Newswise — Want to know if your child’s height and weight are on track? Check the growth chart that the doctor gives you after each yearly checkup. Want to know if your child’s brain is on track for healthy attention abilities? Someday, your doctor might have a growth chart for that too. New research from the University of Michigan Medical School suggests that it might be possible to create a growth chart of brain networks that could identify early signs of attention difficulties and, potentially, attention deficit hyperactivity disorder. The team created the experimental growth chart by mapping the development of brain networks in more than 500 children and teens. They found networks are underdeveloped in those who have attention difficulties. While it’s far too soon to start offering such charting to families, future development of the technique could mean better chances for children to get a firm diagnosis of ADHD sooner. It could also help track whether their ADHD treatment is improving their attention functioning, which can help them in school and life. Growth charts as biomarkers The research, published in JAMA Psychiatry, shows the potential for brain imaging “biomarkers” for attention problems. But the idea could extend to other psychological conditions. Traditional growth charts show a child’s height and weight as points on curves that are based on data from hundreds of thousands of other children, and indicate normal, near-normal and problematic development. “Growth charts enable a family and their physician to quickly spot problematic development, and when necessary, intervene appropriately,” said team leader and U-M psychiatrist Chandra Sripada, M.D., Ph.D. “In the future, we want to provide clinicians with the same sort of guidance about brain development that we can about things like height and weight.” Maturing networks The researchers launched the growth-charting research after noticing a gap in the state of the science. Lead author Daniel Kessler explains, “We knew that the ability to sustain attention for an extended time increases dramatically during childhood and adolescence. We also knew that over the same time period, there are big changes in brain networks involved in attention. We came up with the idea of growth charting as a way to test if these two patterns were related: Would children with underdeveloped brain networks also have more difficulty with attention?” Along with colleague Michael Angstadt, MAS, the researchers used data from 519 children and teens who had genetic testing, brain imaging and tests of their cognitive development as part of the Philadelphia Neurodevelopmental Cohort based at the University of Pennsylvania. The researchers created growth charts that reflected the configuration of what are called intrinsic connectivity networks -- important units of functional brain organization. The way these networks interact may hold the key to healthy attention. For example, one called the default mode network seems to be involved in daydreaming and inwardly focused thought, whereas another set of networks are involved in cognitively demanding tasks. As we grow from children into adults, these two systems become more defined and separate, working in tandem like pistons: when one is on, the other turns off. But in children and those with attention difficulties, the “pistons” often misfire: the default mode network turns on and interrupts the other networks thereby interrupting attention. The researchers who gathered the data that the growth chart is based on measured attention functioning using a standard test in which children had to respond to a sequence of letters and numbers on a computer screen. The Michigan researchers then compared the brain development seen on the scans to attention functioning. It turned out they could actually predict how well a child would do on the attention test based on their place on (or off) the brain network growth chart. The children with ADHD symptoms, and those with the lowest performance for their age on the attention tests, were the furthest off the curve of brain network development. “These brain network growth charts show real promise,” said Sripada. “But they are far away from being ready for clinical use.” Future research paths The research used advanced MRI imaging, but Sripada and his colleagues hope to develop ways to track network maturity using less-expensive techniques such as electroencephalography, or EEG. They’re working with other U-M researchers, led by Mary Heitzeg, Ph.D., and Robert Zucker, Ph.D., to see if the growth charting method will be useful in the Adolescent Brain Cognitive Development study (ABCD for short) that will involve 10,000 teens over several years. “The ABCD study is unprecedented in size and provides a real chance to develop definitive growth charts for brain networks,” explained Sripada. “We have the opportunity to understand how brain network development relates to a variety of outcomes, including cognition, emotion, personality, and behavior.”
Newswise — What do you do when you’re out in public and you witness what you believe to be child abuse? The standard suggestions are to:• start a conversation with the adult to direct attention away from the child.• talk to the child to refocus his or her energy.• look for an opportunity to praise the parent or child.• offer assistance.• avoid negative remarks or looks. In many situations, those are easier said than done. According to Dr. Lori Frasier, director of the Center for the Protection of Children at Penn State Children’s Hospital, it’s a judgment call. “I think it's hard because people might be fearful to intervene,” Frasier said. “It does take a special person to take action when they see something that they think might be abuse. It’s important to consider that if someone is doing something like this in public and they don't care who sees them, what will they do in the privacy of their own home? It could be worse.” What is – and isn’t – abuse? Frasier said it’s hard to know what constitutes abuse. “What is abusive to one person may not be to another,” Frasier said. The law states that child abuse is subjecting a child to bodily injury, neglect or sexual abuse. Some examples include shaking, hitting, kicking, punching or burning a child. “The law states that you must have a reasonable suspicion of abuse in order to report it,” Frasier said. “You don't have to know for sure.” While physical abuse, like hitting or kicking is easy to recognize, verbal abuse like berating, screaming or threatening, can be a gray area. When should you call ChildLine or 911? ChildLine (1-800-932-0313) is available 24 hours a day to accept calls regarding suspected child abuse from mandated reporters as well as the general public in Pennsylvania. Each call is answered by a trained specialist who determines the most appropriate course of action. Callers are asked to provide the child’s name, location and name of the offender. ChildLine then contacts Child Protective Services in the appropriate area, which must respond within 24 hours. “Child and Family Services have to have a way to find out who a child is,” Frasier said. “If you think a child is at risk and needs an immediate response, call the police.” Try to intervene If you are able to intervene, try not to be aggressive or critical, which could put you at risk. "In such a moment, a parent is under great stress and they may not take it well if someone tells them they’re doing something wrong," Frasier said. If you are able to assess the situation and can determine the cause of the stress, you may be able to offer help. Because of distrust of strangers, the offer may be met negatively. Be willing to step back if there is a poor response. Sharing your own struggles of parenthood might be a better approach. "It's important to be relatable to the person; that you're not there to judge them; you've been in their shoes. We've all been in those shoes when we get frustrated," she said. Frasier believes we all have an obligation to protect children. "You don't want to think it's none of your business and then a couple of days later realize that that same child you were worried about has been killed or seriously injured," she said. Frasier had a case where a bystander in Walmart alerted security of a child covered in bruises. The guard called police. "They didn't confront the family directly, but they felt the situation looked scary enough that they needed to alert somebody," she said, noting their suspicions were correct. "It is everybody's business. To not intervene is a mistake," Frasier said.
Newswise — New research in monkeys exposed to SIV, the animal equivalent of HIV, reveals what happens in the very earliest stages of infection, before virus is even detectable in the blood, which is a critical but difficult period to study in humans. The findings, published online today in the journal Cell, have important implications for vaccine development and other strategies to prevent infection. “The events during the first few days after exposure to the virus and prior to the initial detection of virus in the blood are critical in determining the course of infection, but this period is essentially impossible to study in humans,” said lead author Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center (BIDMC) and Professor of Medicine at Harvard Medical School. “Our study is the most comprehensive evaluation of acute HIV/SIV infection to date.” The study was initiated as part of the National Institutes of Health–funded Consortium for AIDS Vaccine Research and involved multiple collaborating laboratories, including those headed by Rafick-Pierre Sekaly, PhD, of Case Western Reserve University and Jeffrey Lifson, MD, of the Frederick National Laboratory for Cancer Research. When Barouch and his colleagues exposed 44 rhesus monkeys to SIV and conducted analyses of the animals on days 0, 1, 3, 7 and 10 following exposure, they found that SIV could disseminate rapidly through the body, with viral RNA (SIV’s genetic material) present in at least one tissue outside the reproductive tract in most monkeys analyzed 24 hours after exposure. “In addition to rapid viral dissemination, the virus triggered a local inflammatory response that appears to suppress antiviral innate and adaptive immunity, thus potentially augmenting its own replication,” explained Barouch. “These data provide important insights into the earliest events of infection.” The inflammatory response occurred in virus-infected tissues soon after exposure to SIV, and increasing amounts of viral RNA correlated with rising amounts of a host protein called NLRX1, which inhibits antiviral immune responses. In addition, the TGF-beta cell-signaling pathway, which suppresses adaptive immune responses, was triggered and correlated with lower levels of antiviral T immune cell responses, as well as higher levels of SIV replication. The researchers observed elevated expression of genes in the TGF-beta pathway in tissues that contained viral RNA as early as day 1 after exposure to the virus. The findings suggest that there may be a very narrow window of opportunity to contain or eliminate the virus. HIV prevention strategies should take these factors into account. “We believe that these insights into early HIV/SIV infection will be critical for the development of interventions to block infection, such as vaccines, antibodies, microbicides and drugs,” Barouch said. “The next step in this line of research is to evaluate how various interventions may impact these early events.”
Newswise — Previous research on an apparent narrowing of the historical “gender gap” in drinking prevalence found that girls were more likely to start drinking before 18 years of age compared to boys. This research seeks to extend these epidemiological findings by estimating the fine-grained, age-specific incidence of becoming a drinker among 12- to 24-year-old U.S. males and females, and comparing incidence estimates with prevalence proportions. Researchers examined a population comprised of 12- to-24-year-old, non-institutionalized U.S. civilian residents. The participants were drawn from 12 successive U.S. National Surveys on Drug Use and Health: nationally representative samples drawn each year from 2002 to 2013 and assessed via computer-assisted self-interviews (n~=390,000). Results confirm that the so-called “gender gap” in the risk of becoming a drinker has narrowed to the point of being no gap at all. In fact, during mid-adolescence the risk of starting to drink is greater for females than for males. That said, a greater prevalence of recently active drinking was subsequently seen in males after 19 years of age.
Newswise — In the U.S., where one of five children entering elementary school is overweight, a healthy diet is critical for preschool children, who are setting their eating patterns for the future. In 2009, more fruits, vegetables, whole grains and low-fat milk were included in the food voucher package provided by USDA’s Special Supplemental Nutrition Program for Women, Infants and Children (WIC). As a result, the diet quality improved for the roughly 4 million children who are served by WIC, according to a study by researchers at UCSF Benioff Children’s Hospital in Oakland, UC San Francisco and UC Agriculture and Natural Resources’ Nutrition Policy Institute. “Although the findings only showed significant improvement for consumption of greens and beans, the other areas for which WIC has put in important efforts – increased consumption of whole fruits rather than fruit juice, increased whole grains – all show trends in the right direction,” said lead author June Tester, a physician at UCSF Benioff Children’s Hospital Oakland, “and there is opportunity for further study in the future when more years have passed after this landmark change in the WIC package.” For the UC study, to be published Thursday, April 7, in the April issue of the journal Pediatrics, researchers analyzed the diets of 1,197 children, ages 2 to 4 years, from low-income households before and after the 2009 change in the food package. The researchers used the National Health and Nutrition Examination Survey (NHANES) to compare a nationally representative sample from 2003 to 2008 with diets in 2011 to 2012. The researchers calculated the Healthy Eating Index (HEI-2010), which is a score with 100 possible points measuring adherence to dietary guidelines, from two recalls by parents of their children’s diets over the previous 24-hour period. For children in households using WIC, this score increased from 52.4 to 58.3 after the policy change. After adjusting for characteristics in the sample and trends in the comparison group, the researchers showed that there was an increase of 3.7 points that was attributable to the WIC package change. This represents important evidence of an improvement in the diets for these children in WIC households. “Vegetables are part of a healthful diet, but in general, children don’t eat enough of them,” Tester said. Using the Healthy Eating Index, the researchers calculated the Greens and Beans score, which counts dark green vegetables and includes any legumes, such as beans and peas, that were not already counted as protein foods on a different score. After the food package was changed, the Greens and Beans score increased for children in WIC but not for their counterparts. Roughly half of the children in WIC households had eaten some vegetables, whereas only one in five non-WIC children had consumed any green vegetables at all in the two days their parents were surveyed. The change in the WIC food package is an important policy change in the effort to improve the quality of diets of young children, said Tester, a pediatrician. Tester noted that the results of this study will be useful to the Institute of Medicine committee that is reviewing and assessing the nutritional status and food needs of the WIC-eligible population and the impact of the 2009 revision to WIC food packages. The committee will make recommendations for changing the food packages. “Increasing consumption of nutritious foods such as green leafy vegetables and whole grains in the low-income children served by WIC will help them establish healthier eating patterns for their future,” said co-author Patricia Crawford, UC Cooperative Extension nutrition specialist with UC ANR’s Nutrition Policy Institute. The switch from whole milk to low-fat milk was well received by the clientele and did not result in decreased milk consumption among the preschoolers, noted Tester, Crawford and co-author Cindy Leung, postdoctoral scholar at UCSF Center for Health and Community. This study is the first to report on the significant improvements in diet quality in young children associated with the WIC package change using a nationally representative sample, and the first to do so with the updated Healthy Eating Index (HEI-2010). The National Institutes for Health funded this study.
Newswise — There may be a hidden cost to the old adage of pulling oneself up by the bootstraps: Research out of the University of Georgia suggests the unintended stress spurred by upward mobility can pose an unintended health risk later down the road. Previous studies have shown the negative health effect that stress can cause, particularly on people coming from lower socioeconomic backgrounds. But this study specified the approach and narrowed it down to just look at the effect on “future oriented” adolescents who strive to break the cycle and earn higher levels of education and income. Researchers in the UGA College of Family and Consumer Sciences, including professor K.A.S. Wickrama, assistant research scientist Catherine O’Neal and graduate student Tae Kyoung Lee, combed through a 13-year national study that contained clinical health data from over 11,000 participants as they aged into adulthood. They found that young adults who come from adverse backgrounds—but also show resilience to break that pattern and achieve a higher social status—are more likely to be unhealthy later in life than those not motivated to change their circumstances. Specifically, the researchers found that stress increased participants’ risk of developing cardio-metabolic diseases, like diabetes, heart disease and stroke. The study, published in the Journal of Youth and Adolescence, relied on self-reported stress from participants to determine the cause and clinical markers including blood pressure, body mass index, glucose levels and others to determine subsequent health effects. As young adults work to break the cycle of poverty or strive toward being the first in their family to go to college, they experience a disproportionate burden of stress—and were not resilient in terms of their future health due to the combined burden of lived adversity and striving to change it. This stress is then likely to cause irreversible weathering in their body systems. “The act of striving for socioeconomic attainment is itself stressful for youth already experiencing stressful life events,” said Wickrama, the Athletic Association Professor in Human Development and Family Science. The findings suggest that although there may be long-term health benefits associated with increased socioeconomic status, there may also be consequences due to the subsequent mental and physical strain. The notion seems counterintuitive at first, but the relationship between stress and health risks has been shown before. This study shows the intensification of health effects for future-oriented youth with a stressful family background. Researchers said that the study shows the need for institutional policy that supports young people who show signs of future upward orientation and come from disadvantaged backgrounds. “In order to reduce health vulnerability and the burden that comes as a cost of succeeding,” said O’Neal, at-risk youth “need support through preventative measures.”
Newswise — A research team led by University of Arkansas chemist Jingyi Chen and University of Arkansas for Medical Sciences microbiologist Mark Smeltzer has developed an alternative therapeutic approach to fighting antibiotic-resistant infections. The novel method uses a targeted, light-activated nanodrug consisting of antibiotic-loaded nanoconstructs, which are nanoscale cages made of gold and coated with polydopamine. The antibiotic is loaded into the polydopamine coating. The gold nanocages convert laser irradiation to heat, resulting in the photothermal effect and simultaneously releasing the antibiotic from the polydopamine coating. “We believe that this approach could facilitate the effective treatment of infections caused by antibiotic-resistant bacteria, including those associated with bacterial biofilms, which are involved in a wide variety of bacterial infections,” said Chen, assistant professor in the Department of Chemistry and Biochemistry in the J. William Fulbright College of Arts and Sciences. Microbial resistance to antibiotics has become a growing public health concern in hospitals and the community at large, so much so that the Infectious Diseases Society of America has designated six bacterial species as “ESKAPE pathogens” – Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species. This designation reflects the limited availability of antibiotics that can be used to treat infections caused by these species. “It is also estimated that 80 percent of all bacterial infections involve formation of a biofilm, and all of these infections share the common characteristic of intrinsic resistance to conventional antibiotic therapy,” said Smeltzer, professor in the Department of Microbiology and Immunology at UAMS and director of the Center for Microbial Pathogenesis and Host Inflammatory Responses. “Intrinsic resistance refers to the fact that bacteria within a biofilm exhibit a therapeutically relevant level of resistance to essentially all antibiotics." Researchers in Smeltzer’s laboratory study the ESKAPE pathogen Staphylococcus aureus. They focus on how the pathogen causes biofilm-associated bone infection and infections associated with orthopaedic implants. But, as Smeltzer explains, there are many other examples in infections – intravenous catheters and vascular grafts, for example – caused by Staphylococcus aureus. The team used Staphylococcus aureus as the proof-of-principle pathogen to demonstrate the potency of their nanodrug. The combination of achieving a photothermal effect and controlled release of antibiotics directly at the site of infection was achieved by laser irradiation at levels within the current safety standard for use in humans. The therapeutic effects of this approach were validated using planktonic bacterial cultures – bacterial cells that are free-floating rather than contained with a biofilm – of both methicillin-sensitive and methicillin-resistant Staphylococcus aureus strains. However, the method was subsequently shown to be effective even in the context of an intrinsically resistant biofilm. “The even better news is that the technology we developed would be readily adaptable to other bacterial pathogens that cause such infections, including the other ESKAPE pathogens,” Smeltzer said. The researchers’ work was recently published in ACS Infectious Diseases, a publication of the American Chemical Society (ACS) and “the first journal to highlight chemistry and its role in the multidisciplinary and collaborative field of infectious disease research.”
Newswise — A single dose of oxytocin nasal spray, known to reduce food intake, decreases impulsive behavior in overweight and obese men, according to a preliminary study to be presented Saturday at the Endocrine Society’s 98th annual meeting in Boston. Oxytocin nasal spray (made by Novartis) is a synthetic version of the hormone oxytocin, which is important for controlling food intake and weight. It is approved in Europe but not in the United States other than in clinical trials. Oxytocin is available in the United States as an intravenous or injectable drug (Pitocin) to induce labor. Researchers from Massachusetts General Hospital reported last year that oxytocin nasal spray reduced intake of calories and fat at a test meal without affecting appetite, but they were not sure how the drug has that affect. Results of their new pilot study in 10 overweight and obese men suggest that one way oxytocin lowers food intake might be by improving self-control, said co-investigator Franziska Plessow, PhD, an instructor in medicine at Harvard Medical School and a research fellow in the Neuroendocrine Unit at Massachusetts General Hospital, Boston. “Knowing the mechanisms of action of intranasal oxytocin is important to investigating oxytocin as a novel treatment strategy for obesity,” Plessow said. “This information may allow us to move forward to large clinical trials, identify who can benefit from the drug, and help optimize the treatment.” To demonstrate the study subjects’ ability to suppress impulsive behavior, the investigators administered a psychology research test called the stop-signal task. In this test, the subject sat in front of a computer and became trained to respond to a square symbol on the computer screen by pressing a designated left button on the keyboard and to a triangle by pressing a right button. After the subject became familiar with that task, he was told to not press a button when he saw a symbol but heard a beep (the stop signal). Because the beep occurred after the symbols appeared with a varying delay that was adjusted to each subject, the new task required the subject to control the behavioral impulse to respond, Plessow explained. Participants took the test on two occasions 15 minutes after they self-administered a dose of nasal spray in each nostril. In a randomly assigned order, one day they received oxytocin and another they received a placebo, or dummy drug. Neither participants nor the tester knew which treatment they received. The men ranged in age from 23 to 43 years and were overweight or obese (BMI ranging from 27.7-33.9 kg/m2). The study, which received pilot grants from the National Institutes of Health-funded Boston Nutrition Obesity Research Center and Nutrition Obesity Research Center at Harvard, had exciting results, according to Plessow. After receiving oxytocin, participants less frequently pressed the button when they were not supposed to. This demonstrated that they were acting less impulsively and exerting more control over their behavior after receiving oxytocin, she said. Plessow said more study is necessary to determine how oxytocin alters self-control and how important this mechanism is in regulating food intake since not all overeating relates to poor self-control. They also will need to test the drug in women. “Our preliminary results in men are promising,” she said. “Oxytocin nasal spray showed no strong side effects and is not as invasive as obesity surgery.” Endocrinologists are at the core of solving the most pressing health problems of our time, from diabetes and obesity to infertility, bone health, and hormone-related cancers. The Endocrine Society is the world’s oldest and largest organization of scientists devoted to hormone research and physicians who care for people with hormone-related conditions.
Newswise — Consumption of fructose, a fruit-derived sugar present in many sweetened beverages and processed foods, has been associated with epidemic levels of diabetes, obesity, metabolic syndrome and hypertension in the U.S. and around the world. New research presented today at the Experimental Biology 2016 meeting in San Diego further supports this link, finding that high levels of fructose similar to amounts consumed within the American diet may predispose individuals to fast-onset, salt-sensitive hypertension. “A majority of American adults consume 10 percent or more of total calories from added sugars with a subset taking in more than 25 percent of total calories from added sugars,” said lead author Kevin Gordish, PhD. Because beverages are the most common source of added sugars in the American diet, the research team gave rats drinking water with 20 percent fructose—to simulate excessive human soft-drink consumption—and compared them with rats who received plain water in addition to their food for two weeks. During the second week, the rats receiving 20 percent fructose were also given additional salt in their diets. “The specific combination of fructose and high salt introduced in the second week rapidly increased blood pressure, resulting in hypertension. Fructose-linked hypertension was associated with increased sodium retention, decreased sodium excretion and diminished factors that help rid the body of excess salt. This observation of fructose-linked hypertension was only seen a diet with fructose and high salt and not a normal salt diet,” Gordish said. “Fructose intake, similar to amounts consumed within the American diet, predisposed normal rats to a rapid onset of salt-sensitive hypertension. Fructose-linked hypertension was unambiguously due to fructose (and not glucose). Further, fructose had distinct deleterious effects in the kidney not seen with the same amount of glucose.” The results have implications for the U.S. in general and certain ethnic groups such as African Americans, who have a high rate of incidence of salt-sensitive hypertension, in particular. Overall, these findings raise concern about the amount of fructose and salt found in the American diet.
“LIQUID BIOPSY” BLOOD TEST ACCURATELY DETECTS KEY GENETIC MUTATIONS IN MOST COMMON FORM OF LUNG CANCER, STUDY FINDS
Newswise — A simple blood test can rapidly and accurately detect mutations in two key genes in non-small cell lung tumors, researchers at Dana-Farber Cancer Institute and other institutions report in a new study – demonstrating the test’s potential as a clinical tool for identifying patients who can benefit from drugs targeting those mutations. The test, known as a liquid biopsy, proved so reliable in the study that the Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) this week became the first medical facility in the country to offer it to all patients with non-small cell lung cancer (NSCLC), either at the time of first diagnosis or of relapse following previous treatment. NSCLC is the most common form of lung cancer, diagnosed in more than 200,000 people in the United States each year, according to the American Cancer Society. An estimated 30 percent of NSCLC patients have mutations in either of the genes included in the study, and can often be treated with targeted therapies. The study is being published online today by the journal JAMA Oncology. The liquid biopsy tested in the study – technically known as rapid plasma genotyping – involves taking a test tube-full of blood, which contains free-floating DNA from cancer cells, and analyzing that DNA for mutations or other abnormalities. (When tumor cells die, their DNA spills into the bloodstream, where it’s known as cell-free DNA.) The technique, which provides a “snapshot” of key genetic irregularities in a tumor, is a common tool in research for probing the molecular make-up of different kinds of cancers. “We see plasma genotyping as having enormous potential as a clinical test, or assay – a rapid, noninvasive way of screening a cancer for common genetic fingerprints, while avoiding the challenges of traditional invasive biopsies,” said the senior author of the study, Geoffrey Oxnard, MD, thoracic oncologist and lung cancer researcher at Dana-Farber and Brigham and Women’s Hospital. “Our study was the first to demonstrate prospectively that a liquid biopsy technique can be a practical tool for making treatment decisions in cancer patients. The trial was such a success that we are transitioning the assay into a clinical test for lung cancer patients at DF/BWCC.” The study involved 180 patients with NSCLC, 120 of whom were newly diagnosed, and 60 of whom had become resistant to a previous treatment, allowing the disease to recur. Participants’ cell-free DNA was tested for mutations in the EGFR and KRAS genes, and for a separate mutation in EGFR that allows tumor cells to become resistant to front-line targeted drugs. The test was performed with a technique known as droplet digital polymerase chain reaction (ddPCR), which counts the individual letters of the genetic code in cell-free DNA to determine if specific mutations are present. Each participant also underwent a conventional tissue biopsy to test for the same mutations. The results of the liquid biopsies were then compared to those of the tissue biopsies. The data showed that liquid biopsies returned results much more quickly. The median turnaround time for liquid biopsies was three days, compared to 12 days for tissue biopsies in newly diagnosed patients and 27 days in drug-resistant patients. Liquid biopsy was also found to be highly accurate. In newly diagnosed patients, the “predictive value” of plasma ddPCR was 100 percent for the primary EGFR mutation and the KRAS mutation – meaning that a patient who tested positive for either mutation was certain to have that mutation in his or her tumor. For patients with the EGFR resistance mutation, the predictive value of the ddPCR test was 79 percent, suggesting the blood test was able to find additional cases with the mutation that were missed using standard biopsies. “In some patients with the EGFR resistance mutation, ddPCR detected mutations missed by standard tissue biopsy,” Oxnard remarked. “A resistant tumor is inherently made up of multiple subsets of cells, some of which carry different patterns of genetic mutations. A single biopsy is only analyzing a single part of the tumor, and may miss a mutation present elsewhere in the body. A liquid biopsy, in contrast, may better reflect the distribution of mutations in the tumor as a whole.” When ddPCR failed to detect these mutations, the cause was less clear-cut, Oxnard says. It could indicate that the tumor cells don’t carry the mutations or, alternatively, that the tumor isn’t shedding its DNA into the bloodstream. This discrepancy between the test results and the presence of mutations was less common in patients whose cancer had metastasized to multiple sites in the body, researchers found. The ddPCR-based test, or assay, was piloted and optimized for patients at the Translational Resarch lab of the Belfer Center for Applied Cancer Science at Dana-Farber. It was then validated for clinical use at Dana-Farber’s Lowe Center for Thoracic Oncology. An advantage of this form of liquid biopsy is that it can help doctors quickly determine whether a patient is responding to therapy. Fifty participants in the study had repeat testing done after starting treatment for their cancer. “Those whose blood tests showed a disappearance of the mutations within two weeks were more likely to stay on the treatment than patients who didn’t see such a reduction,” said the study’s lead author, Adrian Sacher, MD, of Dana-Farber and Brigham and Women’s Hospital. And because tumors are constantly evolving and acquiring additional mutations, repeated liquid biopsies can provide early detection of a new mutation – such as the EGFR resistance mutation – that can potentially be treated with targeted agents. “The study data are compelling,” said DF/BWCC pathologist Lynette Sholl, MD, explaining the center’s decision to begin offering ddPCR-based liquid biopsy to all lung cancer patients. “We validated the authors’ findings by cross-comparing results from liquid and tissue biopsies in 34 NSCLC patients. To work as a real-world clinical test, liquid biopsy needs to provide reliable, accurate data and be logistically practical. That’s what we’ve seen with the ddPCR-based blood test. “The test has great utility both for patients newly diagnosed with NSCLC and for those with a recurrence of the disease,” she continued. “It’s fast, it’s quantitative (it indicates the amount of mutant DNA in a sample), and it can be readily employed at a cancer treatment center.” The co-authors of the study are Cloud Paweletz, PhD, Allison O’Connell, BSc, and Nora Feeney, BSc, of the Belfer Center for Applied Cancer Science at Dana-Farber; Ryan S. Alden BSc, and Stacy L. Mach BA, of Dana-Farber; Suzanne E. Dahlberg, PhD, of Dana-Farber and Harvard T.H. Chan School of Public Health; and Pasi A. Jänne, MD, PhD, of Dana-Farber, the Belfer Center, and Brigham and Women’s Hospital.