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There have been some exciting developments in work to expand the number of markers that can be measured in tissue. The constraints are cost and regulatory acceptance. Multiplexing of proteins in soluble samples (e.g. serum, plasma, urine) have advanced to true high-throughput, with arrays of ELISA-related technologies. However, tissue multiplexing remains difficult.
Immunofluorescence can easily do 3-4 antibodies on a tissue, and quantum dot approaches promise more, but quantum dots are unlikely to be run in the clinic for a number of reasons. Immunofluorescence in general suffers from two disadvantages — regulatory and tissue context. There are a total of 16 IHC based FDA clearances for protein expression with digital imaging using brightfield, and none using fluorescence (FISH doesn’t count). In companion diagnostics development, pharma cannot afford the risk to be first, waiting on clearance and acceptance for a novel technology. There are enough difficulties and risk along the long road of therapeutic development, adding in an unproven regulatory path on a companion diagnostics won’t help. The other difficult with immunofluorescence is the lack of the tissue context. Despite claims to the contrary (watch for these in presentations!), there are no antibodies that will perfectly bind to tumor with no other unwanted binding effect. If you happen to have one, immediately start your own biotech company, you have the holy grail of tumor targets in your hand. Thus any approach that looks to mask tumor with an antibody will require QA by a technician and then a pathologist. We do this regularly at Flagship in our digital pathology services. In brightfield with whole slide images this pathology review of image analysis is fast and cost-effective.
There are at least three emerging technologies to keep an eye on in tissue multiplexing.
20/20 Gene Systems in Maryland have a novel approach called L-IHC (layered IHC), where they sequentially pull off an antibody onto a absorbed layer, with a DNA probe that can hybridize to a fluorochrome.
GE has an approach that was presented at Pathology Informatics where they sequentially bind a fluorochrome-labeled antigen, image, remove, and bind the next one, image, remove, all on the same slide.
And finally, at Flagship we have just launched a new technology called FACTS (Feature Analysis on Consecutive Tissue Sections), where we utilize thin histology sections with image registration techniques from radiology to multiplex from 4 to 8 markers. I suspect we will hear more about multiplexing with digital pathology at Path Visions next week. The new techniques are exciting, with the end goal being an expansion of usage of tissue-based IVDMIAs.
I was walking through the grocery store yesterday and saw the cover of Denver’s 5280 magazine, Top Docs for 2010. I thought to myself… I wonder if there are any pathologists listed? If there are, I’ll buy it and can find out what makes these pathologists “Top Docs.” Sure enough, there were three pathologists! Happy to see this, I checked out with my chicken,vegetables, egg noodles (I was making homemade chicken noodle soup for dinner) and the 5280 magazine.
After my yummy dinner, I settled down to read the article. Quickly I realized this article was not going to be what I had hoped for; it was just a list. A list that is created by physicians who vote on each other, not who are voted on by their patients. Sadly, I now knew why pathologists were listed. It would be rare for patients to have interaction with their pathologist; however physicians would (I hope!) have had some interaction. Yet this still brings me to the bigger question, what really makes a Top Doc or in our case a Top Pathologist?
In Denver, the top three pathologists are:
Although I am not sure why these docs won, I am curious to understand what you think makes a great pathologist?
As for the Top Doc lists, these should be created by surveying physicians and area residents; furthermore, they should have a description of what makes these “Top Docs” special and/or unique. There wasn’t even a profile for the doctor on the cover, a diagnostic radiologist. What made him soo special to be on the cover? Could it be his good looks? Understanding”why” a doctor was chosen is the reason people buy this or other similar Top Doc city magazines.
If you are physician, and have taken one of these surveys for your city I would appreciate your comments and impression of the process and outcome. Do you feel this fairly markets “Top Docs” to area residents or is just a bunch of show to sell magazines? As for me, I lost my blind faith in healthcare and doctors a long time ago; I need facts! So unless the survey process changes and/or provides more “why” information, I will not buy this issue again.
Pardon my skepticism… but another digital pathology middleware company?
On October 7, 2010 a new company, PixcellData, was formed out of Dublin. PixcellData will be the third digital pathology middleware company out of Ireland, and will make the fifth middleware company within the digital pathology industry joining Apollo, AuroraMSC, SlidePath, and i-Path in this niche market space.
Middleware solutions are common in healthcare, and even in labs to help streamline workflow and improve interoperability and their is no doubt that this is needed. Today, the marketed and perceived benefits of digital pathology middleware companies are:
These are nice benefits, however can they compete effectively against their middleware competitors and the ever growing marketplace of digital pathology hardware manufacturers?
Hardware manufacturers like Aperio, Bioimagene, CRi, Olympus, Omnyx, Philips, etc would likely challenge that they offer all this and more within their solutions. For example, Aperio’s SecondSlide has over 3000 users worldwide, and Bioimagene’s PathXchange has over 8600 users worldwide collaborating in an easy to use environment that is scaleable, supports a variety of image files and formats, and are designed to organize and deliver large datasets. PathXchange even launched an “APP” this week- it seriously cannot get easier than that! On top of all of this, DICOM (a universal healthcare file format) was just been approved for whole slide images (WSI). With a universal format established, WSI could soon be integrated in to radiology PACS, LIS, and other middleware systems improving the interoperability hurdle that our industry has been burdened with. Now what are the benefits of a digital pathology middleware company?
Digital pathology middleware companies have achieved some business success through dissatisfied, frustrated current and prospective digital pathology customers. It’s not that current manufacturers cannot do what middleware companies can do, it’s just that they often do not address the specific needs and fears of their customers well and often cannot deliver on all the “promises” made. In this type of environment the middleware company could appear to be a knight in shining armor to the customer, the one who can answer all their specific needs and hold their hand throughout the process. Yet, this might only be a band-aid approach to a bigger problem.
The bigger problem is that the pathology community continues to be confused with the “who, what, where, when, why, and how” of digital pathology. WHO should we choose??? WHAT should we buy???? WHERE should we do this??? WHEN should we buy it???? WHY are we buying this???? HOW am I going to actually do this???? If these questions are not clearly answered and a plan established then often there is disappointment with the solution once an investment is made. I do believe middleware has a place in laboratory workflow and interoperability; however, it’s a very tough niche market to define and an even harder one to compete in.
Advance for Laboratory Professionals, in their September magazine issue, published an article titled “Digital Pathology Roundtable” where vendors could respond to questions about the current state of digital pathology. One of the questions was,
Digital pathology is described as a ‘disruptive’ technology. What is your company doing to mitigate the disruption?
Most respondents talked about how they try to manage the “change” factor, and some even stated that they do not believe digital pathology is disruptive. BUT what’s so bad or wrong with being disruptive? Why are we trying to downplay or dance around the disruption? Shouldn’t we as an industry be proud of the fact that digital pathology is disruptive?
I read an article this morning titled “5 Reasons Why It’s More Fun Being a Disruptor” and one of my favorite points is that when you disrupt you have the power to enable great change and make a positive difference. Isn’t that EXACTLY what we are trying to do- create change for the better of pathology?
Here are few of my favorite reasons and how they relate to digital pathology:
You will change the world! (Even if it’s only in small ways… at first.)
Digital Pathology was created by innovators who thought outside the box and did not follow the trends of the industry. The author of this article Jean Aw says…”If you don’t follow trends, you could end up creating a whole new industry, business model or lifestyle. Many people will think you’re nuts… until they can’t remember how life was before your idea. There’s room for radical ideas in every field.” Digital Pathology still needs more radical ideas. These ideas will help our industry get to a time where we will not remember how life was before. Well, I’ll always remember how it was “before” so that I can proudly say to all the naysayers… I told you so!!
You can’t go wrong…
This is an important aspect for those fearful of the change or who continue to wait to adopt digital pathology in their lab. Jean Aw continues to say, “People who assume the way things are now is the best way are wrong. Life is constantly evolving, and being a disruptor means you’re the source of some of that evolution. So by being a part of the change, you can’t be wrong since there is no “right” way doing things yet. Even when you fail or go off course, it will just be a step on your journey toward making a big change that will better things.”
You will help people.
Be a leader not a follower and use Digital Pathology to serve a need that isn’t being served. If you do this you will make a difference and help others.
I recently wrote,
Change is hard, but if we overestimate the importance of pathology’s capabilities today, we will underestimate the significance of what the field could become tomorrow.
So let’s be proud of the fact that we are disruptors! Let’s look change in the eye and recognize that this disruption will pave the road to a better future for laboratory medicine and pathology.
After my article last month, Advance offered me the opportunity to write a web article to compliment their vendor roundtable article. Below is the article.
Imagine your digital future. You walk into your office, and on the desk is a computer; your microscope is covered and untouched; on the shelves are books and journals, and nothing is on the floor. Paper and glass do not cover every inch of your office. Gone are the numerous external hard drives filled with countless images. All that remains is you, your knowledge and a computer.
This computer is your diagnostic workstation, customized to you and providing you with resources to improve diagnostic outcomes, advise on treatments and monitor patient response to those treatments. Digital pathology will enable and frame our digital future. However, forging this vision has not been easy, and realization of the vision is a constant work in progress.
History In the 1990s, the first robotic microscope was controlled over the Internet by Ronald S. Weinstein, MD,1 and the first slide scanner was invented to measure preinvasive cancer by James W. Bacus, MD, and his son Jim V. Bacus Jr.2 At about the same time, Dirk G. Soenksen, founder of Aperio, was imagining a world where microscopists looked at computer monitors rather than microscopes.3 These four inventors established the foundation for our digital future. As visionaries and advocates, they have brought digital pathology to life.
Resistant to Change
Ask around and the consensus is that digital pathology is our future. However, the timeline of when our future becomes a reality is widely debated. The digital pathology industry, pathology organizations and consumer crusaders have worked hard over the past 15 years to educate the market on the benefits of digital pathology, yet they are often met with a fierce resistance to change. The resistance is often driven by fear–not of change but of being changed.
No one pathologist, department or company can be forced to adopt and learn something new. Therefore, we must continue to educate and create an understanding of the tangible advantages, which instills a desire to change. Change is hard, but if we overestimate the importance of pathology’s capabilities today, we will underestimate the significance of what the field could become tomorrow.
Tangible Advantages
Digital pathology can reduce subjectivity, increase diagnostic confidence and ensure diagnoses are reproducible–all important advantages, especially when incidences of misdiagnosis have been publicized lately and the practice of pathology and laboratory medicine scrutinized. It is well-known that risk for human error in slide preparation and patient identification is greatly reduced when the histology process is bar coded.
A 2009 publication in the American Journal of Clinical Pathology about the Henry Ford Health System surgical pathology lab highlights a 62% reduction in the overall misidentification case rate.3 Add digital pathology to the picture, and you will enable scanning of glass slides, software (instead of technicians) correlating patient data and whole slide images, and electronic delivery of patient information and slides to the pathologist. Risk of error will continue to drop while powerful tools will support the pathologist throughout the diagnostic process.
Have a difficult case? No problem. The pathologist can simply assign the case or send an e-mail request to a specialized pathologist for a second opinion. This digital consultation process, often described as telepathology, is more secure and eliminates the risk of patient slides being lost or damaged, decreases the turnaround time to hours rather than days and reduces subjectivity while controlling costs. Still want more diagnostic support? Search the digital pathology slide database to review relevant clinical slides, quickly retrieve historical patient data, perform image analysis to obtain quantitative support, or easily set up a tumor board with physicians to illustrate the patient case and create a forum to discuss the next step or design a treatment plan.
All the tangible advantages described above can be done today and are being done, although the process is not perfect. Yet to achieve perfection you must find imperfections and then take time to transform those imperfections for the better.
Transformation
Government demands and consumer expectations are growing for transparency in medicine, improvements in patient safety and identification, electronic medical records and more personalized treatment plans. At the same time, the perception of laboratory medicine and pathology needs to improve, especially given its essential and significant role in patient care.
Digital pathology supports this healthcare evolution and enables the digital transformation of pathology and laboratory medicine. Our transformation is not easy. The process is not perfect, but the benefits are powerful and will outweigh the fears. Do not resist the transformation, embrace it.
Click here read the vendor roundtable print article and web article.
For over 10 years, the digital pathology industry has been riddled with vendors speaking their own language or languages (aka file format). Today a major milestone in interoperability was achieved with the final approval of Supplement 145; a DICOM universal format for whole slide images. Although vendors will never give up their native tongue, this new supplement creates a universal language everyone can understand in digital pathology, even those outside of our industry.
WG-26, lead by Bruce Beckwith, MD, has worked hard for several years to create supplement 145. Harry Solomon of GE Healthcare contributed a lot of help over the past year to move this to ballot and beyond. Harry put forward the following comments in an email to WG-26 today:
I’d like to add my thanks to the members of DICOM WG-26 for the significant body of pathology domain knowledge that has been added to the DICOM Standard, both in this new Supplement 145, and in Supplement 122 in 2008. That knowledge is now available to further improve interoperability in a field that was early to health informatics standards with the Systematized Nomenclature of Pathology, now known as the Systematized Nomenclature of Medicine (SNOMED), and is now poised for a significant leap with digital pathology. Here are some statistics on that domain knowledge base: One major new DICOM Information Object Definition (Whole Slide Imaging) with new concepts to manage the huge WSI data set A major revision of a DICOM Information Entity (Specimen) with a rigorous information model 56 new data elements added to the DICOM Standard in 14 new or revised modules 7 new or revised DICOM structured data templates and 18 new defined value sets 80 new coded terminology concepts added to SNOMED, and 36 added to DICOM 40 pages of explanatory information about pathology workflow and imaging
I’d like to add my thanks to the members of DICOM WG-26 for the significant body of pathology domain knowledge that has been added to the DICOM Standard, both in this new Supplement 145, and in Supplement 122 in 2008. That knowledge is now available to further improve interoperability in a field that was early to health informatics standards with the Systematized Nomenclature of Pathology, now known as the Systematized Nomenclature of Medicine (SNOMED), and is now poised for a significant leap with digital pathology.
Here are some statistics on that domain knowledge base:
Overall, this is another major step forward in the clinical use of digital pathology. Thank you to everyone who worked hard to make this a reality! The final document will be available within the next week.
One week from today on August 10th at 12 PM EST / 9 AM PST, the second webinar in a new series titled “Pathology 2.0″ will be presented by Keith Kaplan, MD.
Topic Overview
This webinar is designed to enhance your knowledge of Pathology 2.0. Dr. Kaplan will Increase your knowledge of 2.0 tools and technologies, teach you how 2.0 will apply to the daily practice of surgical pathology, and give you an understanding of the long-term implications of 2.0 for our practices. In addition, you’ll learn how to improve your services and showcase your specialty while providing information to patients that was once locked away. To learn more about Pathology 2.0 read an article from CAP Today “Manifest destiny—Pathology 2.0 is here,and it’s clear. Time to climb aboard.”
About Keith J Kaplan, MD
Dr. Kaplan is a surgical pathologist and chief information officer for Carolinas Pathology Group and Celligent Diagnostics. He was formerly associate professor of pathology at Mayo Clinic College of Medicine where he served as Biospecimens Director for the North Central Cancer Treatment Group (NCCTG). He received his MD degree from Northwestern University Feinberg School of Medicine followed by residency training in anatomic and clinical pathology at Walter Reed Army Medical Center. While at Walter Reed, in conjunction with the Armed Forces Institute of Pathology he founded and directed the Army Telepathology Program connecting 25 hospitals worldwide for consultation via telepathology. He has authored over 60 peer-reviewed scientific articles book chapters, editorials and scientific abstracts. His subspecialty interests include gastrointestinal and hepatic pathology, cytopathology and pathology informatics and has presented at national and international meetings on those topics. Dr. Kaplan’s research interests involve gastrointestinal and hepatobiliary pathology, hyperspectral imaging, image analysis and the use of Web 2.0 tools in pathology. He is active in many medical societies including the College of American Pathologists where he has chaired or served on several committees, serves as a reviewer for many scientific journals, serves on the editorial board for Human Pathology and blogs daily at www.tissuepathology.com.
REGISTER TODAY
This webinar is provided by www.thedigitalpathologywiki.com and it’s sponsors.
Just like the Olympics, multiple gold medals were given out at the first annual European Scanner Contest. The gold medals went to Leica, Olympus, & 3DHistech!
In a previous post, “Going For The Gold! A Digital Pathology Olympics” I discussed how on May 25th-26th the first contest was held with six companies choosing to participate. The participants had the option of competing in up to three disciplines with a maximum of two scanners.
The disciplines were:
The following awards were presented at the 10th Annual European Congress on Virtual Microscopy in Vilnius, Lithuania July 1-3, 2010, based on specific requirements and evaluation rules.
Congratulations to the winning companies and their instruments, and I look forward to future contests and encourage more companies in our industry to participate. For additional information, download the following powerpoint presentation about the contest and an overall summary of results.
My first position in digital pathology sales, was to sell virtual microscopy server software to medical, dental, and veterinary schools as an adjunct to microscopy or for the replacement of microscopes. I loved selling this product and I loved the people I sold it to; this position truly sparked my passion for digital pathology.
With one of my favorite annual educational meetings the International Association of Medical Science Educators (IAMSE) starting this weekend in New Orleans, I thought it was the perfect time to talk about the current state of digital pathology in education and provide some helpful advice to those who use virtual slides or are considering adding virtual slides to their curriculum.
Want to add virtual slides to your curriculum?
A few years ago education was a big area of focus for several manufacturers, but now the focus has shifted to the clinical use of digital pathology for primary diagnosis. Although this shift is not a surprise, we must not forget that without the acceptance of digital pathology in education we would not be where we are today. The foundation that digital pathology in education creates is essential to the growth and acceptance of this technology worldwide, and to the interest of histology and pathology as medical professions.
Need to change or update your virtual slide based curriculum?
The kindness, generosity, and patience of educators is remarkable. One of my favorite moments was when Dr. Mark Braun of Indiana University in Bloomington gave thanks to me on his poster at an IAMSE meeting, but really it is me who should be giving thanks. Thank you to all the educators who I have worked with over the years- you all contributed to my professional growth and understanding of histology and pathology.
If you are a member of CAP, take the FREE Digital Pathology Interactive Presentation: The Exciting and Expanding Role of Digital Pathology in Pathology Education
Current providers of digital pathology solutions for education:
By Steve Potts, PhD
The formal training of pathologists has an impressive history, and pathology boards for both medical and veterinary pathologists are very difficult professional exams. As digital pathology slowly makes it way from a early adopter technology to mainstream, there will be an increased need for training of the “digital” pathologists, both in working remotely with digital slides (which is fairly quick to pick up) to image analysis (which takes more time and specialization). The vendors of digital pathology scanners generally offer basic and generic software training, and have done a good job of educating the pathologists in how to use the tools. However, much more work needs to be done across the industry in improving training opportunities for pathologists using quantitative analysis, both in the research and clinical markets.
The challenge of image analysis training in the clinical environment is illustrated by a question I had from the audience at a talk I gave recently on Validation of Image Analysis in GLP and CLIA environments. Someone asked,
We use the ER/PR algorithms from the manufacturer on Ki67 out of the box, and we want to know how to validate them?
The problem with this simplistic approach is that Ki-67 has a binary thresholding criteria rather than multilevel in ER/PR, and the Ki-67 staining patterns are generally much different in the nuclei than ER/PR and usually require tuning changes in how the software scores. And Ki-67 is a very simple marker! The best validation process is useless unless the pathologist knows how the algorithms work, and has a generally good understanding of image analysis concepts. While we are working actively on better validation approaches for image analysis for both clinical and GLP preclinical environments, real world training in image analysis must come first.
So prior to our plans for image analysis validation services, we first need to make training of image analysis more accessible to pathologists as well as imaging scientists and support personnel at pathology centers. This is a difficult activity for vendors to do, as it really should be taught by a combination of pathologists and image analysis experts. So many image analysis results heavily depend on the condition of the tissue in staining, fixation, or other histology steps, the pathologist needs to be involved in training to be able to point out some of these things. IHC overstaining is the precise reason that pathologists need to work closely with histotechnologists in determining the exact antibody dilution to use with each stain. Close communication avoids other artifact pitfalls that affect pathology endpoints and analytical consistencies. Some antibody vendors actually customize their IHC processes to make the antibody stains much darker, which might(?) be helpful to the human eye, but is poor for image analysis, where lighter staining is usually much better. If I had a dollar for every time someone has asked for an algorithm that will work on overstained IHC slides, well, I could buy a couple more slide scanners.
The other reason it is difficult for vendors is that under strict medical device manufacturing guidelines, particularly in the clinical environment, vendors need to stick to discussing and training on the markers for which they are cleared. This means training on the familiar three amigos ER/PR/HER2, and usually on only the subtype of breast cancer for which they have been validated and cleared. There is much more to this limitation than can be addressed here, but it clearly limits for good reason clinical IHC software vendors conducting broad training in image analysis.
The other challenge in training pathologists is time. Due to the heavy workload of many pathologists, there is often little time to devote to attendance at a two-day course either onsite or at the scanner vendor location. The histologist and the lab manager may go, but usually the pathologist simply cannot get the time free in his or her schedule.
To respond to this need, Flagship Biosciences is offering a once-a-week, six week image analysis course online, scheduled each Thursday. It is co-led by an image analysis expert and a board-certified pathologist, which makes for a fascinating interaction. Each session only lasts 2 hours (we may cut it to 90 minutes in the future, this is the limit that people can absorb information), and it gives a week in between for attendees to try out the concepts, see what worked and didn’t work, and come back with questions. We will start with basic cell and area measurement, and move toward more advanced, sophisticated software-aided approaches as the courses progress. We hope that after a pathologist and a pathology lab knows how the algorithms work and how to relook at their IHC approaches for quantitation, the next steps will be image analysis validation training.
It will be interesting to see if image analysis becomes something every pathologist is familiar with and can run, or will be the domain of pathology specialists. I hope for the former, but I am betting on the latter.
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