血管内皮生长因子、p53在卵巢上皮癌中表达的临床意义

目的:探讨血管内皮生长因子(VEGF)和癌基因p53在卵巢上皮癌表达的相关性及其与卵巢上皮癌临床病理因素的关系以及对卵巢癌患者预后的影响。方法:用免疫组化二步法检测73例卵巢上皮肿瘤组织中VEGF、p53蛋白的表达(良性上皮瘤24例,交界性上皮瘤7例,上皮性癌42例)。结果:VEGF在卵巢上皮肿瘤组织中的表达,恶性组阳性表达率(86.36 %)明显高于交界性组(66.67 %)及良性组(37.50 %)(P<0.005);在恶性组中,VEGF表达在不同的病理分级、临床分期中无明显差异(P>0.05)。p53在卵巢上皮肿瘤组织中的表达,恶性组阳性表达率(76.19 %)明显高于交界性组(28.57 %)及良性组(9.09 %)(P<0.01)。在恶性组中临床晚期患者p53阳性表达率(89.29 %)高于早期患者(50.00 %)(P<0.01);在不同的病理分级中p53阳性表达率无明显差异。VEGF与p53在卵巢上皮癌中的表达呈正相关,(r =0.571 4,P<0.01)。VEGF、p53表达双阴性患者的3 a生存率66.7 %(2/3)明显高于VEGF 、p53表达双阳性患者20.00 %(5/25)。结论:VEGF与p53表达呈正相关,和卵巢癌生物学特性有关,可作为估计卵巢癌预后的重要因素。     

上皮性卵巢癌组织CK2β和p53蛋白表达临床意义分析

目的研究蛋白激酶CK2β及抑癌基因蛋白p53在卵巢癌组织中的表达情况,并分析其表达与卵巢癌临床病理参数及预后的关系。方法收集2003-01-01-2005-12-31就诊于浙江大学医学院附属妇产科医院的上皮性卵巢肿瘤患者148例(包括108例上皮性卵巢癌,20例卵巢良性上皮性肿瘤及20例卵巢交界性肿瘤),应用免疫组化法检测CK2β及p53在肿瘤组织中的表达情况,并分析两者在不同肿瘤组织中的表达差异及其与上皮性卵巢癌预后的关系。结果上皮性卵巢癌组织CK2β阳性表达68例(63.0%),p53阳性表达58例(53.7%);卵巢交界性肿瘤CK2β阳性表达6例(30.0%),p53阳性表达4例(20.0%);卵巢良性上皮性肿瘤CK2β和p53阳性表达均为0例;CK2β在卵巢癌组织中的表达强度显著高于卵巢良性肿瘤组织(P<0.001)和交界性肿瘤组织(P=0.003);p53在卵巢癌组织中的表达强度显著高于卵巢良性肿瘤组织(P<0.001)及交界性肿瘤组织(P=0.006);CK2β和p53之间具有显著相关性,r=0.377,P<0.001。CK2β蛋白表达与卵巢癌临床分期(P=0.001)、术前血清CA125水平(P<0.001)及化疗敏感性(P=0.012)显著相关;p53蛋白表达与组织分化程度(P=0.027)及术前血清CA125水平(P=0.027)相关。CK2β及p53阳性表达与上皮性卵巢癌患者的无瘤生存预后及总生存预后显著相关(P值均<0.05);多因素回归显示,临床分期(P<0.001)和p53阳性表达(P=0.018)可作为预测卵巢癌无瘤生存预后的独立因素,而临床分期(P=0.001)、术前CA125水平(P=0.040)和p53阳性表达(P=0.041)可作为预测卵巢癌总生存预后的独立因素。结论 CK2β和p53蛋白阳性表达可能与卵巢癌的发生发展有密切关系,p53阳性表达对卵巢癌预后预测具有一定的价值。     

卵巢上皮性癌组织MUC4和NF-κB及VEGF表达临床意义的探讨

目的:研究粘附分子(MUC4)、核转录因子(NF-κB)p65和血管内皮生长因子(VEGF)在卵巢上皮性癌组织中的表达及意义.旨在为卵巢上皮性癌的早期诊断及预后的判断寻找标志,并为卵巢上皮性癌的发病和转移机制提供理论依据.方法:应用免疫组化SP法,检测MUC4、p65和VEGF在10例正常卵巢组织、20例卵巢良性上皮性肿瘤和60例卵巢上皮性癌组织中的表达,并分析它们的相关性.结果:卵巢上皮性癌组织中,MUC4阳性表达率显著高于正常卵巢组织及卵巢良性肿瘤组织,P＜0.05. MUC4的表达与病理分级有关,x2=14.332,P=0 008;与临床分期、CA125值和有无淋巴结转移等无关,P＞0.05. p65及VEGF的表达与淋巴结转移、临床分期、病理分级和CA125值有关,P＜0.05;VEGF与腹水形成有关,x2=10.651,P=0.032.在Ⅰ～Ⅱ期卵巢上皮性癌中,MUC4的阳性表达率显著高于p65和VEGF,P＜0.05.p65和VEGF、MUC4的表达呈正相关(r=0.209,P=0.048;r=0.279,P=0.008).结论:MUC4是上皮性卵巢癌早期诊断的候选指标,VEGF与预后有关;p65对MUC4和VEGF有调控作用.     

p53和nm23在卵巢癌中的表达及意义

目的 研究p53抑癌基因和nm23肿瘤转移抑制基因与卵巢上皮性癌的关系.方法采用免疫组化SP法检测12例正常卵巢组织,20例卵巢良性肿瘤,16例交界性肿瘤以及79例卵巢上皮性癌组织中p53及nm23的表达情况.结果 p53表达率于卵巢上皮性癌为48.1%,其他组织均呈阴性,与组织类型无关,但与分化程度成反比,与分期、淋巴结转移成正相关.COX模型单因素及多因素分析显示,p53表达与预后相关;nm23表达率于卵巢上皮性癌中为49.3%,且与组织类型、细胞分化,临床分期以及淋巴结转移均有相关性,COX模型单因素分析表明nm23表达与预后有关.结论 p53和nm23可作为估计患者预后的指标,前者阳性者预后欠佳,后者阳性者预后较好.     

抑癌基因p16和转移抑制基因nm 23在卵巢上皮性肿瘤中的表达

目的:探讨抑癌基因p16及转移抑制基因nm23与卵巢上皮性肿瘤病理特点及生物学行为的关系。方法:免疫组化SP法检测30例正常卵巢,50例卵巢上皮性良性肿瘤及50例卵巢癌组织中P16蛋白和nm23蛋白,并分析其阳性表达与肿瘤的关系。结果:nm23蛋白在卵巢癌组织中的阳性率(70.0%)明显高于正常卵巢(43.3%)及良性肿瘤组(44.0%)(P<0.05);在浆液性癌(87.5%)和粘液性癌(47.8%)中的阳性差率也有显著差异(P<0.05);特别是在有淋巴结转移(39.1%)和无淋巴结转移(92.6%)的中检出率相非常显著(P<0.01),而与卵巢癌的临床分期及病理分级无明显相关性。p16蛋白在卵巢癌中的检出率(26.0%)明显低于正常卵巢(80.0%)和良性上皮性肿瘤(52.0%)(P<0.01),在晚期肿瘤中的表达率(20.5%)也远低于早期肿瘤(63.6%),而且在高度恶性组织中表达水平(11.1%)与中低度恶性组织的表达水平(43.5%)也有显著差异(P<0.05)。结论:nm23基因的表达与卵巢癌的淋巴结转移等生物学行为有关,p16基因可作为临床判断预后的重要指标之一。nm23、p16基因与卵巢上皮性肿瘤的发生、发展密切相关。     

卵巢浆液性癌中p-Akt473 Ser、p53及Ki-67的表达与临床意义

目的:探讨p-Akt473Ser、p53及Ki-67蛋白在卵巢癌组织中的表达及其相互关系。方法:应用免疫组化法,检测10例正常卵巢、12例卵巢良性上皮性肿瘤、15例卵巢交界性上皮性肿瘤、60例卵巢浆液性癌中p-Akt473Ser、p53及Ki-67蛋白的表达,分析p-Akt473Ser与p53及Ki-67三者间的关系。结果:pAkt473Ser、p53及Ki-67蛋白在正常卵巢组织中的阳性蛋白率分别是10%、20%、10%;pAkt473Ser、p53及Ki-67蛋白在卵巢良性上皮性肿瘤组织中的阳性蛋白率分别是17%、25%、25%,均显著低于卵巢浆液性囊腺癌组织中的60%、67%、83%(P<0.01)。pAkt473Ser、p53及Ki-67蛋白在交界性肿瘤组织中的阳性表达率分别为40%、60%、67%,交界性肿瘤与卵巢癌组织比较,差异无统计学意义(P>0.05),而与组织学分化、临床分期有关(P<0.01)。结论:pAkt473Ser、p53及Ki-67蛋白在卵巢癌中过表达,可能共同参与卵巢癌的发生、发展。     

卵巢上皮癌组织微血管密度及血管形成相关分子的检测及预后价值

目的 探讨卵巢上皮癌组织微血管密度(MVD)、血管内皮生长因子(VEGF)、血小板反应素1(TSP1)和p53蛋白表达与患者预后的关系.方法 采用免疫组化法检测57例原发性卵巢上皮癌组织中VEGF、TSP1和p53蛋白的表达情况,用CD34免疫染色后计数MVD.对VEGF、TSP1、p53蛋白和MVD与患者复发及生存时间的关系进行回顾性分析.结果卵巢上皮癌组织中VEGF、TSP1和p53蛋白表达阳性率分别为70.2%(40/57)、47.4%(27/57)和61.4%(35/57),MVD为30.3±8.5,MVD、VEGF和TSP1与复发相关(P值分别为0.030、0.025和0.026).高MVD、VEGF和p53蛋白阳性患者的中位生存时间短于低MVD、VEGF和p53蛋白阴性者(P值分别为0.0187,0.010和0.005),MVD、VEGF和p53蛋白是影响预后的危险因素.TSP1是影响患者预后的保护因素,其阳性患者的中位生存时间长于阴性患者(P=0.042).多因素分析表明,MVD和p53蛋白是影响卵巢上皮癌预后的独立因素(P值分别为0.018和0.009).结论 VEGF、TSP1和p53蛋白可能参与了卵巢上皮癌的血管形成,MVD和p53是影响卵巢上皮癌预后的独立因素.     

上皮性卵巢癌组织中p21WAF1表达及其与P53和PCNA的相关性

背景与目的:近年研究表明,p21WAF1下调与多种肿瘤发生、发展有关,但其与上皮性卵巢癌的关系研究甚少,本研究从mRNA和蛋白水平探讨p21WAF1基因在上皮性卵巢癌发生发展中的作用及其与P53和PCNA蛋白表达的相关性.方法:应用RT-PCR法检测55例上皮性卵巢癌、32例良性卵巢肿瘤和30例正常卵巢组织中p21WAF1 mRNA表达,免疫组化法检测P21WAF1、P53、PCNA蛋白表达,并结合其临床病理参数及预后进行分析.结果:上皮性卵巢癌、良性卵巢肿瘤、正常卵巢组织中p21WAF1 mRNA阳性率分别为40.00%、56.25%、73.33%(P=0.012),P21WAF1蛋白阳性率分别为36.36%、56.25%、80.00%(P=0.001).上皮性卵巢癌p21WAF1 mRNA及其蛋白表达均低于其它两组,而P53、PCNA蛋白表达阳性率显著高于其它两组(P＜0.05).上皮性卵巢癌中p21WAF1 mRNA表达与其蛋白表达呈显著性正相关,与PCNA表达呈负相关,与P53表达无显著性相关.P21WAF1蛋白表达与PCNA、P53表达均呈负相关.P21WAF1蛋白低表达与卵巢癌FIGO分期晚有显著性相关(P=0.032),与患者年龄、组织学类型、病理分级、残余肿瘤大小无显著性相关(P＞0.05),而p21WAF1 mRNA与上述各项临床病理参数均无显著性相关(P＞0.05).单因素分析显示p21WAF1 mRNA与P21WAF1蛋白低表达患者预后差(P＜0.05).结论:上皮性卵巢癌组织中P21WAF1表达下调.p21WAF1基因检测结果有可能作为预测上皮性卵巢癌预后的一种参考指标.     

卵巢浆液性癌中p-Akt~（473） Ser、p53及Ki-67的表达与临床意义

目的：探讨p-Akt473Ser、p53及Ki-67蛋白在卵巢癌组织中的表达及其相互关系。方法：应用免疫组化法,检测10例正常卵巢、12例卵巢良性上皮性肿瘤、15例卵巢交界性上皮性肿瘤、60例卵巢浆液性癌中p-Akt473Ser、p53及Ki-67蛋白的表达,分析p-Akt473Ser与p53及Ki-67三者间的关系。结果：pAkt473Ser、p53及Ki-67蛋白在正常卵巢组织中的阳性蛋白率分别是10%、20%、10%;pAkt473Ser、p53及Ki-67蛋白在卵巢良性上皮性肿瘤组织中的阳性蛋白率分别是17%、25%、25%,均显著低于卵巢浆液性囊腺癌组织中的60%、67%、83%（P〈0.01）。pAkt473Ser、p53及Ki-67蛋白在交界性肿瘤组织中的阳性表达率分别为40%、60%、67%,交界性肿瘤与卵巢癌组织比较,差异无统计学意义（P〉0.05）,而与组织学分化、临床分期有关（P〈0.01）。结论：pAkt473Ser、p53及Ki-67蛋白在卵巢癌中过表达,可能共同参与卵巢癌的发生、发展。     

卵巢上皮癌bcl-2、p53基因与多药耐药的相关研究

目的探讨卵巢上皮癌bcl-2、p53基因与肿瘤多药耐药的相关关系.方法用免疫组化LSAB法检测70例卵巢上皮癌和15例交界瘤的bcl-2、p53基因水平的表达.结果卵巢癌的bcl-2基因水平呈低表达,浆液性癌、粘液性癌的bcl-2基因表达率分别为11%(5/45)和20%(5/25),交界瘤呈阴性反应.p53抑制基因在浆液性癌、粘液性癌和交界瘤的表达率则分别为77%、72%和0%,P-gp基因在卵巢癌呈高表达,上述三类标本的阳性率分别为88%、80%及33%.结论bcl-2与p53基因水平的表达与肿瘤细胞的多药耐药相关,bcl-2可作为预测肿瘤预后及药物敏感性的重要指标之一.     

Experience in the treatment of synchronous and metachronous carcinoma of the oesophagus and the head and neck

BACKGROUND AND OBJECTIVES: Treatment of multiple primary squamous cell carcinomas of the head and neck and oesophagus is controversial. The poor prognosis of these 2 types of carcinoma taken individually and their anatomic proximity complicate the therapeutic strategy and limit the treatment choices for each location. METHODS: From 1986 to 1998, 43 patients received curative treatment for multiple synchronous (n = 30) or metachronous (n = 13) primary neoplasms of the oesophagus and head and neck. For synchronous cancers, the therapeutic strategy consisted of first curing the head and neck cancer and then planning oesophagectomy according to the type of head and neck cancer therapy. RESULTS: Ten total oesopharyngolaryngectomies and 33 subtotal oesophagectomies were performed. The postoperative mortality rate was 9.3% (4/43). The rate of anastomotic leakage was 30% (13/43), and all such leaks were cervical. Pulmonary infection occurred in 19% of cases (8/43). A past history of cervical radiation therapy or cervicotomy did not appear to be a significant risk factor for anastomotic leakage or pulmonary complications. Oesophagectomy did not affect the functional results in the 31 patients whose larynx could be preserved. CONCLUSIONS: Oesophagectomy after head and neck cancer treatment is possible with a low mortality rate and acceptable morbidity.     

Clinicopathological study of carcinomas of the lip and the mucosa of the upper and lower lips

BACKGROUND: Lip carcinomas are rare oral tumors, and there have been few reports of lip carcinoma in Japan. METHODS: Of 914 patients with oral carcinomas treated between January 1980 and December 1998, 12 (1.3%) had lip carcinoma and 5 (0.5%) had lip mucosal carcinoma. We investigated the clinicopathological features of these 17 patients. RESULTS: Of the 12 patients with carcinoma of the lip, 10 had squamous cell carcinomas (9, external lower lip; 1 commissures) and 2 had mucoepidermoid carcinomas (external upper lip). Of the 5 patients with lip mucosal carcinoma, 3 had squamous cell carcinomas (2, mucosa of the lower lip; 1, mucosa of the upper lip), 1 had mucoepidermoid carcinoma (mucosa of the lower lip), and 1 had acinic cell carcinoma (mucosa of the lower lip). Of the 12 patients with lip carcinoma, 9 were classified as stage I, 2 as stage II, and 1 as stage III; all 5 of the patients with lip mucosal carcinoma were stage I. Five patients with lip carcinoma were treated by resection, 5 by a combination of resection and reconstruction, and 2 by radiotherapy alone. All patients with lip mucosal carcinoma were treated by resection. After the initial therapy, 3 patients without neck dissection had regional recurrences and received delayed neck dissection, and 2 died with neck regional recurrence after dissection. The 5-year cumulative survival rates of the patients with lip carcinoma and those with lip mucosal carcinoma were 82.5% and 80.0%, respectively. CONCLUSION: We suggest that early-stage carcinomas of the lip and of the mucosa of the upper and lower lips are frequent, and we found that the outcome of these patients was excellent. However, an aggressive therapeutic approach to the lip carcinoma patient with cervical metastasis appears warranted, in an attempt to improve locoregional control and ultimate survival.     

The relation between the aging of the steroid generating system and the geneses of cancers of the stomach, the breast and the uterine cervix

The purpose of the present study is to test the validity of the steroid carcinogenesis hypothesis in humans by investigating the problem whether or not a cancer-specific change of the hormonal milieu emerges at a specified stage of life where the growth rate of cancer risk is at its zenith. A case-control study of 14 urinary steroid excretions was conducted for each of 3 human neoplasias. The identification and the size (in parenthesis) of the population units used in this study were,given as follows: a) the male gastric cancer group (421); b) the male control group (104); c) the female breast cancer group (245); d) the cervical cancer group (345); e) the female control group (127). Two kinds of steroid parameters were employed for the statistical analysis of hormonal data: a) the logarithm of a steroid excretion figure (mu g/day), as expressed by log x; b) the logarithm of a relative weight of a given steroid to tetrahydrocortisol, as expressed by log x/THF. The case-control difference for each parameter was expressed in terms of a t-value of Student's t-test. The steroid deviation profile was prepared for each neoplasia and for each of the log x data set and the log x/THF data set. The results obtained are as follows: a) the 2 steroid parameters (log x and log x/THF) for each of 14 urinary steroids were both subject to change with the progress of host age. The rate of age-dependent change was different for each steroid parameter and for each population unit. b) The above differential age dependency of the steroid parameters gave rise to a continual transition of the steroid deviation profile in the course of aging. c) The hormonal traits of male gastric cancer, female breast cancer and cervical cancer were described each as a complex of androgen depression and glucocorticoid stimulation (male gastric cancer), a sequential emergence of premenopausal progestin depression and postmenopausal predominance of glucocorticoid over androgen (female breast cancer), and a complex of androgen-glucocorticoid depression over progestin (cervical cancer). d) The emergence of the above cancer-specific steroid disorders chronologically coincided with the quasiexponential growth phase of cancer risk (and slow growth phase of cancer risk in postmenopausal breast cancer). e) The usefulness of the log x/THF type deviation profile for the assessment of the hormonal milieu of the host was verified by both theoretical approach to the problem and its application to the real data of a case-control study. f) The age dependent decline of androgens was generally much faster in their progressions than that of glucocorticoids - a finding to suggest the possibility that the production of a cancer-specific steroid deviation profile might have taken the form of the stress shift of Hans Selye, since both phenomena share depletion of gonadal steroids relative to glucocorticoid in common. The etiological relevancy of the 3 cancer-specific steroid changes to the geneses of 3 cancers:was discussed in the light of the experimental pathology studies in our laboratory as well as in other laboratories.     

Effect of freezing the helix and the rim or edge of the human and pig ear

We have studied the effect of increasing freeze times on the normal pig's ear and on a variety of lesions of the human ear. The clinical and laboratory data suggest that cartilage necrosis secondary to cryosurgery is a dose-related phenomenon and is uncommon with the freeze times used in clinical practice. Cryosurgery is an effective and cosmetically acceptable treatment for superficial skin lesions of the ear.     

Degree of manifestation of therapeutic pathomorphosis and the nature of the change in the estrogen and progesterone receptors after the radiation and chemotherapy of breast cancer

Estradiol and progesterone receptor levels were measured in 130 patients with stage III breast tumors before treatment and following preoperative radiation or chemotherapy. The data were evaluated versus the morphologic features of posttreatment pathomorphosis of tumor. Standard fractionated radiation (total dose of 70 Gy) was followed by pronounced postradiation pathomorphosis and a decrease in the level and incidence of steroid receptors in 72.7-87.5%. The essentially unchanged receptor profile of tumor following large-fraction (total dose-20 Gy) irradiation as well as presence of estradiol and progesterone receptors in the originally receptor-negative neoplasms after chemotherapy were matched by a slight degree of pathomorphosis.     

Urbanization and the incidence of abnormalities of squamous and glandular epithelium of the cervix

BACKGROUND: The large data bases of the Dutch cervical screening program can be exploited to establish the relation between urbanization and the incidence of abnormalities of the squamous and glandular epithelium, including mild or greater changes of the squamous and glandular epithelium of the cervix. METHODS: Six cytology laboratories in the context of the Dutch cervical screening program screened over 190,000 cervical smears. Urbanization (place of residence) data were derived from postal codes. All smears were coded with the Dutch national coding system, the Dutch national classification system KOPAC, in which squamous abnormalities are coded S4-S9, and glandular cell changes are coded G4-G9. From the scores per 1000 screened women, the relative risk (RR) of living in a large city compared with living in rural areas was calculated. To investigate a trend in incidence in relation to urbanization, the Schaafsma method was used. RESULTS: Of the smears with positive cytology, mild squamous dysplasia (S4) had the highest incidence per 1000 screened women (4.32), and the lowest incidence was found for adenocarcinoma (in situ; G7/G9; RR, 0.07). The RR for urban women ranged from 1.73 for moderate squamous dysplasia (S5) to 7.55 for adenocarcinoma (in situ; G7/G9). For smears with positive cytology for both squamous and glandular abnormalities, the Schaafsma method indicated a significant positive trend. CONCLUSIONS: The incidence of squamous and glandular abnormalities are maximal in women who live in a large city, which, in The Netherlands, is where there also is a population at high risk for human papillomavirus and bacterial vaginosis.     

Patient-reported outcomes: Assessment and current perspectives of the guidelines of the Food and Drug Administration and the reflection paper of the European Medicines Agency

AimsPatient-reported outcomes (PROs) have recently gained greater credibility with regulatory bodies aiming to standardise their use and interpretation in RCTs, thereby supporting medicinal product submissions. For this reason, the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have released guidelines. This review paper provides an overview of the current perspectives and views on these guidelines.MethodTo evaluate the FDA and EMEA PRO guidelines, 47 expert responses to the FDA guidance were qualitatively reviewed. Two reviewers independently extracted data from these letters and checked these responses to warrant consistency and agreement in the evaluation process. A PubMed literature review was systematically examined to obtain supporting evidence or related articles for both the guidance documents.ResultsGenerally, there is agreement between regulatory authorities and the research community on the contents of the FDA and EMEA PRO draft guidance. However, disagreements exist on significant philosophical topics (e.g. the FDA focuses more on conceptual models and symptoms than the EMEA) and design topics (e.g. the FDA is more restrictive on issues of recall bias, blinding of oncology trials and degrees of psychometric validation than researchers and the EMEA). This could influence the approval of PRO claims.ConclusionPRO guidance from the EMEA and FDA has been valuable, and has raised the profile and active debate of PROs in oncology. However, our review of the current opinion shows that there are controversial aspects of the guidance. Consequently, greater latitude should be given to how the guidance is interpreted and applied.     

Osteonecrosis of the jaw and the role of macrophages

Nitrogen-containing bisphosphonates have been associated with the development of osteonecrosis of the jaws (ONJ), but the lack of reliable epidemiological data and appropriate animal models has restricted our understanding of ONJ pathophysiology and limited its management. The best available information is from histopathologic findings, which implicate bone necrosis and infection, although it is not clear which is primary. However, there are data suggesting that macrophages could well be the central factor in allowing the infection to develop first, followed by local necrosis, which could also account for the development of ONJ in patients treated with denosumab, a human monoclonal antibody to the receptor activator of nuclear factor-κB ligand. This review examines the evidence that macrophages could play a prominent role in development of ONJ and the proposal that it may be more appropriate to view ONJ as a drug and not only a bisphosphonate-related complication.