Bcl-2和Bax的表达与乳腺癌组织学分级及预后的关系

目的：探讨bcl-2和bax基因在乳腺癌中的表达与乳腺癌组织学分级及预后的关系。方法：应用SP免疫组化染色方法，检测40例乳腺癌组织中bcl-2、bax的表达情况。结果：组织学I级＋Ⅱ级乳腺癌中bcl-2蛋白阳性表达率与组织学Ⅲ级乳腺癌中bcl-2蛋白阳性表达率有显著差异（P〈0．01），Ⅰ＋Ⅱ级组bax蛋白阳性表达率与Ⅲ级组bax蛋白阳性率表达无显著差异（P〉0．05），Ⅰ级＋Ⅱ级组bcl-2高表达和bax低表达（bcl-2／bax≥1）与Ⅲ级组bcl-2高表达和bax低表达（bcl-2／bax≥1）有显著差异（P〈0．01）。10年以上存活组中bcl-2阳性表达率与10年以下存活组有显著差异（P〈0．01）；10年以上存活组bax阳性表达率与10年以下存活组有显著差异（P〈0．05）；10年以上存活组bcl-2高表达和bax低表达（bcl-2／bax≥1）与10年以下存活组bcl-2高表达和bax低表达（bcl-2／bax≥1）有显著差异（P〈0．05）。结论：bcl-2和bax比值与乳腺癌组织学分级、预后关系密切，bcl-2高表达和bax低表达的乳腺癌患者组织学分级好，预后好。     

Survivin、PTEN和Cx43基因在皮肤基底细胞癌中的表达

背景与目的：探讨Survivin、PTEN和Cx43基因与皮肤基底细胞癌（basal cell carcinoma,BCC）的相关性。材料与方法：采用免疫组织化学S-P法分别检测35例皮肤BCC、10例正常皮肤组织中Survivin、PTEN和Cx43蛋白的表达;运用核酸分子原位杂交技术检测Cx43mRNA的表达。应用图像分析系统采集分析图像,分别检测BCC和正常皮肤组织中各项检测指标的表达水平（阳性面积）和表达强度（光密度）。结果：Survivin蛋白在正常皮肤中呈阴性表达,在BCC中呈弱阳性表达,其差异有统计学意义（P〈0．05）;PTEN蛋白在正常皮肤组织中呈强阳性表达,在BCC中呈阳性或弱阳性表达,其差异具有统计学意义（P〈0．05）。而Cx43蛋白和Cx43mRNA在正常皮肤组织中的表达均呈强阳性,而在BCC组织中均呈阳性或弱阳性,差异均具有统计学意义（P均〈0．01）。相关性分析显示,BCC组织中,PTEN蛋白的表达与Cx43蛋白呈正相关（r=0．519,P〈0．01）,Cx43蛋白的表达与Cx43mRNA也呈正相关（r=0．732,P〈0．01）。结论：PTEN蛋白、Cx43蛋白和Cx43mRNA在BCC中的低表达;Survivin蛋白在BCC中的高表达,可能在BCC发生发展的过程中发挥重要作用。     

P33ING1、p53在膀胱移行细胞癌中的表达及与细胞凋亡的相关性

目的：探讨抑癌基因P33ING1在膀胱移行细胞癌（BTCC）中的表达及其与p53蛋白表达及细胞凋亡的相关性。方法：利用免疫组化S-P法和TUNEL法检测83例BTCC及11例正常膀胱黏膜组织P33ING1、p53的表达及细胞凋亡指数（AI）。结果：83例膀胱移行细胞癌组织中,P33ING1蛋白的阳性表达率为59.03%,而正常膀胱黏膜组织中P33ING1蛋白阳性表达率为90.9%。P33ING1蛋白表达与膀胱移行细胞癌的WHO肿瘤分级有相关性。Spearman相关分析表明P33ING1蛋白表达与p53蛋白表达正相关（P〈0.05）。AI与P33ING1及p53蛋白表达无相关性。结论：P33ING1在膀胱移行细胞癌中表达下降可能在膀胱移行细胞癌的发生、发展过程中起重要作用,P33ING1与p53基因具有协同作用,同时检测p53的状态和P33ING1表达水平,对于膀胱癌的诊断、治疗和预后判断可能具有积极意义。     

FHIT基因在乳腺癌中的表达及意义

目的 探讨FHIT基因在乳腺癌中的表达与临床病理分期的关系。方法 应用免疫组织化学S．P法对99例乳腺癌组织及其癌旁组织标本（其中临床病理分期：0期15例，Ⅰ期9例，Ⅱ期52例，Ⅲ期15例，Ⅳ期3例）对FHIT蛋白表达水平检测，观察FHIT基因在癌旁组织中的低水平表达或缺失情况的意义。结果 0期乳腺癌FHIT蛋白低表达率26．67％（4／15），与Ⅰ期乳腺癌FHIT蛋白的低表达率55．56％（5／9）比较，差异无显著性（四格表精确检验法P=0．132〈1．963，P〉0．05）；Ⅰ期乳腺癌FHIT蛋白的低表达率55．56％（5／9）与Ⅱ期乳腺癌FHIT蛋白的低表达率66．67％（38／57）比较，差异无显著性（x^2=0．075〈x^2 0．05（1）=3．841，P〉0．05）；Ⅱ期乳腺癌FHIT蛋白的低表达率66．67％（38／57）与0期乳腺癌FHIT蛋白的低表达率26．67％（4／15）比较，有非常显著性差异（x^2=7．817〉x^2 0．01（1）=6．635，P〈0．01）。Ⅱ期乳腺癌FHIT蛋白的低表达率66．67％（38／57）与Ⅲ-Ⅳ期乳腺癌FHIT蛋白的低表达率94．44％（17／18）比较，差异有显著性（x^2=4．071〉x^2 0．05（1）=3．841，P〉0．05））；0-Ⅰ期乳腺癌FHIT蛋白的低表达率37．5％（9／24）与Ⅱ期以上乳腺癌FHIT蛋白的低表达率73．33％（55／75）比较，有非常显著性差异（x^2=10．215〉x^2 0．01（1）=6．635，P〈0．01）。结论 FHIT抑癌基因表达强度的下降与乳腺癌的临床病理分期有关。     

MDR1/P-gp在膀胱移行细胞癌中的表达及与Fas和Survivin蛋白表达的关系

目的：探讨膀胱移行细胞癌中MDR1基因（P-糖蛋白）与Fas、Survivin表达的相互关系及其与膀耽癌生物学行为的相关性。方法：应用免疫组织化学方法检测64例膀耽移行细胞癌和12例正常膀胱粘膜中P—GP、Fas、Survivin的表达。结果：膀胱移行细胞癌中P—GP、Survivin的表达阳性率高于正常粘膜，与膀胱癌的分级有关（P〈0．01）;而Fas在膀胱正常粘膜中表达高于移行细胞癌，差异有统计学意义（P〈0．01）复发性膀胱癌P-GP的阳性表达率高于初发膀胱癌（P〈0．01）、膀胱移行细胞癌P—GP的表达与Fas呈负相关．而与Survivin表达无关.结论：膀胱移行细胞癌的MDR1（多药耐药基因）与Fas的表达密切相关．而与凋亡抑制蛋白Sureivin的表达无关.本研究为采用MDR逆转剂或Fas干扰剂以增加膀胱移行细胞癌的化疗敏感性提供实验依据。     

前列腺癌中BAG-1、bcl-2及bax的表达及意义

目的：检测凋亡抑制因子BAG-1在前列腺癌组织（PCa）中的表达，探讨其与前列腺癌发生发展的关系及其与bcl-2和bax表达的关系。方法：采用免疫组织化学染色法检测BAG-1、bcl-2、bax在10例前列腺增生组织（BPH）、45例PCa组织中的表达。结果：BAG-1在BPH、PCa中的阳性表达率分别为20％（2／10）、91．1％（41／45）。PCa中BAG-1表达水平明显高于BPH（P〈0．05），且在癌组织中与肿瘤临床分期（P〈0．01）、病理分级（P〈0．01）呈正相关。BAG-1与bcl-2在PCa中的表达正相关（P〈0．05）。BAG-1与bax在PCa中的表达也呈正相关（P〈0．05）。结论：BAG-1基因可能通过抑制凋亡在PCa的发生发展中发挥重要作用，且其表达与bcl-2、bag的异常表达密切相关     

P33ING1、p53基因在膀胱移行细胞癌中的表达及其意义

目的探讨抑癌基因P33ING1在膀胱移行细胞癌中的表达及其与p53蛋白表达的相关性。方法采用免疫组化S-P法,检测83例膀胱移行细胞癌及11例正常膀胱黏膜组织中P33ING1、p53的表达。结果83例膀胱移行细胞癌组织中P33ING1蛋白阳性表达率为59．03％,而正常膀胱黏膜组织中P33ING1蛋白阳性表达率为90．90％。P33ING1蛋白表达与膀胱移行细胞癌的WHO肿瘤分级相关。根据Spearman相关分析表明P33INGI蛋白表达与p53蛋白表达呈正相关关系（P〈0．05）。结论P33ING1基因可能在膀胱移行细胞癌的发生、发展过程中起重要作用,P33ING1与p53基因具有协同作用,同时检测p53和P33ING1表达水平,对膀胱癌的诊断、治疗和预后判断可能具有积极意义。     

Livinα在膀胱移行细胞癌组织中表达的研究

目的：研究膀胱癌相关Livin基因在膀胱移行细胞癌组织中的表达以及Livin基因表达与膀胱移行癌生物学行为的关系;研究抑癌基因p53在膀胱癌组织中突变以及Livin表达与p53基因突变的关系。方法：100例膀胱移行细胞癌组织,设计Livinα引物,以半定量RT—PCR的方法,检测膀胱癌组织LivinαmRNA,以免疫组化法检测癌组织中p53蛋白。将膀胱肿瘤病理分级、临床分期、是否复发等生物学行为及p53蛋白染色强度分别量化,与组织LivinαmRNA RT-PCR产物量进行等级相关分析。并以10例正常膀胱黏膜作为对照。结果：100例膀胱移行细胞癌,67例检测到LivinαmRNA表达,10例正常膀胱黏膜组织未检测到LivinαmRNA表达,LivinαmRNA在膀胱移行细胞癌组织中表达率高于正常膀胱黏膜,x^2=14．4,P=0．000。LivinαmRNA在膀胱癌组织中表达与p53蛋白阳性（rs=0．465,P=0．002）及肿瘤病理分级（rs=0．463,P=0．002）有相关性。结论：膀胱移行细胞癌组织中可见LivinαmRNA高表达,LivinαmRNA表达与膀胱癌病理分级及癌组织中p53蛋白呈正相关。     

膀胱癌组织VEGF-C表达与淋巴管生成和淋巴结转移之间关系的研究

目的：应用特异的淋巴管内皮标志物podoplanin检测膀胱移行细胞癌（BTCC）组织中淋巴管，用淋巴管密度（LVD）表示淋巴管生成情况，探讨BTCC内VEGF-C表达与淋巴管生成和淋巴结转移的关系。方法：收集45例BTCC和10例正常膀胱组织标本，应用免疫组化检测VEGF-C、podoplanin的表达，计算VEGF-C阳性表达率及淋巴管密度值，分析两者的关系。结果：BTCC组织内VEGF-C阳性表达率显著高于正常膀胱组织（71．1％vs．10．0％，P〈0．01）；BTCC高中分化和低分化之间VEGF-C阳性表达率无显著性差异（70．6％US．72．7％，P〉0．05），而淋巴结阳性组显著高于淋巴结阴性组（81．3％vs．65．5％，P〈0．05）.BTCC组织内LVD显著高于正常膀胱组织（6．8±1．3vs．1．2±0．3，P〈0．01）；BTCC中，VEGF-C阳性组LVD显著高于VEGF-C阴性组（7．6±1．5vs．4．7±0．9，P〈0．05），而淋巴结阳性组显著高于淋巴结阴性组（8．3±1．4vs．5．1±1．1，P〈0．05）。结论：淋巴管生成可能是BTCC淋巴结转移的重要因素，VEGF-C参与BTCC淋巴管生成，从而促进淋巴结转移。     

膀胱移行细胞癌中survivin基因和血管内皮生长因子的表达和意义

目的：探讨survivin基因和血管内皮生长因子（vascularendothelialgrowthfactor,VEGF）在膀胱移行细胞癌中的表达和意义。方法：用免疫组化二步法检测58例膀胱移行细胞癌组织及20例正常膀胱粘膜组织中VEGF和survivin的表达。结果：20例正常膀胱粘膜组织中VEGF、survivin表达均为阴性;survivin、VEGF在膀胱移行细胞癌阳性表达分别为33例（56．9％）、30例（51．7％）。肿瘤不同分级中随恶性程度的增高,表达增高,Ⅰ级与Ⅲ级比较,差异有显著性意义（P〈0．05）。不同临床分期中随分期的增高,表达增高,Tis—T1与T2-T4比较,差异有显著性意义（P〈0．05）。survivin、VEGF在膀胱移行细胞癌表达呈正相关（r=0．385,P〈0．01）。结论：VEGF和survivin在膀胱移行细胞癌的发生、发展过程中起着重要的作用。survivin基因可能参与了肿瘤血管的形成。     

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.