兔转移性乳腺癌模型:肿瘤生长及转移

目的:建立移植性兔VX2乳腺癌模型,观察肿瘤生长及转移进程。方法:采用组织块悬液注射法制作兔VX2乳腺癌模型 28只,测量并记录瘤体大小变化,触诊检查有无腋窝淋巴结转移,影像学方法检查有无远处组织或器官转移,记录荷瘤生存时间,兔死亡后解剖并做病理检查。结果: 28只兔植瘤后 1周均在注射部位形成可触及的实体瘤。除去 5只中途意外死亡兔,共有 23只兔进入研究。全部模型肿瘤增长迅速,腋窝淋巴结转移发生率21 /23(91. 3% ),纵隔淋巴结转移发生率 5 /23(21. 7% ),腹腔淋巴结转移发生率 2 /23 (8. 7% ),肺转移发生率 6 /23(26. 1% ),肝转移发生率 3 /23(13. 0% ),骨转移发生率 1 /23(4. 3% )。肿瘤局部浸润侵犯胸膜腔 2 /23(8. 7% ),胃2 /23(8. 7% )。荷瘤兔平均生存时间(51. 2±8. 6)天,瘤灶病理切片检查符合乳腺鳞状细胞癌。结论:兔VX2乳腺癌模型的生物学行为和病程进展与人类转移性乳腺癌相似,是进行人类晚期乳腺癌实验研究的理想动物模型。     

兔VX2鼻咽移植癌的PET-CT与病理结果对照研究

目的:观察VX2兔鼻咽癌生长特点,并与所获病理和MRI结果比较,探讨18F-FDGPET-CT在鼻咽肿物检测中的作用。方法:建立VX2兔鼻咽癌模型后,完成18F-FDGPET-CT和MRI扫描并解剖;在肉眼所见肿瘤周围不同的距离取标本并完整取出斜坡作病理诊断;测量鼻咽肿物最大标准摄取值(SUV),在PET-CT和MRI图像上勾画鼻咽肿物体积。结果:VX2兔鼻咽癌可向周围组织呈广泛浸润性生长;30只兔中经病理确诊有9只兔斜坡受癌细胞侵犯,PET-CT发现6例(66.7%),MRI发现5例(55.6%),CT发现1例(11.1%);兔VX2鼻咽癌的最大SUV值与鼻咽肿物的体积呈负相关,r=-0.426,P=0.03;30只兔在18F-FDGPET-CT图像上所勾画的鼻咽肿物体积较在MRI图像上勾画体积小,差异无统计学意义,P=0.17。结论:18F-FDGPET-CT能对鼻咽癌病灶范围的确定、放疗靶区的准确勾画提供有用的信息。     

人类胃癌裸鼠淋巴结转移模型的建立

 目的　研究胃癌淋巴结转移动物模型的建立方法。方法　人类胃癌低分化细胞系SGC-7901体外培养、传代并扩增后，收集细胞行皮下种植成瘤，鼠间传代至第6代，以皮下肿瘤组织块原位种植于裸鼠胃壁建立动物模型。种植后第9周处死裸鼠，观察原位种植瘤生长、淋巴结转移及其他脏器转移情况，测定荷瘤裸鼠血清癌胚抗原（CEA）值。结果　原位移植瘤种植成功率100 ％，胃周淋巴结转移率93.3 ％，移植瘤可发生局部浸润及远处脏器转移，荷瘤裸鼠CEA值明显高于正常裸鼠（P＜0.01）。结论　应用SGC-7901细胞系可成功建立胃癌的淋巴结转移动物模型。     

兔VX2腹膜转移癌模型的建立及转移特征研究

目的:建立大动物腹膜转移癌模型,鉴定其生物学行为.方法:36只新西兰大白兔分为开腹包埋、开腹穿刺及直接经皮穿刺种植三组(每组12只),每组又分为6只瘤块接种,6只悬液接种,接种VX2肿瘤.观察肿瘤生长状况,通过病理学和影像学检查分析局部区域及远处转移情况.结果:三种方法构建模型的成功率分别是100%(12/12)、91.7%(11/12)和58.3%(7/12),开腹法与经皮穿刺法相比有显著性差异(P＜0.05).接种2周后,形成典型溃疡型胃癌并腹膜转移癌表现,宿主衰竭,4周出现肺转移.病理学检查符合典型VX2组织学特点.结论:开腹包埋与开腹穿刺接种制作VX2兔腹膜转移癌模型简单,实验周期短,接种率高,其病理表现类似人类腹膜转移癌,为腹膜癌治疗的实验研究提供可靠的大型动物模型.     

PET-CT诊断兔鼻咽VX2 移植癌颈部转移淋巴结的价值*

目的:探讨Biograph Sensation 16PET-CT 一体大型机在诊断兔鼻咽VX2 肿瘤颈部转移淋巴结性质上的价值。方法:建立兔鼻咽VX2 肿瘤模型,利用Biograph Sensation 16PET-CT 一体大型机完成18F-FDG PET-CT 扫描,测量淋巴结最大标准摄取值。解剖清扫双侧颈部淋巴结,分别标记,测量淋巴结最短径,获得病理结果。将PET-CT 诊断结果与病理结果比较。结果:1）30只移植成功并存活的鼻咽VX2 肿瘤兔,解剖检出颈部淋巴结共53枚,病理证实转移淋巴结42枚。28只兔发现颈部淋巴结转移,转移率93.3% 。2）18F-FDG PET-CT 诊断真阳性的28枚淋巴结SUV 为3.820 ± 1.658,其淋巴结最短径为0.83± 0.37cm,大于PET-CT诊断假阴性的14枚淋巴结最短径（0.38± 0.15cm）,两者差异有统计学意义（t=5.599,P=0.000）。 3）18F-FDG PET-CT 对淋巴结最短径<0.5cm及≥0.5cm两组诊断的敏感性分别为0.250、0.833,相比较差异有统计学意义（t=13.125,P=0.000）。 准确性分别为0.571、0.844,相比较差异有统计学意义（t=4.837,P=0.028）。 4）在转移淋巴结较小,仅结内侵犯时或被膜下侵犯时,PET-CT 能发现部分病灶,但假阴性高。结论:Biograph Sensation 16PET-CT 一体大型机能很好显示中型动物的兔VX2 鼻咽移植癌颈部淋巴结;对于最短径≥0.5cm的颈部转移淋巴结,18F-FDG PET-CT 的诊断敏感性、准确性高,特异性为100% ,是有价值的影像检查;对于仅结内侵犯或被膜下侵犯的小淋巴结,18F-FDG PET-CT 能发现部分病灶,但假阴性高。      

人胃癌组织块裸鼠原位移植/转移模型的建立

 目的　用肿瘤组织块原位移植 ,建立人胃癌裸小鼠原位移植 /转移模型。方法　以人胃低分化腺癌细胞系接种于裸小鼠皮下 ,形成稳定传代的皮下移植瘤 ,再取该肿瘤组织块原位移植于裸鼠胃壁 ,观察移植肿瘤的生长状况、移植成功率和自发转移的发生率。结果　原位移植成功率 (成瘤率 )为 1 0 0 %、局部淋巴结转移率 1 0 0 %、远处淋巴结转移率 90 %、肝转移发生率为 75%。荷瘤鼠的中位生存期为 1 4周 ,晚期出现消瘦和全身衰竭。结论　该裸小鼠原位移植 /转移模型的生物学行为与人胃癌自然生长和转移过程相似 ,可作为一种有价值的工具用于胃癌转移机理和抗转移实验治疗的研究。     

VX2移植性兔直肠癌淋巴结转移动物模型的建立及其生物学特性

背景与目的：直肠癌淋巴结转移模型是研究肿瘤发生、发展、转移及抗肿瘤治疗的工具,但较大型动物模型鲜见报道。该研究旨在建立可行性强、重复率高的VX2移植性兔直肠癌淋巴结转移模型。方法：采用原位移植方法,将切好的小瘤块置入穿刺针内,并使用穿刺针将小瘤块推入到新西兰大白兔的直肠壁内。共制作模型20只。每周使用MR扫描2只实验兔,MR上观察肿瘤生长情况及肠周淋巴结个数,使用MR后处理软件测量实验兔的直肠壁肿瘤体积,扫描完成后进行详细解剖,切除直肠壁上肿瘤及肠周淋巴结,进行标本固定及HE染色,并探讨肿瘤体积与生长时间及转移淋巴结个数的关系。结果：成功制作模型13只,成功率为65%。于第4周开始在MR上可观察到局限于直肠壁肿块。随着时间增长,肿瘤体积不断增大,且不同时期(生长周数)肿瘤体积差异有统计学意义(F=52.865,P<0.05);进一步分析得出,肿瘤的平均体积与生长周数呈正线性相关(r=0.910),差异有统计学意义(P<0.05)。当肿瘤体积大于9 cm3时,实验兔开始出现转移性淋巴结,第9周开始转移淋巴结个数明显增多。统计分析得出肿瘤体积越大,转移性淋巴结个数就越多(F=92.531, P<0.05),且两者呈线性相关(r=0.945),差异有统计学意义(P<0.05)。结论：本实验将组织学完整的VX2移植瘤组织块原位种植到新西兰大白兔直肠内,成功建立了VX2移植性兔直肠癌的淋巴结转移模型。本模型对于研究直肠癌的局部生长、浸润机制、淋巴结转移灶及生物学特性均有一定价值。     

神经母细胞瘤细胞系裸鼠转移模型及局部皮下荷瘤模型的建立

目的 建立人神经母细胞瘤(NB)裸鼠荷瘤模型,研究NB的侵袭、转移机制以及实验治疗的可能性.方法 体外培养人NB细胞系,取对数生长期瘤细胞,以1×107个/0.1ml细胞悬液接种于裸小鼠右侧前肢肋腹部皮下,观察倚瘤的生物学特性,并进行病理组织学检查及基因芯片分析,检测皮下荷瘤组织、转移瘤组织和患儿原发肿瘤组织的神经元特异性烯醇化酶(NSE)表达.结果 48只裸鼠中,荷瘤成功36只,总荷瘤率为75.0%.其中5只裸鼠肿瘤体积很大,甚至达到裸鼠自身体重的1/2,但未发生转移;4只裸鼠接种部位无肿瘤生长,却发生全身转移;6只裸鼠既有局部肿瘤生长,又发生转移.本组有10只裸鼠发生转移,转移率为20.8%(10/48).结论 成功建立人NB裸鼠荷瘤模型并稳定传代,肿瘤的移植生长率和转移率均较高,是NB体内研究理想的动物模型.NB具有异质性,可能是NB转移的重要原因.     

兔VX2食管癌模型的建立及生物学特性观察

目的:建立兔VX2食管癌移植瘤模型,探讨其成瘤率、生长特性及转移情况,为进一步研究食管癌及寻找有效治疗方法提供平台.方法:将兔VX2肿瘤剪碎至1 mm3左右的组织块,通过外科手术将肿瘤块植入腹段食管黏膜下层,于接种后第1、2及3周分别行食管造影和CT扫描检查,观察肿瘤生长情况.3周后,处死兔子取标本行病理学检测.结果:12只兔子除2只死于手术并发症外(胃穿孔及误缝食管所致的梗阻),其余10只接种后1周,未见肿瘤生长;2周后食管造影显示食管下段充盈缺损.CT扫描示食管下段走行区局限性管壁增厚,有明显软组织肿块影,平均最大径为1.04 cm (0.7～1.5 cm);3周后兔子消瘦明显,食管造影示食管下段黏膜破坏,充盈缺损明显,4只兔子出现食管穿孔.CT扫描示食管下段软组织肿块影明显增大,平均最大径为2.28 cm (1.7～4.3 cm).瘤体及淋巴结病理检查证实,成瘤及淋巴结转移成功率为100%.结论:采用兔VX2瘤块移植法可成功建立食管癌移植模型,且具有周期短,成瘤率高,生长迅速等特点.     

BNX小鼠人胃癌原位移植模型的建立及其生物学特性的观察

目的应用T、B、NK细胞联合免疫缺陷的BNX小鼠建立人胃癌原位移植高转移模型.方法将MKN-45细胞株接种至BNX小鼠皮下,成瘤后将肿瘤组织剪成小块通过手术移植至BNX小鼠的胃壁,观察肿瘤生长与转移情况,8周后对动物进行解剖.结果胃壁原位移植瘤浸润破坏胃壁各层组织结构,并直接扩散至周围脏器.肿瘤的移植成功率为100%(23/23),表现出很高的侵袭和转移特性:原位肿瘤平均体积2837.07±1044.04 mm3,局部和远处淋巴结转移率达83%(19/23),肝转移率为83%(19/23),肺转移率为65%(15/23),膈转移率为39%(9/23),发生腹腔种植与腹水的动物为35%(8/23),此外,还有个别脾转移.结论通过T、B、NK细胞联合免疫缺陷的BNX小鼠建立人胃癌原位移植模型可以更好地模拟人胃癌侵袭与转移本身的自然过程,对人胃癌防治及其转移机理的研究提供一个更为理想的模型.     

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.     

胆囊结石及胆囊切除与结直肠癌的关系探讨

目的 探讨胆囊结石及胆囊切除与结直肠癌的关系.方法 回顾性分析347例结直肠癌及608例其他消化道癌的临床资料.结果 结直肠癌患者胆囊结石发生率及既往胆囊切除率显著高于对照组(P<0.05).结论 胆囊结石及胆囊切除可能是结直肠癌的高危因素.