tolerance induction across discordant xenogeneic barriers

BACKGROUND: Mixed hematopoietic chimerism is a reliable means of tolerance induction, but its utility has not been demonstrated in discordant xenogeneic combinations because of the difficulty in achieving lasting hematopoietic engraftment. Miniature swine are likely to be suitable organ donors for humans. To evaluate the ability of mixed chimerism to induce swine-specific tolerance in widely disparate xenogeneic recipients, this study aimed to achieve long-lasting chimerism in a pig to mouse combination. METHODS: Immunodeficient transgenic mice were developed by crossing transgenic founders carrying porcine interleukin-3, granulocyte macrophage-colony stimulating factor, and stem cell factor genes with severe combined immunodeficient mice or non-obese diabetic/severe combined immunodeficient mice. Swine bone marrow transplantation was performed in these mice, and porcine chimerism was followed for 20 weeks. RESULTS: Whereas swine cells became undetectable in all non-Tg littermates by 7 weeks, high levels of porcine hematopoietic chimerism, including the presence of porcine class II+ cells in the host thymus were maintained in Tg mice for >20 weeks. Colony-forming assays revealed the presence of large numbers of swine hematopoietic progenitor cells in the marrow of these mice at 20 weeks after bone marrow transplantation. CONCLUSIONS: These transgenic mice demonstrate for the first time that spontaneous migration of marrow donor antigen-presenting cells to an intact recipient thymus can occur and that porcine stem cells can persist in this highly disparate species combination. These data therefore support the feasibility of the eventual goal of tolerance induction by mixed chimerism in discordant xenogeneic combinations.