Digital Pathology Blog

Nanotechnology may eventually benefit patients with inoperable cancers

BBC News (3/10) reported, "Nanotechnology has been used for the first time to destroy cancer cells with a highly targeted package of 'tumor busting' genes," and it "could potentially offer hope to people with hard-to-treat cancers where surgery is not possible." Detailing their work, researchers in the UK explained that first they wrapped the genes "in microscopic nano-particles 80,000 times smaller than the width of a human hair, which were taken up by cancer cells, but not their healthy neighbors." Then, "once inside, the genes stimulated production of a protein which destroys the cancer," the authors added. Specifically, "the gene enclosed in the particle recognizes the cancerous environment and switches on." Although the "result is toxic," it only impinges on "the offending cells, leaving healthy tissue unaffected," whereas "traditional chemotherapy indiscriminately kills cells in the affected area of the body, which can cause side effects like fatigue, hair loss, or nausea."

MRE for imaging liver disease

About a week ago I posted a note concerning virtual colonoscopy techniques and my concern about diminishing numbers of colon biopsies potentially. A comment to that post made the point of potentially fewer normal biopsies but more atypical ones or positive (vis-a-vis) malignant biopsies.

A valid point and one to watch as these technologies gain use clinically. 

Aside from reading GI biopsies I also spend my days reading liver biopsies - a large number of liver biopsies are done to assess "stage" or degree of fibrosis of known chronic liver disease (hepatitis B, hepatitis C, steatohepatitis, autoimmune, etc).  Of course liver biopsy requires an invasive technique and investigators have for years been pursuing other modalities, namely through serum chemistries and non-invasive imaging to try to find other markers for assessing degree of liver fibrosis.

In the past none have been found to be as sensitive or specific as biopsy but some of my clinical colleagues here at Mayo have reported their experience with magnetic resonance elastography (MRE) and how far this technique can go to determine stage of chronic liver disease.

Below is a link for the Mayo Clinic news blog with the story.

http://newsblog.mayoclinic.org/2008/10/27/new-mre-imaging-for-liver-disease/

BJC Study Identifies New Approach to Treating Cancer

This is exciting news - finding the cells that matter... Look for more to come on this!

Last week Ikonisys announced positive results from a clinical study conducted by the Weatherall Institute of Molecular Medicine at Oxford University, validating the company’s CellOptics® platform and proprietary digital microscope, the Ikoniscope®, as a viable method for quickly and easily detecting and detailing circulating tumor cells (CTC) in the blood.

The study identifies a completely new approach for detecting circulating tumor cells (CTCs) in the blood. Published in the British Journal of Cancer, the study proves how important the detection of these cells is for providing a new and effective approach to the overall management of cancer. The study’s findings represent a significant milestone for screening, early detection of recurrence and evaluation of treatment response for a variety of cancers, including prostate, colorectal and ovarian.

With the recent widespread news surrounding prostate screenings and the shortcomings of the current PSA test, the study results are especially exciting, as they suggest this method may be an effective way to reduce the number of false positives for malignancy based on elevated PSA levels.

From virtual microscopy to virtual colonoscopy

Virtual microscopy (whole slide imaging) at current resolutions is nearly if not as good as glass slide microscopy.  With current technologies it may be better for some purposes, given all the deliverables of a digital image (image processing, image analysis, rare event detection, spectroscopy, archiving, etc...).

In our teaching conferences now using a digital camera and high-end projector, most attendings and residents prefer to look at the digital imagery as opposed to sitting at the microscope given the optics of that system compared with the projected digital image.

While you may miss certain findings on virtual microscopy or need additional information beyond what the slide shows, the same is certainly true of glass slides.  The same analogy can be drawn on virtual CT colonography compared with endoscopic evaluation.  It appears there may be a role for both technologies, with increased numbers of patients getting screened for colon cancer which is responsible for 52,000 deaths a year. 

And I think the same is true of virtual slides and glass slides.  While one may not entirely replace or be more sensitive/specific than the other for particular diagnoses, the two formats may be complimentary to one another with each having a specific role in terms of clinical utlity and public health.

Radiology and gastroenterology have been looking at virtual colonoscopy and studying results from a large multi-center trial recently published in the New England Journal of Medicine. 

It turns out gastroenterologists who perform colonoscopies should not be worried that they may lose business to virtual colonoscopies, despite reports that both approaches work equally well at detecting colon cancer, a gastroenterology expert recently said based on details of the study published this week.

Partial results had been presented at medical meetings. Dr. Daniel Johnson of the Mayo Clinic in Scottsdale, Arizona and colleagues did both virtual colonoscopies and standard colonoscopies on 2,500 volunteers. They found that the virtual technique, which uses an X-ray computed tomography or CT scanner, detected 90 percent of precancerous polyps 10 millimeters or larger.

Regular colonoscopies are done by gastroenterologists using a flexible lit tube passed through the bowel. A device on the end can remove polyps for testing right away.

But with a virtual colonoscopy, also known as CT colonography or CTC, there is no sedation, so patients can quickly go back to their normal activities, the cost is significantly lower than a colonoscopy, and there is less risk of the bowel being punctured.

Both require drinking strong laxatives, a major complaint among patients. And if lesions are spotted during a virtual colonoscopy, the patient will require a standard procedure to remove them.

Virtual colonoscopies can also be uncomfortable because they require briefly inflating the bowel with carbon dioxide while the patient lies on a scanner.

"Both techniques are going to miss some lesions, both polyps and cancers," Johnson said in a telephone interview with a news agency. 

"In our study, there was a patient with a 35 millimeter mass that was missed in colonoscopy but found in CT colonography. None of these tests are perfect."

Colorectal cancer kills 52,000 people in the United States each year, according to the American Cancer Society. Most Americans are advised to begin getting regular colonoscopies at age 50.

Only about half of the 70 million Americans at risk for colon cancer are getting screened now, and the choice of CTC may encourage more people to be tested, he said. Gastroenterologists "are nervous that a lot of business will be taken away from them," Johnson said.

But the availability of a noninvasive method "has actually increased our colonoscopy volume," said Dr. Brooks Cash of the American Gastroenterology Association and a gastroenterologist at the National Naval Medical Center in Bethesda, Maryland, where both techniques are used.

That means more people need a follow-up colonoscopy to remove any polyps that could grow into tumors.

Cash estimated that colonoscopies typically account for 50 to 60 percent of a gastroenterologist's income.

"It appears to be a very reasonable, very accurate test for colon cancer screening," he said in a telephone interview. "It will get them (patients) into the store, if you will. Then they can use either test."

Johnson said CTC uses half the radiation of a standard CT scan.

Virtual Biopsy Can Tell Whether Colon Polyp Is Benign without Removal

Fewer normal colon biopsies on the horizon?

A probe so sensitive that it can tell whether or not a cell living within the human body is veering towards cancer development may revolutionize how future colonoscopies are done, say researchers from the Mayo Clinic in Jacksonville, Fla. 

Newswise — A probe so sensitive that it can tell whether or not a cell living within the human body is veering towards cancer development may revolutionize how future colonoscopies are done, say researchers from the Mayo Clinic in Jacksonville, Fla.

Investigators have found that technology known as a high resolution confocal endomicroscopy probe system can determine whether a colon polyp is benign (not precancerous) - without having to remove it for examination by a pathologist.

Their study, to be presented at the Digestive Disease Week, a scientific meeting of gastrointestinal specialists and researchers held in San Diego, shows that using the probe system was 89 percent accurate in identifying whether polyps were either precancerous or benign. But more importantly, it was correct 98 percent of the time in flagging polyps that were benign, which would then not need to be removed for biopsy. The Mayo researchers, who are the first in the U.S. to comprehensively test the system in the colon, believe they can push accuracy close to 100 percent with more research.

What this means is that the probe system can be used to during a colonoscopy to rule out removal of polyps that are not harmful, says the study’s senior author, Michael Wallace, M.D., M.P.H., Professor of Medicine at Mayo Clinic.
“Today, half of all polyps surgically removed during colonoscopy procedures are benign, and so this virtual biopsy will save time and expense, and reduce complications that can occur,” he says.

The device is a tiny imaging tool, only 1/16th of an inch in diameter, which can be attached to a variety of endoscopes that are already being used during colonoscopies, Dr. Wallace says. When a suspicious polyp is seen during a colonoscopy, a physician can use the probe to look closely at the lesion. To do this, a small amount of fluorescent contrast is used to illuminate the area, and the probe magnifies it by 1,000 times – enough to see a single red blood cell as it moves through a blood vessel.

In this study, the researchers first tested 10 precancerous (“adenomatous”) lesions as well as 10 benign (“hyperplastic”) lesions using the probe system in order to understand the differences in appearance between the two. (The status of the polyps was later verified by pathologists.) Among other things, they looked at changes in cell color and size, how nuclei within the cells looked, and whether cells were crowed within tissue, or fused.

They then, without knowledge of the pathologists’ diagnosis, used their new grading system to determine the status of 37 polyps within 25 patients, which were then removed. The most important clinical result is that the probe was 98 percent accurate in identifying lesions that were not cancerous. “That is what you want in a device like this,” says the project’s lead research fellow, Anna M. Buchner, M.D., who will be presenting the findings. “Removing a polyp that looks precancerous, but turns out to be benign, is okay, but you don’t want to leave polyps intact in the colon that are actually cancerous,” she says. “This probe is almost perfectly reliable in that regard and with more experience I am sure we can improve accuracy to nearly 100 percent.”

Wallace says the technology, which is also being tested in the esophagus, has the capacity to fundamentally change how many different endoscopy procedures are done. “This will shift our role from one of going in and getting tissue for a pathologist to examine to one in which we can do the pathology ourselves,” Dr. Wallace says. “This is instantaneous, real time pathology.”

The study was supported by the American Society for Gastrointestinal Endoscopy.

Researchers use MRI to non-invasively characterize tumors

Science Daily (3/24) reported that researchers at the University of California-San Diego's School of Medicine "have shown that Magnetic Resonance Imaging (MRI) technology has the potential to non-invasively characterize tumors and determine which of them may be responsive to specific forms of treatment, based on their specific molecular properties." To do this, Michael Kuo, M.D., and colleagues, "analyzed more than 2,000 genes that had previously been shown to have altered expression in Glioblastoma multiforme (GBM) tumors." After "mapp[ing] the correlations between gene expression and MRI features," the researchers "identified characteristic imaging features associated with overall survival of patients with GBM, the most common and lethal type of primary brain tumor." They "discovered five distinct MRI features that were significantly linked with particular gene expression patterns."

The AFP (3/25) adds that, while the "study was focused on mapping the molecular features of the most common and deadly primary brain tumor," it could also "be used to better identify other tumor types." The study can be found in the Mar. 24 edition of the Proceedings of the National Academy of Science.

New scanners fast-track autopsies

Two state-of-the-art scanning machines for the city's forensic pathology services laboratories that will drastically cut time spent on autopsies were unveiled by Health MEC Pierre Uys.

The Lodox Statscan machines at laboratories at Salt River and Tygerberg cost R5,4-million and form part of the provincial Department of Health's R161-million budget for new equipment in this financial year.

Uys said the Lodox Statscan machines were low-dosage digitalradiography equipment, designed specifically to meet the needs of forensic pathology, as well as emergency centres.

The machines are able to provide scans of both bone and soft tissue, useful in the diagnosis of a wide range of traumatic injuries.

Full-body x-rays can be completed in 13 seconds, and non-specialised personnel are now able to perform procedures rapidly, at a much-reduced risk of radiation exposure.

They are particularly useful for detecting bullets, shrapnel, fractures and foreign objects which would previously not have been picked up.

The images are digital, so they can be transferred across a computer network, rotated and manipulated without loss in quality. There is also no need for x-ray film or cartridges, thereby reducing costs.

"Due to the fact that the body can be scanned and the image displayed within one minute, the Lodox Statscan will bring about less invasive work required on the body, as the location of foreign objects... will be expedited. Vital evidence previously undetected will assist with criminal proceedings and, in some instances, assist with the identification of the deceased," said Uys.

• This article was originally published on page 6 of The Cape Times on December 07, 2007

Particles Send Drugs Remotely

CAMBRIDGE, Mass., Nov. 20, 2007 -- Remotely controlled nanoparticles that, when pulsed with an electromagnetic field, release drugs to attack tumors have been devised at the Massachusetts Institute of Technology in research that could lead to the improved diagnosis and targeted treatment of cancer.

A team led by Sangeeta Bhatia, MD, PhD, an associate professor in the Harvard-MIT Division of Health Sciences & Technology (HST) and in MIT's Department of Electrical Engineering and Computer Science, had earlier developed injectable multifunctional nanoparticles designed to flow through the bloodstream, home to tumors, and clump together. Clumped particles help clinicians visualize tumors through magnetic resonance imaging (MRI).

With the ability to see the clumped particles, Bhatia's co-author in current research, Geoff von Maltzahn, asked the next question: “Can we talk back to them?”

The answer is yes, the team found. The system that makes it possible consists of tiny particles (billionths of a meter in size) that are superparamagnetic, a property that causes them to give off heat when they are exposed to a magnetic field. Tethered to these particles are active molecules such as therapeutic drugs.

Exposing the particles to a low-frequency electromagnetic field causes the particles to radiate heat that, in turn, melts the tethers and releases the drugs. The waves in this magnetic field have frequencies between 350 and 400 kHz -- the same range as radio waves. These waves pass harmlessly through the body and heat only the nanoparticles. For comparison, microwaves -- which will cook tissue -- have frequencies measured in gigahertz, or about a million times more powerful.

The tethers in the system consist of strands of DNA, “a classical heat sensitive material,” said von Maltzahn, a graduate student in HST. Two strands of DNA link together through hydrogen bonds that break when heated. In the presence of the magnetic field, heat generated by the nanoparticles breaks these, leaving one strand attached to the particle and allowing the other to float away with its cargo.

One advantage of a DNA tether is that its melting point is tunable. Longer strands and differently coded strands require different amounts of heat to break. This heat-sensitive tuneability makes it possible for a single particle to simultaneously carry many different types of cargo, each of which can be released at different times or in various combinations by applying different frequencies or durations of electromagnetic pulses.

To test the particles, the researchers implanted mice with a tumor- like gel saturated with nanoparticles. They placed the implanted mouse into the well of a cup-shaped electrical coil and activated the magnetic pulse. The results confirm that without the pulse, the tethers remain unbroken. With the pulse, the tethers break and release the drugs into the surrounding tissue.

The experiment is a proof of principal demonstrating a safe and effective means of tunable remote activation. However, work remains to be done before such therapies become viable in the clinic.

To heat the region, for example, a critical mass of injected particles must clump together inside the tumor. The team is still working to make intravenously injected particles clump effectively enough to achieve this critical mass.

“Our overall goal is to create multifunctional nanoparticles that home to a tumor, accumulate, and provide customizable remotely activated drug delivery right at the site of the disease,” said Bhatia.

Co-authors on the paper are Austin M. Derfus, a graduate student at the University of California at San Diego; Todd Harris, an HST graduate student; Erkki Ruoslahti and Tasmia Duza of The Burnham Institute in La Jolla, Calif.; and Kenneth S. Vecchio of the University of San Diego.

The research was supported by grants from the David and Lucile Packard Foundation, the National Cancer Institute of the National Institutes of Health. Dervis was supported by a G.R.E.A.T fellowship from the University of California Biotechnology Research and Educational Program.

Digital Infrared Thermal Imaging In Medical Therapy

Digital technology now makes Digital Infrared Thermal Imaging available to all. There now is a completely safe test that can aid in diagnosis, treatment and monitoring with absolutely no risk or radiation exposure.

DITI, or digital infrared thermal imaging, is a noninvasive diagnostic test that allows a health practitioner to see and measure changes in skin surface temperature. An infrared scanning camera translates infrared radiation emitted from the skin surface and records them on a color monitor. This visual image graphically maps the body temperature and is referred to as a thermogram. The spectrum of colors indicates an increase or decrease in the amount of infrared radiation being emitted from the body surface. In healthy people, there is a symmetrical skin pattern which is consistent and reproducible for any individual.

DITI is highly sensitive and can therefore be used clinically to detect disease in the vascular, muscular, neural and skeletal systems. Medical DITI has been used extensively in human medicine in the United States, Europe and Asia for the past 20 years. Until now, bulky equipment has hindered its diagnostic and economic feasibility. Now, PC-based infrared technology designed specifically for clinical application has changed all this.

Clinical uses for DITI include, defining the extent of a lesion of which a diagnosis has previously been made (for example, vascular disease); localizing an abnormal area not previously identified, so further diagnostic tests can be performed (as in Irritable Bowel Syndrome); detecting early lesions before they are clinically evident (as in breast cancer or other breast diseases); and monitoring the healing process before a patient returns to work or training (as in workmans compensation claims).

Medical DITI is filling the gap in clinical diagnosis; X-ray, Computed Tomography, Ultrasound and Magnetic Resonance Imaging (MRI), are tests of anatomy or structure. DITI is unique in its capability to show physiological or functional changes and metabolic processes. It has also proven to be a very useful complementary procedure to other diagnostic procedures.

Unlike most diagnostic modalities DITI is non invasive. It is a very sensitive and reliable means of graphically mapping and displaying skin surface temperature. With DITI you can diagnosis, evaluate, monitor and document a large number of injuries and conditions, including soft tissue injuries and sensory/autonomic nerve fiber dysfunction. Medical DITI can offer considerable financial savings by avoiding the need for more expensive investigation for many patients. Medical DITI can graphically display the biased feeling of pain by accurately displaying the changes in skin surface temperature. Disease states commonly associated with pain include Reflex Sympathetic Dystrophy or RSD, Fibromyalgia and Rheumatoid arthritis.

Medical DITI can show a combined effect of the autonomic nervous system and the vascular system, down to capillary dysfunctions. The effects of these changes reveal an asymmetry in temperature distribution on the surface of the body. DITI is a monitor of thermal abnormalities present in a number of diseases and physical injuries. It is used as an aid for diagnosis and prognosis, as well as therapy follow up and rehabilitation monitoring, within clinical fields that include rheumatology, neurology, physiotherapy, sports medicine, oncology, pediatrics, orthopedics and many others.

Results obtained with medical DITI systems are totally objective and show excellent correlation with other diagnostic tests.

Thermographic screening is not covered by most insurance companies but is surprisingly affordable for most people.

VivaScope(R) Confocal Imager May Eliminate Need for Routine Skin Biopsies for Dermatology Patients

Many routine surgical biopsies could become a thing of the past as dermatologists may soon be sharing, reviewing and diagnosing noninvasive digital images of skin cells via the Internet, using Lucid Inc.'s VivaNet(TM) telemedicine server and its VivaScope(R) confocal imagers.

The technology, which relies on using special microscopes to digitally image a patient's skin, may bypass the need to surgically biopsy many patients. "VivaScope imaging sessions require only 5 to 10 minutes of a physician's assistant's time," said Jay Eastman, Ph.D., CEO, Lucid Inc. (http://www.lucid-tech.com).

The cellular resolution images may then be used by physicians to assist in forming a clinical judgment for a variety of skin conditions, including, for example, melanoma, basal cell carcinoma, actinic keratoses, and contact dermatitis.

A typical VivaScope imaging session produces two types of images of the patient's skin: dermatoscopic-quality, full-color macroscopic pictures, and microscopic, cellular resolution images. Like a routine biopsy, the images can then be read by a dermatologist or a pathologist and the diagnosis presented to the patient.

"Just as MRI and CT scans have largely eliminated the need for routine exploratory surgery, in-vivo confocal imaging may one day eliminate the need for routine invasive skin biopsy," Eastman stated.

 

Already, dozens of Lucid's VivaScopes are in regular use throughout the

U.S.

and

Europe

. "Lucid's VivaScope(R) 1500 has the capability of imaging virtually all types of skin cancers, which makes it useful for many everyday procedures in a dermatology practice," stated Dr. Harold Rabinovitz, a

Florida

based dermatologist who specializes in skin cancer. "The VivaScope is an incredible diagnostic tool and now routinely aids me in the clinical evaluation of potential skin cancers."

The Company is also developing an Internet-based application, the Lucid VivaNet(TM), to enable the transfer of VivaScope digital images between practitioners and pathologists for rapid review of confocal images. The VivaNet technology conforms to DICOM (Digital Imaging and Communications in Medicine), an internationally accepted standard for the secure storage, retrieval and transfer of medical images, and it complies with federal HIPAA requirements for privacy and integrity of medical data.

Ultimately, the VivaNet could make VivaScope images available for review by other dermatologists and pathologists -- anywhere in the world -- in minutes, not days -- thus enabling rapid, real-time professional collaboration. The ultimate goal is that practitioners will rapidly receive a pathologic interpretation of confocal images from a VivaScope session, potentially assisting the practitioner in arriving at a clinical judgment while the patient is still in the doctor's office, Eastman said.

"It's our hope that the VivaScope and VivaNet will improve the quality of life for dermatology patients by eliminating the need for painful, invasive skin biopsies and drastically reducing the time required for diagnosis and treatment," Eastman said.

For information on Lucid's VivaScope or VivaNet technology, contact Lucid by phone at 585-239-9800, by email at info@lucid-tech.com, or on the web at http://www.lucid-tech.com.