Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

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Final presentation given by Ileana Lulic and Ivor Kovic at the end of Scientific research in gastro-intestinal & liver diseases Sunday, July 8 - Friday, August 3, 2007 Amsterdam, Academisch Medisch Centrum

Economy & Finance Health & Medicine

Identiﬁcation of Barrett’s
esophagus patients at higher risk
for adenocarcinoma development

Ileana Lulic, Ivor Kovic

Deﬁnition

“... a change in the esophageal epithelium of any length
that can be recognized at endoscopy and is conﬁrmed
to have intestinal metaplasia by biopsy ...”

American College of Gastroenterology

Characteristics
• Caucasian males – middle age
• Rapidly rising incidence in Western countries
• Around 150x higher risk of esophageal adenocarcinoma
compared to general population

• 0.5% of BE patients will develop EAC
• Overall survival rate of EAC = 20-25%

Progression
Squamous esophageal epithelium

Intestinal metaplasia

Dysplasia

Esophageal adenocarcinoma

Progression
Squamous esophageal epithelium

GERD

Intestinal metaplasia

Dysplasia

Esophageal adenocarcinoma

Progression
Squamous esophageal epithelium
Obesity
Diet
?
GERD Tobacco
Alcohol
Bacteria
Intestinal metaplasia

Dysplasia

Esophageal adenocarcinoma

Progression
Squamous esophageal epithelium
Obesity
Diet
?
GERD Tobacco
Alcohol
Bacteria
Intestinal metaplasia

Dysplasia
Low grade

High grade
Esophageal adenocarcinoma

Diagnosis
Normal Metaplasia Adenocarcinoma

Endoscopy

Pathology

Diagnosis
Normal Metaplasia Adenocarcinoma

Endoscopy

Pathology
http://www.gastrointestinalatlas.com/

Surveillance problems
Endoscopy Pathology

• • Intra-observer variability
Difﬁculty of identifying
early neoplastic lesions
• Inter-observer variability
• Sampling errors
• Expensive and time
consuming

Potential of genetic markers
• Prediction of risk for disease progression in endoscopic
surveillance program
• Early detection of high grade dysplasia and invasive
adenocarcinoma
• Staging and prognosis
• Prediction of chemosensitivity
• Novel targets for anticancer therapies

Genetic markers
p16/9p-loss
p53/17p-loss

Y chromosome loss
Aneuploidy/tetraploidy

Losses - 3p, 4p, 7q, 12q,17q
Gains – 2p, 8q, 20q

Genetic markers
p16/9p-loss No dysplasia
p53/17p-loss

Low grade dysplasia
Y chromosome loss
Aneuploidy/tetraploidy
High grade dysplasia

Losses - 3p, 4p, 7q, 12q,17q
Esophageal adenocarcinoma
Gains – 2p, 8q, 20q

Genetic markers
p16/9p-loss Fluorescent in situ hybridization
p53/17p-loss

Y chromosome loss
Image cytometry
Aneuploidy/tetraploidy

Losses - 3p, 4p, 7q, 12q,17q
Gains – 2p, 8q, 20q

Procedure
Image cytometry

Brush cytology Slides preparation

FISH

FISH

• Fluorescent probe

• Fluorescent microscopy

FISH

• Numerical chromosomal
changes: aneuploidy
• Locus speciﬁc losses: tumor
suppressor genes
• Ampliﬁcations: oncogenes
and growth factor

Image cytometry
• DNA ploidy analysis

• Aneuploidy – from 2N to 4N, DNA index

• Measurement of optical density

FISH results
Cep1 p16 p53
Patient Hystology
loss gain loss gain loss gain

+ +
1 LGD

+
2 LGD

+ + +
3 HGD

+ +
4 HGD

+ + +
5 HGD

+ +
6 HGD

Total 2 3 5 0 3 0

Results
LGD HGD
6

5

4

3

2

1

0
Cep 1 gain p16 loss p53 loss

Results from 151 patients
(n=114)
(n=24)
(n=13)

Conclusion

• p53 loss and aneuploidy are promising markers for
dysplasia development in BE

• Ongoing follow up study to demonstrate the true
predictive value of these markers

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原版一模一样【微信：741003700 】【(cwu毕业证书)美国中央华盛顿大学毕业证成绩单】【微信：741003700 】学位证，留信认证（真实可查，永久存档）原件一模一样纸张工艺/offer、雅思、外壳等材料/诚信可靠,可直接看成品样本，帮您解决无法毕业带来的各种难题！外壳，原版制作，诚信可靠，可直接看成品样本。行业标杆！精益求精，诚心合作，真诚制作！多年品质 ,按需精细制作，24小时接单,全套进口原装设备。十五年致力于帮助留学生解决难题，包您满意。本公司拥有海外各大学样板无数，能完美还原。 1:1完美还原海外各大学毕业材料上的工艺：水印，阴影底纹，钢印LOGO烫金烫银，LOGO烫金烫银复合重叠。文字图案浮雕、激光镭射、紫外荧光、温感、复印防伪等防伪工艺。材料咨询办理、认证咨询办理请加学历顾问Q/微741003700 【主营项目】一.毕业证【q微741003700】成绩单、使馆认证、教育部认证、雅思托福成绩单、学生卡等！二.真实使馆公证(即留学回国人员证明,不成功不收费) 三.真实教育部学历学位认证（教育部存档！教育部留服网站永久可查）四.办理各国各大学文凭(一对一专业服务,可全程监控跟踪进度) 如果您处于以下几种情况： ◇在校期间，因各种原因未能顺利毕业……拿不到官方毕业证【q/微741003700】 ◇面对父母的压力，希望尽快拿到； ◇不清楚认证流程以及材料该如何准备； ◇回国时间很长，忘记办理； ◇回国马上就要找工作，办给用人单位看； ◇企事业单位必须要求办理的 ◇需要报考公务员、购买免税车、落转户口 ◇申请留学生创业基金留信网认证的作用: 1:该专业认证可证明留学生真实身份 2:同时对留学生所学专业登记给予评定 3:国家专业人才认证中心颁发入库证书 4:这个认证书并且可以归档倒地方 5:凡事获得留信网入网的信息将会逐步更新到个人身份内，将在公安局网内查询个人身份证信息后，同步读取人才网入库信息 6:个人职称评审加20分 7:个人信誉贷款加10分 8:在国家人才网主办的国家网络招聘大会中纳入资料，供国家高端企业选择人才办理(cwu毕业证书)美国中央华盛顿大学毕业证【微信：741003700 】外观非常简单，由纸质材料制成，上面印有校徽、校名、毕业生姓名、专业等信息。办理(cwu毕业证书)美国中央华盛顿大学毕业证【微信：741003700 】格式相对统一，各专业都有相应的模板。通常包括以下部分：校徽：象征着学校的荣誉和传承。校名:学校英文全称授予学位：本部分将注明获得的具体学位名称。毕业生姓名：这是最重要的信息之一，标志着该证书是由特定人员获得的。颁发日期：这是毕业正式生效的时间，也代表着毕业生学业的结束。其他信息：根据不同的专业和学位，可能会有一些特定的信息或章节。办理(cwu毕业证书)美国中央华盛顿大学毕业证【微信：741003700 】价值很高，需要妥善保管。一般来说，应放置在安全、干燥、防潮的地方，避免长时间暴露在阳光下。如需使用，最好使用复印件而不是原件，以免丢失。综上所述，办理(cwu毕业证书)美国中央华盛顿大学毕业证【微信：741003700 】是证明身份和学历的高价值文件。外观简单庄重，格式统一，包括重要的个人信息和发布日期。对持有人来说，妥善保管是非常重要的。

The various stages, after the initial invitation has been made to the public ...

Yashwanth Rm

一比一原版宾夕法尼亚大学毕业证(UPenn毕业证书)学历如何办理

vpqasyb

挂科购买【微信号:176555708】【挂科购买(UPenn毕业证书)】【微信号:176555708】《成绩单、外壳、offer、真实留信官方学历认证（永久存档/真实可查）》采用学校原版纸张、特殊工艺完全按照原版一比一制作（包括：隐形水印，阴影底纹，钢印LOGO烫金烫银，LOGO烫金烫银复合重叠，文字图案浮雕，激光镭射，紫外荧光，温感，复印防伪）行业标杆！精益求精，诚心合作，真诚制作！多年品质 ,按需精细制作，24小时接单,全套进口原装设备，十五年致力于帮助留学生解决难题，业务范围有加拿大、英国、澳洲、韩国、美国、新加坡，新西兰等学历材料，包您满意。【我们承诺采用的是学校原版纸张（纸质、底色、纹路）我们拥有全套进口原装设备，特殊工艺都是采用不同机器制作，仿真度基本可以达到100%，所有工艺效果都可提前给客户展示，不满意可以根据客户要求进行调整，直到满意为止！】【业务选择办理准则】一、工作未确定，回国需先给父母、亲戚朋友看下文凭的情况，办理一份就读学校的毕业证【微信号:176555708】文凭即可二、回国进私企、外企、自己做生意的情况，这些单位是不查询毕业证真伪的，而且国内没有渠道去查询国外文凭的真假，也不需要提供真实教育部认证。鉴于此，办理一份毕业证【微信号:176555708】即可三、进国企，银行，事业单位，考公务员等等，这些单位是必需要提供真实教育部认证的，办理教育部认证所需资料众多且烦琐，所有材料您都必须提供原件，我们凭借丰富的经验，快捷的绿色通道帮您快速整合材料，让您少走弯路。留信网认证的作用: 1:该专业认证可证明留学生真实身份 2:同时对留学生所学专业登记给予评定 3:国家专业人才认证中心颁发入库证书 4:这个认证书并且可以归档倒地方 5:凡事获得留信网入网的信息将会逐步更新到个人身份内，将在公安局网内查询个人身份证信息后，同步读取人才网入库信息 6:个人职称评审加20分 7:个人信誉贷款加10分 8:在国家人才网主办的国家网络招聘大会中纳入资料，供国家高端企业选择人才留信网服务项目： 1、留学生专业人才库服务（留信分析） 2、国（境）学习人员提供就业推荐信服务 3、留学人员区块链存储服务【关于价格问题（保证一手价格）】我们所定的价格是非常合理的，而且我们现在做得单子大多数都是代理和回头客户介绍的所以一般现在有新的单子我给客户的都是第一手的代理价格，因为我想坦诚对待大家不想跟大家在价格方面浪费时间对于老客户或者被老客户介绍过来的朋友，我们都会适当给一些优惠。选择实体注册公司办理，更放心，更安全！我们的承诺：客户在留信官方认证查询网站查询到认证通过结果后付款，不成功不收费！

10 geo ch 7 lifelines of economy and studies

RhemanRaphael

Fabular Frames and the Four Ratio Problem

Majid Iqbal

Digital, interactive art showing the struggle of a society in providing for its present population while also saving planetary resources for future generations. Spread across several frames, the art is actually the rendering of real and speculative data. The stereographic projections change shape in response to prompts and provocations. Visitors interact with the model through speculative statements about how to increase savings across communities, regions, ecosystems and environments. Their fabulations combined with random noise, i.e. factors beyond control, have a dramatic effect on the societal transition. Things get better. Things get worse. The aim is to give visitors a new grasp and feel of the ongoing struggles in democracies around the world. Stunning art in the small multiples format brings out the spatiotemporal nature of societal transitions, against backdrop issues such as energy, housing, waste, farmland and forest. In each frame we see hopeful and frightful interplays between spending and saving. Problems emerge when one of the two parts of the existential anaglyph rapidly shrinks like Arctic ice, as factors cross thresholds. Ecological wealth and intergenerational equity areFour at stake. Not enough spending could mean economic stress, social unrest and political conflict. Not enough saving and there will be climate breakdown and ‘bankruptcy’. So where does speculative design start and the gambling and betting end? Behind each fabular frame is a four ratio problem. Each ratio reflects the level of sacrifice and self-restraint a society is willing to accept, against promises of prosperity and freedom. Some values seem to stabilise a frame while others cause collapse. Get the ratios right and we can have it all. Get them wrong and things get more desperate.

PM pre reads for the product manager framework

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一比一原版(cwu毕业证书)美国中央华盛顿大学毕业证如何办理

The various stages, after the initial invitation has been made to the public ...

一比一原版宾夕法尼亚大学毕业证(UPenn毕业证书)学历如何办理

10 geo ch 7 lifelines of economy and studies

Fabular Frames and the Four Ratio Problem

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Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

1. Identiﬁcation of Barrett’s esophagus patients at higher risk for adenocarcinoma development Ileana Lulic, Ivor Kovic

2. Deﬁnition “... a change in the esophageal epithelium of any length that can be recognized at endoscopy and is conﬁrmed to have intestinal metaplasia by biopsy ...” American College of Gastroenterology

3. Characteristics • Caucasian males – middle age • Rapidly rising incidence in Western countries • Around 150x higher risk of esophageal adenocarcinoma compared to general population • 0.5% of BE patients will develop EAC • Overall survival rate of EAC = 20-25%

4. Progression Squamous esophageal epithelium Intestinal metaplasia Dysplasia Esophageal adenocarcinoma

5. Progression Squamous esophageal epithelium GERD Intestinal metaplasia Dysplasia Esophageal adenocarcinoma

6. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Esophageal adenocarcinoma

7. Progression Squamous esophageal epithelium Obesity Diet ? GERD Tobacco Alcohol Bacteria Intestinal metaplasia Dysplasia Low grade High grade Esophageal adenocarcinoma

8. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology

9. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology http://www.gastrointestinalatlas.com/

10. Diagnosis Normal Metaplasia Adenocarcinoma Endoscopy Pathology

11. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difﬁculty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming

12. Surveillance problems Endoscopy Pathology • • Intra-observer variability Difﬁculty of identifying early neoplastic lesions • Inter-observer variability • Sampling errors • Expensive and time consuming Questionable cost-effectiveness

13. Potential of genetic markers • Prediction of risk for disease progression in endoscopic surveillance program • Early detection of high grade dysplasia and invasive adenocarcinoma • Staging and prognosis • Prediction of chemosensitivity • Novel targets for anticancer therapies

14. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q

15. Genetic markers p16/9p-loss No dysplasia p53/17p-loss Low grade dysplasia Y chromosome loss Aneuploidy/tetraploidy High grade dysplasia Losses - 3p, 4p, 7q, 12q,17q Esophageal adenocarcinoma Gains – 2p, 8q, 20q

16. Genetic markers p16/9p-loss p53/17p-loss Y chromosome loss Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q

17. Genetic markers p16/9p-loss Fluorescent in situ hybridization p53/17p-loss Y chromosome loss Image cytometry Aneuploidy/tetraploidy Losses - 3p, 4p, 7q, 12q,17q Gains – 2p, 8q, 20q

18. Procedure Image cytometry Brush cytology Slides preparation FISH

19. FISH • Fluorescent probe • Fluorescent microscopy

20. FISH • Numerical chromosomal changes: aneuploidy • Locus speciﬁc losses: tumor suppressor genes • Ampliﬁcations: oncogenes and growth factor

21. Image cytometry • DNA ploidy analysis • Aneuploidy – from 2N to 4N, DNA index • Measurement of optical density

22. FISH results Cep1 p16 p53 Patient Hystology loss gain loss gain loss gain + + 1 LGD + 2 LGD + + + 3 HGD + + 4 HGD + + + 5 HGD + + 6 HGD Total 2 3 5 0 3 0

23. Image cytometry results

24. Image cytometry results

25. Results LGD HGD 6 5 4 3 2 1 0 Cep 1 gain p16 loss p53 loss

26. Results from 151 patients (n=114) (n=24) (n=13)

27. Conclusion • p53 loss and aneuploidy are promising markers for dysplasia development in BE • Ongoing follow up study to demonstrate the true predictive value of these markers

28.

29. Agnieszka Rygiel Francesca Milano Sheila Krishnadath Wendy Bruins Willemijn van Dop

Identification of Barrett’s esophagus patients at higher risk for adenocarcinoma development

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