TAG: "Imaging"

‘Gold standard’ method created for measuring key early sign of Alzheimer’s


UCLA helps validate first standardized protocol for measuring an early sign of Alzheimer’s.

Liana Apostolova, UCLA

By Mark Wheeler, UCLA

After six years of painstaking research, a UCLA-led team has validated the first standardized protocol for measuring one of the earliest signs of Alzheimer’s disease — the atrophy of the part of the brain known as the hippocampus.

The finding marks the final step in an international consortium’s successful effort to develop a unified and reliable approach to assessing signs of Alzheimer’s-related neurodegeneration through structural imaging tests, a staple in the diagnosis and monitoring of the disease. The study is published in the journal Alzheimer’s and Dementia.

Using brain tissue of deceased Alzheimer’s disease patients, a group headed by Dr. Liana Apostolova, director of the neuroimaging laboratory at the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, confirmed that the newly agreed-upon method for measuring hippocampal atrophy in structural MRI tests correlates with the pathologic changes that are known to be hallmarks of the disease — the progressive development of amyloid plaques and neurofibrillary tangles in the brain.

“This hippocampal protocol will now become the gold standard in the field, adopted by many if not all research groups across the globe in their study of Alzheimer’s disease,” said Apostolova, who was invited to play a key role in the consortium because of her reputation as one of the world’s leading experts in hippocampal structural anatomy and atrophy. “It will serve as a powerful tool in clinical trials for measuring the efficacy of new drugs in slowing or halting disease progression.”

The brain is the least accessible and most challenging organ to study in the human body; as a result, Alzheimer’s disease can be diagnosed definitively only by examining brain tissue after death. In living patients, physicians diagnose Alzheimer’s by evaluating other health factors, known as biomarkers, in combination with memory loss and other cognitive symptoms.

The hippocampus is a small region of the brain that is associated with memory formation, and memory loss is the earliest clinical feature of Alzheimer’s disease. Its shrinkage or atrophy, as determined by a structural MRI exam, is a well-established biomarker for the disease and is commonly used in both clinical and research settings to diagnose the disease and monitor its progression.

But until now, the effectiveness of structural MRI has been limited because of the widely different approaches being used to identify the hippocampus and measure its volume — which has called into question the validity of this approach. A typical hippocampus is about 3,000 to 4,000 cubic millimeters in volume. But, Apostolova notes, two scientists analyzing the same structure can come up with a difference of as much as 2,000 cubic millimeters.

In addition, no previous study had verified whether estimates for the volume of the hippocampus using MRI corresponded to actual tissue loss.

To address these deficiencies, the European Alzheimer’s Disease Consortium–Alzheimer’s Disease Neuroimaging Initiative was established to develop a Harmonized Protocol for Hippocampal Segmentation, or HarP — an effort to establish a definitive method for measuring hippocampal shrinkage through structural MRI in a way that best corresponds to the Alzheimer’s disease process.

Once the HarP was established, Apostolova and four other experts were invited to develop the gold standard for measuring the hippocampus to be used by anyone employing the HarP protocol. The UCLA-led team then validated the technique and ensured the changes in the hippocampus corresponded to the hallmark pathologic changes associated with Alzheimer’s disease.

“The technique is meant to be used on scans of living human subjects, so it’s important that we are absolutely certain that this methodology measures what it is supposed to and captures disease presence accurately,” Apostolova said.

To do that, her group used a powerful 7 Tesla MRI scanner to take images of the brain specimens of 16 deceased individuals — nine who had Alzheimer’s disease and seven who were cognitively normal — each for 60 hours. This provided unprecedented visualization of the hippocampal tissue, Apostolova said.

After applying the protocol to measure the hippocampal structures, the researchers analyzed the tissues for two changes that signify the disease: a buildup of amyloid tau protein and loss of neurons. The team found a significant correlation between hippocampal volume and the Alzheimer’s disease indicators.

“As a result of the years of scientifically rigorous work of this consortium, hippocampal atrophy can finally be reliably and reproducibly established from structural MRI scans,” Apostolova said.

Although the technique can be used immediately in research settings such as clinical trials, the next step, Apostolova noted, will be to use the standardized protocol to validate automated techniques available for measuring the hippocampus so the approach could be used more widely — including for the diagnosis of the disease in doctor’s offices and other patient care settings.

Funding for the study was provided by the National Institute on Aging (P50 AG16570), the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development, the National Institutes of Health (R01 AG040770), and the Alzheimer’s Association (IIRG 10-174022). Please see the paper for a complete list of the study’s authors.

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New clues about risk of cancer from low-dose radiation


Berkeley Lab research could lead to ways to ID people particularly susceptible to cancer.

By Dan Krotz, Berkeley Lab

Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have uncovered new clues about the risk of cancer from low-dose radiation, which in this research they define as equivalent to 100 millisieverts or roughly the dose received from ten full-body CT scans.

They studied mice and found their risk of mammary cancer from low-dose radiation depends a great deal on their genetic makeup. They also learned key details about how genes and the cells immediately surrounding a tumor (also called the tumor microenvironment) affect cancer risk.

In mice that are susceptible to mammary cancer from low-dose radiation, the scientists identified more than a dozen regions in their genomes that contribute to an individual’s sensitivity to low-dose radiation. These genome-environment interactions only become significantly pronounced when the mouse is challenged by low-dose radiation.

The interactions also have a big impact at the cellular level. They change how the tumor microenvironment responds to cancer. Some of these changes can increase the risk of cancer development, the scientists found.

They report their research March 9 in the journal Scientific Reports.

Because mice and humans share many genes, the research could shed light on the effects of low-dose radiation on people. The current model for predicting cancer risk from ionizing radiation holds that risk is directly proportional to dose. But there’s a growing understanding that this linear relationship may not be appropriate at lower doses, since both beneficial and detrimental effects have been reported.

“Our research reinforces this view. We found that cancer susceptibility is related to the complex interplay between exposure to low-dose radiation, an individual mouse’s genes, and their tumor microenvironment,” says Jian-Hua Mao of Berkeley Lab’s Life Sciences Division.

Mao led the research in close collaboration with fellow Life Science Division researchers Gary Karpen, Eleanor Blakely, Mina Bissell and Antoine Snijders, and Mary Helen Barcellos-Hoff of New York University School of Medicine.

The identification of these genetic risk factors could help scientists determine whether some people have a higher cancer risk after exposure to low-dose radiation. It could lead to genetic screening tests that identify people who may be better served by non-radiation therapies and imaging methods.

The scientists used a comprehensive systems biology approach to explore the relationship between genes, low-dose radiation, and cancer. To start, Mao and colleagues developed a genetically diverse mouse population that mimics the diversity of people. They crossed a mouse strain that is highly resistant to cancer with a strain that is highly susceptible. This yielded 350 genetically unique mice. Some were resistant to cancer, some were susceptible, and many were in between.

Next, Mao and colleagues developed a way to study how genes and the tumor microenvironment influence cancer development. They removed epithelial cells from the fourth mammary gland of each mouse, leaving behind the stromal tissue. Half of the mice were then exposed to a single, whole-body, low dose of radiation. They then implanted genetically identical epithelial cells, which were prone to cancer, into the fourth mammary glands that were previously cleared of their epithelial cells.

“We have genetically different mice, but we implanted the same epithelial cells into all of them,” says Mao. “This enabled us to study how genes and the tumor microenvironment — not the tumor itself — affect tumor growth.”

The scientists then tracked each mouse for 18 months. They monitored their tumor development, the function of their immune systems, and the production of cell-signaling proteins called cytokines. The researchers also removed cancerous tissue and examined it under a microscope.

They found that low-dose radiation didn’t change the risk of cancer in most mice. A small minority of mice was actually protected from cancer development by low-dose radiation. And a small minority became more susceptible.

In this latter group, they found thirteen gene-environment interactions, also called “genetic loci,” which contribute to the tumor susceptibility when the mouse is exposed to low-dose radiation. How exactly these genetic loci affect the tumor microenvironment and cancer development is not yet entirely understood.

“In mice that were susceptible to cancer, we found that their genes strongly regulate the contribution of the tumor microenvironment to cancer development following exposure to low-dose radiation,” says Mao.

“If we can identify similar genetic loci in people, and if we could find biomarkers for these gene-environment interactions, then perhaps we could develop a simple blood test that identifies people who are at high risk of cancer from low-dose radiation,” says Mao.

The research was supported by the Department of Energy’s Office of Science.

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Wearable electronics device makes it easier to image infants


Flexible, lightweight and wearable electronics strategy has led to plans for clinical trials.

New wearable electronics will allow an infant to be swaddled in a blanket laced with a network of nearly weightless, printed “coils” for more comfortable, less expensive MRI scanning.

By Wallace Ravven

An infant born three months prematurely fails to flush pink at birth and has an alarmingly low blood pressure. Ultrasound identifies a heart abnormality and doctors rush the newborn to an MRI suite to confirm the diagnosis. But the scanning itself can cause physical agitation that interferes with clear imaging. In some cases, it can make it harder for the baby to breathe.

When scans require high sensitivity on a small area of the body, a hard, heavy vest of metal coils must press down on the baby. The bulky burden weighs more than the newborn. Infants squirm under the pressure, but anesthesia to calm them down adds an unwanted risk. Lightening the load by securing the weighty apparatus off the baby leads to degraded resolution, prompting a need for longer MRI exposures.

The hardware is part of the radio frequency (RF) coil assembly that receives the MRI’s electromagnetic signals. Besides being awkward and heavy, the coils are expensive to manufacture and must be reused for years. Sanitizing the bulky assembly is difficult.

Cut to a faculty lunch in 2011. UC Berkeley MRI expert Miki Lustig hears his colleague Ana Claudia Arias describe her lab’s progress adapting a technique similar to conventional ink jet printing to fabricate electronic devices.

It was a technology, Lustig says, that was “well beyond my comfort zone.” But he wondered if Arias’ printable electronics techniques could fabricate ultra-lightweight, “two-dimensional” RF coils to ease the trauma to tiny tots and improve image quality.

Lustig and Arias, both faculty members in the electrical engineering and computer sciences department, walked back to their offices together.

“I asked her if she thought RF coils could be printed. It just seemed like a good idea. She said ‘let me think about it.’ A few days later — almost immediately — she said we should give it a try. She started ordering materials to test different substrates and putting a team together.”

Printing electronic circuits and devices based on metals and semiconductors from solution is a very young field that Arias first entered in 2003 at the near-legendary Xerox PARC in Palo Alto. She came to PARC from Plastic Logic Limited, where she worked after finishing her Ph.D. in physics at the Cavendish Laboratory at Cambridge University, U.K.

While at Xerox, Arias began to explore fabrication of wearable sensors. Her group developed several components of a flexible sensor that targeted the prevention of brain injuries by monitoring pressure, acoustic and light levels in the battlefield.

When she joined the Berkeley EECS faculty in 2011, she began to expand her collaborations to developed wearable medical devices that could track vital signs and give doctors feedback on their patients health.

“Printed electronics is an ideal technology for fabrication and integration of devices with different functionality, such as sensors, light sources and simple circuits. It is ideal for deposition of unique and customized designs. And when one adds flexible substrates to the equation you could start thinking about truly wearable — and comfortable — electronics”

To make “wearable electronics” for infant MRI patients, her team first tried to print directly onto cloth fabric.

“We wanted to make our coil feel like a swaddle blankie that fits snugly and softly around the babies,” she says.

But the cloth’s texture interfered with the ability to print high-quality capacitors, so the team turned to printing the “electronic inks” layer by layer onto plastic thin film, like what is used in photo transparencies. The lab succeeded in fabricating and demonstrating functioning RF coils with performance properties comparable to conventional RF coils.

Arias is supported by a Bakar Fellowship at Berkeley, support intended to help commercially promising research make the leap from the lab to the real world. She and Lustig plan to start a company to advance the technology into clinical use.

“We, researchers, don’t usually have experience and training with steps such as securing IP protection and developing a business plan to attract investment and ensure success. Mentors we met through the Bakar Program have been very helpful,” she says.

Their proof-in-principle of the flexible, lightweight and wearable electronics strategy has led to plans for clinical trials early next year. She and Lustig are collaborating with pediatrician Shreyas Vasanawala at Lucile Packard Children’s hospital to test the wearable RF coils on babies needing MRI scans. Vasanawala has been a key clinical consultant to the project from the beginning.

Arias sees the technology’s potential for adult MRI scanning as well — helping to make the MRI experience more comfortable and less scary to everyone, while getting better images of parts of the body that the bulky conventional RF coil assemblies don’t fit very well.

Meanwhile, she still has her eyes on developing that electronic blankie. “When you see kids in the hospital, it’s scary for them. When they’re in a blanket, it’s a much more comforting experience. We want to swaddle them.”

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UC Davis designated a lung cancer screening center


The only of its kind currently in the greater Sacramento area.

By Dorsey Griffith, UC Davis

UC Davis Health System has been endorsed by the American College of Radiology as a designated lung cancer screening center, the only of its kind currently in the greater Sacramento area.

The designation means that UC Davis has complied with stringent quality and safety requirements for its computed tomography (CT) scanning practices, and it confirms that UC Davis meets the required radiation-dose standards.

“This designation offers patients the security of an external review process to ensure that such exams are performed at the highest level of quality and safety,” said Friedrich D. Knollmann, professor of clinical radiology in the UC Davis Department of Radiology.

The designation follows a decision by the federal Centers for Medicare and Medicaid Services to recommend CT screening for individuals deemed at high risk for developing lung cancer. Those include men and women who have smoked more than a pack a day for 30 years or two packs a day for 15 years. The screening is limited to individuals over age 55 and up to 77 or 80 depending on the individual’s insurance.

Since Jan. 1, as set forth in the Affordable Care Act, private insurers must cover the screening for people who meet the criteria. The health care reform law stipulates that insurers must provide services recommended by the U.S. Preventive Services Task Force, an independent panel that analyzes data and makes recommendations about health screening.

The task force in December 2013 recommended low-dose CT screening for eligible individuals based on results of the groundbreaking National Lung Screening Trial, which determined that low-dose CT screening reduced the risk of dying from lung cancer in heavy smokers by 20 percent compared to screening with chest X-rays. Data from the trial were published in the New England Journal of Medicine in 2011.

Lung cancer is the third most common cancer and the leading cause of cancer death in the United States. Smoking is the leading cause of lung cancer; about 85 percent of all U.S. lung cancer cases are smoking related. Lung cancer is most commonly diagnosed in people 55 and older.

The American College of Radiology represents more than 37,000 diagnostic radiologists, radiation oncologists, interventional radiologists, nuclear medicine physicians and medical physicists. The organization works to improve, promote and protect the practice of radiology to ensure the quality and safety of patient care.

The UC Davis lung cancer screening program uses a multidisciplinary team of radiologists, thoracic surgeons, pulmonologists, pathologists, medical oncologists and radiation oncologists to develop a patient-centered plan for leading-edge lung cancer care. Individuals interested in lung cancer screening should discuss the pros and cons of the test with their primary care physician, who will, after a shared decision to participate has been reached, refer them to the UC Davis Department of Radiology.

Referrals can be faxed to (916) 703-2254, and screenings can be scheduled by calling (916) 734-0655.

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MRI technique developed for nonalcoholic fatty liver disease in children


UC San Diego study makes strides toward noninvasive diagnostic for pediatric liver disease.

By Heather Buschman, UC San Diego

Between 5 and 8 million children in the United States have nonalcoholic fatty liver disease (NAFLD), yet most cases go undiagnosed. To help address this issue, researchers at UC San Diego School of Medicine have developed a new magnetic resonance imaging (MRI)-based technique to help clinicians and researchers better detect and evaluate NAFLD in children. The study is published today (Feb. 5) in Hepatology.

“Currently, diagnosis of NAFLD requires a liver biopsy, which is not always available or performed. This leads to both misdiagnosis and missed diagnoses, hampering patient care and progress in clinical research,” said Jeffrey B. Schwimmer, M.D., professor of clinical pediatrics at UC San Diego, director of the Fatty Liver Clinic at Rady Children’s Hospital-San Diego and the first author of the study. “Thus, a noninvasive method for diagnosing and/or evaluating NAFLD has the potential to impact millions of children.”

NAFLD is characterized by large droplets of fat in at least 5 percent of a child’s liver cells. Obesity and diabetes are risk factors for NAFLD. Doctors are concerned about NAFLD in children because it can lead to hepatitis, liver scarring, cirrhosis and liver cancer.

Traditionally, NAFLD is diagnosed by a gastroenterologist in consultation with a pathologist, who examines the patient’s biopsied liver tissue under a microscope. The presence and severity of liver fat is graded by the pathologist as none, mild, moderate or severe, based on the percentage of liver cells that contain fat droplets.

In an effort known as the MRI Rosetta Stone Project, Schwimmer and colleagues used a special MRI technique known as magnitude-based MRI, which was previously developed by researchers in the UC San Diego Liver Imaging Group, to estimate liver proton density fat fraction (PDFF), a biomarker of liver fat content.

“Existing techniques for measuring liver fat are dependent upon the individual scanner and the center at which the measurements were made, so they cannot be compared directly,” said Claude B. Sirlin, M.D., professor of radiology at UC San Diego and senior author of the study. “By comparison, PDFF is a standardized marker that is reproducible on different scanners and at different imaging centers. Thus, the results of the current study can be generalized to the broader population.”

In this study, the researchers compared the new MRI technique to the standard liver biopsy method of assessing fat in the liver. To do this, the team enrolled 174 children who were having liver biopsies for clinical care. For each patient, the team performed both MRI-estimated PDFF and compared the results to the standard pathology method of measuring fat on a liver biopsy.

The team found a strong correlation between the amount of liver fat as measured by the new MRI technique and the grade of liver fat determined by pathology. This is an important step towards being able to use this technology for patients. Notably, the correlation was influenced by both the patient’s gender and the amount of scar tissue in the liver. The correlation between the two techniques was strongest in females and in children with minimal scar tissue.

Depending on how the new MRI technology is used, it could correctly classify between 65 and 90 percent of children as having or not having fatty liver tissue.

“Advanced magnitude MRI can be used to estimate PDFF in children, which correlates well with standard analysis of liver biopsies,” Schwimmer said. “We are especially excited about the promise of the technology for following children with NAFLD over time. However, further refinements will be needed before this or any other MRI technique can be used to diagnose NAFLD in an individual child.”

Study co-authors include Michael S. Middleton, Cynthia Behling, Kimberly P. Newton, Hannah I. Awai, Melissa N. Paiz, Jessica Lam, Jonathan C. Hooker, Gavin Hamilton and John Fontanesi, all at UC San Diego.

This research was funded, in part, by the National Institutes of Health (grants UL1RR031980, DK088925-02S1 and R56-DK090350-01A1) and the National Science Foundation (grant 414916).

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California breast density law slow to have an impact


UC Davis research demonstrates need for more physician education.

Jonathan Hargreaves, UC Davis

By Dorsey Griffith, UC Davis

Ten months after California legislators enacted a controversial law mandating that radiologists notify women if they have dense breast tissue, UC Davis researchers have found that half of primary care physicians are still unfamiliar with the law and many don’t feel comfortable answering breast density-related questions from patients. The findings, to be published in the March print edition of Journal of the American College of Radiology, suggest that if the law is going to have any significant impact on patient care, primary care providers need more education about breast density and secondary imaging options.

“Overall, the impact of the breast density legislation probably is not significant if  primary care physicians are not educated or aware of it,” said lead author Kathleen Khong, a UC Davis radiologist and staff physician. “We should put some emphasis on educating the primary care physicians so that when they get questions from patients, they can be comfortable in addressing the issues.”

The California law, which took effect in April 2013, requires that patients whose breast density is defined as “heterogeneously dense” or “extremely dense” (about 50 percent of women), receive the following notification:

“Your mammogram shows that your breast tissue is dense. Dense breast tissue is common and is not abnormal. However, dense breast tissue can make it harder to evaluate the results of your mammogram and may also be associated with an increased risk of breast cancer. This information about the results of your mammogram is given to you to raise your awareness and to inform your conversations with your doctor. Together, you can decide which screening options are right for you. A report of your results was sent to your physician.”

The researchers point out that breast density has long been a required part of any radiological report following mammography, but unless a patient asks to see the report, the information is shared only with the patient’s providers. Led by patient advocates, the legislation is intended to increase awareness of dense breasts and encourage patients to discuss the clinical issues with their doctors. According to published research, 28 states have passed, rejected or considered dense-breast notification legislation since 2009.

But the UC Davis study demonstrated that while women and their doctors are receiving the notifications, many of those physicians are unclear about what to do with the information. As a consequence, the researchers said, it appears that relatively few patients with dense breasts are asking questions about their breast density and its implications.

The UC Davis study surveyed 77 physicians about the new law.  Roughly half (49 percent) reported no knowledge of the legislation and only 32 percent of respondents noted an increase in patient levels of concern about breast density compared to prior years. In addition, a majority of primary care physicians were only “somewhat comfortable” (55 percent) or “not comfortable” (12 percent) with breast-density questions from their patients.

Khong said their survey results were surprising, but acknowledged that many primary care physicians may not feel they have sufficient training to make a clinical recommendation for a particular type of secondary screening. In fact, the study also found that 75 percent of respondents would like more education about the breast-density law and its implications for primary care.

“They are eager to learn and want to help their patients and be part of something positive as a result of this,” Khong said.

Jonathan Hargreaves, assistant professor of clinical radiology and a study co-author, said, for example,  that if a patient has dense breasts she should have a risk assessment, which takes into account her family history of breast cancer, biopsy history and other factors to determine whether a supplemental screening is warranted. Once  complete, the physician should then discuss the potential benefits and risks of supplemental imaging in determining the most appropriate approach for the patient. The use of ancillary screening in addition to mammography is a complex subject and still the subject of considerable debate, explained Hargreaves.

Tomosynthesis, known as 3-D mammography, is one supplemental test that breast radiologists generally agree provides a slight benefit for women with dense breasts over a standard mammogram and can be scheduled for the next annual mammographic screening appointment after receiving a notification. Breast magnetic resonance imaging (MRI) is another secondary imaging option, Hargreaves said, but is generally only used for screening in women who have a very strong family history of breast cancer or have a known high-risk gene, such as BRCA.

“The law has raised a lot of awareness about breast density,” Hargreaves said. “That being said, mammography screening is the primary thing patients need to do, and beyond that, the real benefits of other screening techniques are still the subject of ongoing medical debate.”

Khong and Hargreaves hope to validate their findings by expanding their research to include primary care physicians from other major university health care systems in California.

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Novel imaging technique improves detection of prostate cancer


More accurate diagnoses could mean less invasive interventions, more surveillance.

By Scott LaFee, UC San Diego

In 2014, prostate cancer was the leading cause of newly diagnosed cancers in men and the second leading cause of cancer death in men. Writing in today’s (Jan. 6) issue of the journal Prostate Cancer and Prostatic Disease, a team of scientists and physicians from the UC San Diego School of Medicine, with counterparts at UCLA, describe a novel imaging technique that measurably improves upon current prostate imaging – and may have significant implications for how patients with prostate cancer are ultimately treated.

“This new approach is a more reliable imaging technique for localizing tumors. It provides a better target for biopsies, especially for smaller tumors,” said Rebecca Rakow-Penner, M.D., Ph.D., a research resident in the Department of Radiology and the study’s first author.

The technique is also valuable in surgical planning and image staging, said David S. Karow, M.D., Ph.D., assistant professor of radiology at UC San Diego and the study’s corresponding author. “Doctors at UC San Diego and UCLA now have a non-invasive imaging method to more accurately assess the local extent of the tumor and possibly predict the grade of the tumor, which can help them more precisely and effectively determine appropriate treatment.”

The current standard of care for detecting and diagnosing prostate cancer is contrast enhanced magnetic resonance imaging (MRI), which involves intravenously injecting patients with a contrast agent to highlight blood flow. Greater blood flow is often a requirement of growing cancer cells. When compared to surrounding healthy tissues, it’s hoped that contrast enhanced MRIs will reveal the shape and nature of any tumors present.

But many tumors do not significantly differ from surrounding healthy tissues with contrast enhanced MRI and so evade easy detection. An imaging technique called diffusion MRI measures the diffusion of water and has been a standard imaging technique in the brain and an emerging technique in the prostate. Cancer tissues are denser than healthy tissues and typically limit the amount and mobility of water within them. But diffusion MRI suffers from magnetic field artifacts that can distort the actual location of tumors by as much as 1.2 centimeters or roughly half an inch – a significant distance when surgeons are attempting, for example, to assess whether a tumor extends beyond the prostate and into adjacent nerve bundles.

The new approach described in today’s published paper is called restriction spectrum imaging-MRI or RSI-MRI. It corrects for magnetic field distortions and focuses upon water diffusion within tumor cells. By doing both, the ability of imaging to accurately plot a tumor’s location is increased and there is a more refined sense of the tumor’s extent, said Nathan White, Ph.D., assistant project scientist at UC San Diego, study co-author and co-inventor of the RSI-MRI technique.

In a related paper to be published in the journal Frontiers in Oncology, the same team of researchers reported that RSI-MRI appears to predict tumor grade. Higher grade tumors correlate with higher restricted water volume in the cancer cells’ large nuclei.

“Prostate cancer can often be an indolent disease, where a patient may only require surveillance rather than aggressive surgery,” noted co-author Christopher J. Kane, M.D., professor of urology at UC San Diego.

“If by imaging we could predict the tumor grade,” added Robert Reiter, M.D., professor of urology at UCLA, “we may be able to spare some patients from prostate resection and monitor their cancer with imaging.”

Co-authors include senior author Anders M. Dale, Hyung W. Choi, Joshua M. Kuperman, Natalie M. Schenker-Ahmed, Hauke Bartsch, Robert F. Mattrey and William G. Bradley, Department of Radiology, UCSD; J. Kellogg Parsons and Michael A. Liss, Department of Urology, UCSD; Ahmed Shabaik, Department of Pathology, UCSD; Jiaoti Huang, Department of Pathology, UCLA; Daniel J. Margolis and Steven S. Raman, Department of Radiology, UCLA; Leonard S. Marks, Department of Urology, UCLA.

Funding for this research was provided, in part, by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health, the Department of Defense, Prostate Cancer Research Program, the American Cancer Society and the UC San Diego Clinician Scientist Program.

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NSF grant to improve visualization capabilities for biosciences, geosciences


UC San Diego partnering with National Center for Atmospheric Research.

By Ioana Patringenaru, UC San Diego

The National Center for Atmospheric Research (NCAR) is partnering with UC San Diego to expand and enhance visualization capabilities in the bio- and geosciences through a grant from the National Science Foundation.

The collaboration builds on existing software capabilities developed at NCAR and UC San Diego, and it will combine them to produce new open source tools for scientists to explore large data sets.

The project is known as WASP (Wavelet-enabled Progressive Data Access and Storage Protocol).

Current advances in digital imaging and numerical modeling technologies have enabled the creation of vast amounts of data. A challenge for many researchers is making sense out of these digital outputs. One way of dealing with extremely large data sets is known as progressive data access (PDA), which is the enabling technology behind consumer applications like Google Maps. In mapping applications, PDA reduces data volumes by only loading areas of interest, not the entirety of the map database, and allows the user to view these images in greater detail or lesser detail.

The problem is that similar tools are scarce in the biosciences, despite a need for analyzing data gathered from advanced imaging technologies such as MRI and CT scans. And as the size and complexity of the data increase, the computing resources commonly available for data analysis are over-subscribed. The geosciences encounter similar issues, with models for weather, climate, oceans and other Earth systems generating very large and complex data.

Given the similar nature of the challenge across various disciplines, researchers at NCAR and UC San Diego put their heads together to work on a solution, capitalizing on complementary work that was already ongoing at both institutions. Though the bio- and geosciences are very different scientific disciplines, with different data, the underlying forms of the data and structure of the data are very similar, allowing for shared methods of dealing with the data.

Two software approaches

An NCAR team has developed a software solution known as VAPOR, (Visualization and Analysis Platform for Ocean, Atmosphere and Solar Researchers). VAPOR provides an interactive 3-D visualization environment that runs on most UNIX and Windows systems. At the heart of VAPOR is a progressive data access scheme based on mathematical linear transforms using wavelets. An NSF grant launched the development of the technology in 2003, and VAPOR is currently on its third major release, with over 6,000 users worldwide.

“VAPOR is an application specifically designed to facilitate researchers’ interaction with very large data sets, but while using only relatively modest computing resources,” said John Clyne, a software engineer and computer scientist who is the principal investigator for VAPOR in NCAR’s Computational and Information Systems Laboratory (CISL). “It is already widely used in the geosciences community, and with this award we will not only be able to expand and improve it for its current users, but also make it usable for the biosciences and bioimaging communities.”

At UC San Diego, the Center for Scientific Computation in Imaging has been developing a general analysis and visualization software toolkit for the bioimaging community, known as the Shape Analysis for Phenomics from 3-D Imaging Data (SAPID) ToolKit (STK).

The goal of the SAPID project is to develop advanced computational methods for researchers in evolutionary biology to characterize subtle morphological variations from high-resolution 3-D voxel-based digital imaging modalities. A critical issue that arose in this project was the necessity of being able to handle very large datasets. This new NSF award will address this important issue and thus provide these innovative capabilities to the bio-imaging community.

“This award is exciting because it allows us to take our existing software, combine and reuse it in new ways, and expand its capabilities to serve more broadly across scientific disciplines,” said UC San Diego’s Lawrence Frank, the principal investigator for the WASP award and the SAPID Project, as well as a researcher at the Institute of Engineering in Medicine.

Both Frank and Clyne point out that the most important aspect of this collaboration is that it will reuse existing NSF-funded software to provide a common framework that benefits both biological digital imaging and geosciences numerical modeling communities, and will have a profound impact for scientists working with large data sets.

“We’ll be able to provide better tools to the climate and weather science communities, while providing the first such tools for the biosciences community,” said Clyne. “It’s especially gratifying that NSF’s initial investments in both VAPOR and STK can be augmented with this award to produce an impactful and interdisciplinary tool.”

The University Corporation for Atmospheric Research manages the National Center for Atmospheric Research under sponsorship by the National Science Foundation. Any opinions, findings and conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

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First real-time MRI-guided brain surgery for Parkinson’s in SoCal


Deep brain stimulator also can be used to treat other movement disorders.

By Jackie Carr, UC San Diego

Neurosurgeons at UC San Diego Health System are the first in Southern California to implant a deep brain stimulator (DBS) in a patient with Parkinson’s disease using real-time 3-D magnetic resonance image (MRI) guidance.

Parkinson’s disease is a progressive disorder of the nervous system that affects movement. Symptoms include shaking, slowness of movement and difficulty walking. These unpredictable movements are caused by abnormal nerve cell activity in the brain. DBS therapy, like a heart pacemaker, transmits electrical signals to help restore normal activity.

Traditionally, DBS surgery is conducted while the patient is awake, and under pain management. This approach allows surgeons to continuously monitor the patient’s brain function and to ensure accurate placement of the device.

“Now, for some patients, this surgery can be performed in the MRI suite under general anesthesia so that a patient can sleep during the placement of the DBS electrodes,” David Barba, M.D., director of functional neurosurgery, UC San Diego Health System. “Within a few days of DBS therapy, many patients can resume life’s everyday activities.”

“Placing a DBS device while a patient is awake can be exhausting for the patient due to the length of the procedure and the need to perform neurologic testing in the operating room,” added Clark Chen, M.D., Ph.D., director of stereotactic and radiosurgery, UC San Diego Health System. “Fortunately, with continuous real-time MRI monitoring, we can now place the electrode in a safe location that provides maximal neurological benefit while the patient is under the comfort of general anesthesia.”

Bob S. Carter, M.D., Ph.D., professor and chief of neurosurgery and co-director of the UC San Diego Neurological Institute, said the collaborative endeavor introduces a new technology strategy to improve the care of patients with Parkinson’s and other diseases.

“Our capacity to perform these procedures will be further enhanced in the new A. Vassiliadis Family Hospital for Advanced Surgery at Jacobs Medical Center, which opens in 2016,” said Carter.

DBS also can be used to treat other movement disorders, including dystonia, essential tremor and obsessive compulsive disorder. It is in clinical trial testing as treatment for depression.

UC San Diego Health System is an internationally recognized leader in functional neurosurgery. Barba is a pioneer in the neurosurgical treatment of patients affected with movement disorders. Chen is an expert in MRI guided neurosurgery.

To learn more about MRI-guided DBS placement, please visit: health.ucsd.edu.

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Finding a better way to track emerging cell therapies using MRIs


Technique might speed development of relevant therapies.

Cellular therapeutics – using intact cells to treat and cure disease – is a hugely promising new approach in medicine, but it is hindered by the inability of doctors and scientists to effectively track the movements, destination and persistence of these cells in patients without resorting to invasive procedures, like tissue sampling.

In a paper published Sept. 17 in the online journal Magnetic Resonance in Medicine, researchers at the UC San Diego School of Medicine, University of Pittsburgh and elsewhere describe the first human tests of using a perfluorocarbon (PFC) tracer in combination with non-invasive magnetic resonance imaging (MRI) to track therapeutic immune cells injected into patients with colorectal cancer.

“Initially, we see this technique used for clinical trials that involve tests of new cell therapies,” said first author Eric T. Ahrens, Ph.D., professor in the Department of Radiology at UC San Diego. “Clinical development of cell therapies can be accelerated by providing feedback regarding cell motility, optimal delivery routes, individual therapeutic doses and engraftment success.”

Currently, there is no accepted way to image cells in the human body that covers a broad range of cell types and diseases. Earlier techniques have used metal ion-based vascular MRI contrast agents and radioisotopes. The former have proven difficult to differentiate in vivo; the latter raise concerns about radiation toxicity and do not provide the anatomical detail available with MRIs.

“This is the first human PFC cell tracking agent, which is a new way to do MRI cell tracking,” said Ahrens. “It’s the first example of a clinical MRI agent designed specifically for cell tracking.”

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CT scan is no better than ultrasound to detect kidney stones


UCSF study leader recommends change in standard practice.

Rebecca Smith-Bindman, UC San Francisco

To diagnose painful kidney stones in hospital emergency rooms, CT scans are no better than less-often-used ultrasound exams, according to a clinical study conducted at 15 medical centers and published in the Sept. 18 issue of the New England Journal of Medicine.

Unlike ultrasound, CT exposes patients to significant amounts of radiation. Although CT scans are favored by emergency-room physicians for kidney stone diagnosis, ultrasound should be used as the first step, according to senior study author Rebecca Smith-Bindman, M.D., a professor in the departments of radiology; epidemiology and biostatistics; and obstetrics, gynecology and reproductive medicine at UC San Francisco.

“Ultrasound is the right place to start,” Smith-Bindman said. “Radiation exposure is avoided, without any increase in any category of adverse events, and with no increase in cost.” Patients in the study who were first examined with ultrasound sometimes received a follow-up CT exam at the physician’s discretion.

“Our results do not suggest that patients should undergo only ultrasound imaging, but rather that ultrasonography should be used as the initial diagnostic imaging test, with further imaging studies performed at the discretion of the physician on the basis of clinical judgment,” the study authors said.

Kidney stone rates are increasing, and in a 2010 National Health and Nutrition Examination Survey, one in 11 people reported having had at least one kidney stone. The use of CT to diagnose kidney stones has risen 10-fold in the last 15 years. CT exams generally are conducted by radiologists, while ultrasound exams may be conducted by emergency room physicians as well as radiologists.

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Related link:
Innovation Profile: Rebecca Smith-Bindman

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MRI is a ‘game-changer’ in diagnosing prostate cancer


UC San Diego Health System is first to use new tool in San Diego.

Oncologists at UC San Diego Moores Cancer Center are the first in San Diego to meld magnetic resonance imaging (MRI) technology with a traditional ultrasound prostate exam to create a three-dimensional map of the prostate that allows physicians to view growths that were previously undetectable.

An ultrasound machine provides an imperfect view of the prostate, resulting in an under-diagnosis of cancer, said J. Kellogg Parsons, M.D., M.H.S., the UC San Diego Health System urologic oncologist who, along with Christopher Kane, M.D., chair of the Department of Urology and Karim Kader, M.D., Ph.D., urologic oncologist, is pioneering the new technology at Moores Cancer Center.

“With an ultrasound exam, we are typically unable to see the most suspicious areas of the prostate so we end up sampling different parts of the prostate that statistically speaking are more likely to have cancer,” said Parsons, who is also an associate professor in the Department of Urology at UC San Diego School of Medicine. “The MRI is a game-changer. It allows us to target the biopsy needles exactly where we think the cancer is located. It’s more precise.”

Armondo Lopez, a patient at Moores Cancer Center, had been given a clean bill of health using the traditional ultrasound biopsy method, but when his prostate-specific antigen (PSA) levels, a protein that is often elevated in men with prostate cancer, started to rise he began to worry. Parsons recommended a MRI-guided prostate biopsy. The new technology led to the diagnosis of an aggressive prostate cancer located in an area normally not visible using the ultrasound machine alone. The tumor was still in its early stage and treatable, said Parsons.

An early diagnosis typically improves a patient’s prognosis. In the United States, prostate cancer is the second leading cause of cancer death in men with more than 29,000 estimated deaths expected this year. The average age at the time of diagnosis is about 66.

Lopez is thankful he will be able to celebrate his 58th wedding anniversary with his wife.

“Life is going on as normal,” said Lopez. “This is the wave of the future. I see this new technology as the way to save thousands of lives. I commend Dr. Parsons for taking the lead in San Diego in this area.”

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