Body

A majority of cancer patients don't understand key aspects of the genomic test results they receive as participants in biomarker-driven clinical trials, according to a first-of-its-kind pilot study conducted under the Lung Cancer Master Protocol (Lung-MAP).

In a September 9 presentation at the World Conference on Lung Cancer in Barcelona, Lung-MAP investigator Joshua A. Roth, PhD, MHA will report results of his research conducted as part of Lung-MAP, the first lung cancer precision medicine trial supported by the National Cancer Institute, (NCI) part of the National Institutes of Health (NIH).

Roth, an assistant member of the Hutchinson Institute for Cancer Research Outcomes (HICOR) at the Fred Hutchinson Cancer Research Center, said most patients in his study showed serious gaps in knowledge about the potential uses of gene sequencing results provided in Lung-MAP and other precision medicine trials. In biomarker-driven cancer trials, patients receive genomic testing that detects DNA mutations in cancer cells, known as somatic mutations, which are typically found in tumor tissue samples. Precision trials may also include germline testing, which detects inherited DNA mutations, changes typically detected in blood or saliva.

Both kinds of genetic information are cornerstones of the precision medicine revolution in cancer research. This "precision" approach uses patients' genetic information to match them to a trial treatment that is more likely to be effective - extending or improving their lives and sparing them from potentially costly and painful treatments that aren't likely to improve their health.

Among the 123 participants who took part in a 38-item telephone survey devised by Roth, 86 percent correctly knew that their test results would be used to select their treatment regimen on the Lung-MAP trial. Another 83 percent also reported that they received enough information about their tests to understand the benefits of enrolling in the trial.

In Lung-MAP, patients receive somatic testing of mutated cells found in their cancer tumor. They do not get germline testing for inherited mutations. In Roth's survey, patients were asked about both kinds of tests. Only 9 percent correctly knew that the somatic testing they had could not predict if a family member was at increased risk of getting cancer. And only 12 percent correctly knew that their results can't predict their own increased risk of getting other diseases.

"Given the public conversation about precision medicine, and the sharp increase in biomarker-driven cancer clinical trials, it's clear that lot of people don't really understand these complex trials and the testing that drives them," Roth said. "We need to learn more about the public's knowledge gaps so we can fill them."

Roth's study is the first to investigate the attitudes on tumor genetic testing in cancer clinical trials. He plans to analyze additional findings from his Lung-MAP study and present those at the 2020 American Society of Clinical Oncology Annual Meeting, held every spring in Chicago.

Lung-MAP is the first major NCI cancer trial to test multiple treatments, simultaneously, under one "umbrella" design. Lung-MAP is also a groundbreaking public-private partnership, one that includes the National Cancer Institute and its National Clinical Trials Network (NCTN) including SWOG Cancer Research Network, Friends of Cancer Research, the Foundation for the National Institutes of Health (FNIH), Foundation Medicine, pharmaceutical companies which provide their drugs for the study, and several lung cancer advocacy organizations.

The United States lags behind other countries in home dialysis, but Kaiser Permanente research finds it safe to expand use in a large, integrated health care system.

OAKLAND, Calif. -- The rate of people starting voluntary at-home peritoneal dialysis rose from 15% to 34% over 10 years at Kaiser Permanente in Northern California, providing a convenient and safe way to manage advanced-stage kidney disease compared with center-based hemodialysis, according to research published today in JAMA Internal Medicine.

"Patients who start dialysis at home generally have a better lifestyle, fewer symptoms, and more opportunities to retain employment," said lead author Leonid V. Pravoverov, MD, chief of nephrology for Kaiser Permanente's East Bay service area. "The overall quality of life is known to be better for these patients."

When kidneys fail, dialysis is the most common way to help keep the body in balance by removing excess wastes and maintaining safe levels of minerals in the blood. It also helps to control blood pressure.

The blood can be cleaned in 2 ways: outside the body with hemodialysis, which uses an artificial kidney to remove wastes and takes place in a hospital or dialysis center, 3 or more times per week; or, inside the body with peritoneal dialysis, which is done daily at home, usually during sleep.

In 2008, Kaiser Permanente in Northern California launched a systemwide Optimal Starts approach to increase at-home dialysis, which included patient and caregiver education, provider education and support tools, streamlined systems-level processes, and monitoring and continuous quality improvement.

"The large-scale expansion of in-home dialysis was made feasible using a multidisciplinary, integrated, coordinated-care approach, with excellent outcomes in patients with advanced kidney disease," said senior author Alan S. Go, MD, research scientist with the Kaiser Permanente Division of Research in Oakland, California.

The study identified 13,500 adult members of Kaiser Permanente in Northern California who initiated chronic dialysis between 2008 and 2018. Among people who initiated at-home peritoneal dialysis, 80% of patients remained on it one year after starting, with a significant increase from 2008 (69%) to 2017 (84%). Death rates after one year for patients starting at-home peritoneal or center-based dialysis did not change over 11 years of the study.

Go noted that, compared with the United States, rates of at-home peritoneal dialysis are substantially higher in other parts of the world, including Hong Kong (70%), Mexico's Jalisco region (51%), New Zealand (30%), and Canada (19%). For a variety of reasons, rates of at-home dialysis in the United States are less than 10%.

"Peritoneal dialysis remains underutilized nationally," Go said. "Our study shows that it is possible to greatly expand its use successfully in a large, integrated health care system and improve outcomes for patients with chronic kidney disease."

In addition to Drs. Go and Pravoverov, additional co-authors on the study were Sijie Zheng, MD, PhD; Rishi Parikh, MPH; Thida C. Tan, MPH; Neelam Bhalla, MD; Chita Reddy, MD; Joanna Mroz, MS, MPH; and Tracy Y. Jonelis, MD, all of Kaiser Permanente.

A comprehensive study from Uppsala University, with over 325,000 participants, shows that deep belly fat is a major contributing risk factor for developing diabetes and cardiovascular disease. The study also shows that deep belly fat is a larger risk factor in women compared to men. Moreover, the scientists investigated how our genes affect the accumulation of fat and present a new, simpler method to estimate the amount of deep belly fat.

Visceral fat - fat stored around the organs in the belly and around the intestines - is known to be associated with a higher risk of developing diabetes and cardiovascular disease. In the new study, published in Nature Medicine, the scientists took it one step further and showed, using genetic data, that there is an actual causal relationship between visceral fat and increased risk of diabetes, heart attack, hypertension and hyperlipidemia.

The scientists developed a method to more easily estimate visceral fat content. The method is not only useful for research purposes, but may also be useful in health care.

"To measure the amount of visceral fat, advanced and costly diagnostic imaging techniques are required. We have developed a simple method which instead estimates an individual's amount of deep belly fat from other parameters, more easily measured than the visceral fat itself, and the method can therefore be used in most clinics," says Dr. Torgny Karlsson, statistician at the Department of Immunology, Genetics and Pathology, Uppsala University, and one of the leading researchers of the study.

The method also enabled the researchers to study the effects of visceral fat on a much larger scale than before.

"We were surprised that visceral fat was more strongly linked to risk of disease in women compared to men," says one of the co-authors, Dr. Åsa Johansson, associate professor of molecular epidemiology at the Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University.

"Adding an extra kilogram of visceral fat can increase the risk of type 2 diabetes more than seven times in women, while the same amount of fat accumulation only increases the risk a little more than two times in men," says Dr. Johansson.

The scientists also found that the risk of disease increases most rapidly in people with small or moderate amounts of deep belly fat, but that it does not increase nearly as much if a person with large amounts of fat in the abdomen puts on additional fat.

"Nonlinear effects like this are very interesting to study and may help us to understand the biology behind the link between visceral fat and disease," says Dr. Karlsson.

The scientists also examined millions of positions in the genome to identify genes that affect the amount of visceral fat, and found more than two hundred different genes. Among these, there was a large proportion of genes that are linked to our behaviour, which suggests that the main contributor to abdominal obesity is, after all, that we eat too much and exercise too little. However, there are individual differences in how the fat is distributed in the body, and a person who appears not to be overweight may still have accumulated a harmful amount of visceral fat.

"The findings of this study may enable us to simplify measurements of visceral fat, and thus more easily identify people at high risk of developing diabetes and cardiovascular disease," says Dr. Karlsson.

Scotland has one of the highest rates of lung cancer in the world - 2,592 men and 2,739 women were diagnosed with lung cancer in Scotland in 2017. In that year, 4,069 people with lung cancer in Scotland died.

In the UK, survival from lung cancer is poor with less than 9% of patients still alive at five years after diagnosis, due primarily to the late stage of presentation. In around 80% of cases the cancer has spread beyond the lungs by the time it is diagnosed.

If the disease is diagnosed in the early stages cure rates can be 60-70%.

The Early Detection of Cancer of the Lung Scotland (ECLS) trial has shown that using a blood test to detect lung cancer earlier can significantly reduce late-stage presentation of the disease, allowing for earlier treatment and this is likely to reduce mortality rates

Lung cancer can be spotted earlier and diagnosed more precisely with the help of a blood test, a major study carried out in Scotland has found.

The Early Detection of Cancer of the Lung Scotland (ECLS) is the world's largest clinical biomarker trial looking into detecting early lung cancer using a blood test. It was led by the University of Dundee in collaboration with the University of Glasgow, with further work from the Universities of Aberdeen, St Andrews, Nottingham and Toronto, NHS Scotland, Scottish Government, The Canberra Hospital and Oncimmune, the company that developed the new blood test. Tayside Clinical Trials Unit was responsible for trial delivery, data management and analysis.

The study looked at over 12,000 people in Scotland who volunteered to be part of the study. Adults aged 50 to 75 who had a high risk of developing lung cancer over the next 24 months were eligible to participate, and participants were recruited in the NHS areas of Tayside, Greater Glasgow and Clyde, and Lanarkshire.

The EarlyCDT®-Lung Test, followed by low-dose CT imaging for those who test positive, was found to identify 32% of lung cancers which occurred, with a high specificity of 90%.

Professor Frank Sullivan, co-chief investigator of the study, said, "This study moves us closer to making an earlier diagnosis of lung cancer, which could have a significant impact in saving lives.

"Lung cancer has been notoriously difficult to spot early and to treat. Scanning produces a lot of `false positive' results, which then place demand on resources as they are followed up and investigated.

"The blood test, followed by imaging may be better at identifying those people who actually have cancer. This could reduce by about two-thirds the amount of imaging needed to determine whether someone at high risk actually has lung cancer.

"The question we need to answer next is whether a combination of blood testing and imaging can offer a real step-change in lung cancer diagnosis."

Patients in the study who had a positive result from the test were offered a chest X-ray followed by a CT scan. If the initial CT scan revealed no evidence of lung cancer then subsequent CT scans were offered six-monthly for 24 months.

There were cases where lung cancer was identified early due to people having volunteered for the study, and they were subsequently referred for clinical care as appropriate.

The University of Glasgow recruited and followed over 9,000 patients for this study. Lead researcher there, Professor Frances Mair, said, "The findings of this study offer a viable and positive way forward for earlier diagnosis and treatment of lung cancer. This has the potential to be of huge benefit to patients, although whether this should be used for screening or case finding will require further investigation."

When you experience severe pain, like breaking or shattering a bone, the pain isn't just felt at the sight of the injury. There is an entire network of receptors in your body running from the site of the injury, through your nervous system, along the spine and into the brain that reacts to tell you how much pain you are feeling. This system goes into high alert when the injury occurs, and then usually resets as you heal. However, sometimes, the system doesn't reset, and even though the injury has mended, nerve damage has caused your brain to be permanently altered. It means you still feel the pain, even though the injury has fully healed.

Dr. Gerald Zamponi, PhD, and a team with the Cumming School of Medicine's Hotchkiss Brain Institute (HBI) and researchers at Stanford University, California, have been investigating which brain circuits are changed by injury, in order to develop targeted therapies to reset the brain to stop chronic pain.

"It's a terrible situation for many people living with chronic pain, because there is often very little that works for them to control their pain," says Zamponi, senior associate dean (research) and a professor in the departments of Physiology & Pharmacology and Cell Biology & Anatomy at the CSM. "This doesn't just impact people who have experienced peripheral nerve damage. There are cases of people having a stroke and are experiencing severe pain afterward in another part of their body. It may also explain why some people who have lost a limb can still feel pain in the limb even though it's no longer there."

Working closely with Dr. Junting Huang, PhD, and Dr. Vinicius Gadotti, PhD, co-first authors on the study, along with Dr. Zizhen Zhang, PhD, the team utilized optogenetics to study the neuron connections in the brains of mice. Optogenetics allow scientists to use light to target and control individual neurons in the brain. With this tool, researchers are able to map a pathway showing which neurons are communicating with each other to process a pain signal and then communicate this information all the way back through the spine where painful stimuli are first processed.

"We've known that certain parts of the brain are important for pain, but now we've been able to identify a long range circuit in the brain that carries the message and we've been able to show how it is altered during chronic pain states," says Zamponi who is also a member of the CSM's Alberta Children's Hospital Research Institute.

Much of the research for chronic pain has been focused on the spinal cord and targeting nerve fibres where the pain response is processed. Treatment with current pain relief medications is often ineffective and can have serious side effects. This new understanding of the pain signaling circuit may allow scientists to develop new drug therapies and targeted brain stimulation treatments to address chronic nerve pain, and hopefully provide relief for pain sufferers. Working with mice, Zamponi's lab has proven that targeting certain pathways in the brain can interfere with the pain signal and stop pain sensation.

"If you understand how the brain rewires itself, you can interfere with that and you can restore it. That's important," says Zamponi. "If you think about it, there are some drugs you don't want to give to kids who have chronic pain. What if you could non-invasively stimulate certain brain regions or inhibit them, and bring pain relief that way? I think it would be a tremendous, alternative approach to taking drugs."

Zamponi expects the results the lab has seen in mice will be comparable in humans. While the human brain is very complex, the communication network is similar in the animal brain. Findings are published in Nature Neuroscience.

The Zamponi lab is already applying this research to investigate how this brain circuit interacts with other parts of the brain involved in more complex behaviours like the interaction between pain pathways and addiction, depression, and anxiety.

On July 10, the Department of Health and Human Services (HHS) announced they were aiming to reduce the number of Americans developing end-stage renal disease by 25% by 2030. But, the results of a focus group study done by Johns Hopkins researchers of more than 30 veteran primary care physicians across the United States suggest that these primary care providers lack sufficient knowledge, clinical support tools and time to effectively identify and manage patients with chronic kidney disease (CKD). The study, published Aug. 22 in PloS ONE, suggests that much work is needed in order for HHS to achieve its goal.

By recognizing and diagnosing CKD in its earlier stages, researchers hope that primary care physicians will take the necessary steps to manage patients early on to prevent the physical and financial burden of advanced stage kidney disease.

High blood pressure and diabetes are the major contributors to CKD, now estimated by public health officials to affect 15% of the adult population or 37 million men and women. In a bid to slow the epidemic and reduce the high costs of dialysis, transplants and medical care associated with kidney disease, HHS wants to identify those at risk sooner to prevent disease progression with lifestyle changes and medicines.

The new study's findings suggest that both nephrologists and primary care providers looking to meet the HHS goal face notable, albeit modifiable barriers to success.

"If we can really slow down progression of kidney disease through the earlier stages, it may have a meaningful impact on those complications that can develop, like cardiovascular disease and other health issues," says John Sperati, M.D., associate professor of medicine at the Johns Hopkins University School of Medicine and director of the school's Nephrology Fellowship Training Program. "If we hope to reduce the personal and financial toll of CKD and end-stage kidney failure, primary care physicians must be key players, and we as kidney specialists need to form better partnerships with PCPs, and need to offer more training and resources to them," he adds.

Sperati estimates that there is only about one nephrology specialist for every 2,000 patients with chronic kidney disease across the U.S. Those nephrologists' focus is mainly on the 8% of CKD patients who are in advanced stages with multiple complications or end stage kidney failure. Despite how prevalent this disease is, Sperati believes that, if managed early on by PCPs, some patients can avoid advanced stages.

According to the U.S. Renal Data System, total Medicare-related costs in 2016 were $79 billion for CKD and another $35 billion for end-stage renal disease. Sperati says it's an extraordinarily expensive illness to care for in this country, as 70% of end-stage patients are on dialysis and the remaining 30% have a transplant. In addition, CKD increases the risk for cardiovascular disease, which also leads to earlier deaths. Sperati wants to keep people off dialysis and prevent them from needing transplants by having PCPs address concerns at younger ages and earlier stages.

To learn more about what knowledge primary care physicians have of CKD and the challenges they face in caring for patients, the researchers divided 32 participants from Baltimore, Maryland; St Louis, Missouri; Raleigh, North Carolina; and San Francisco, California, into four focus groups. Each group was composed of eight physicians of various races and ethnicities, diverse sizes and lengths of practice, and ranging in age. The average age of the participants was 53, 19 were male, 21 were white, and 75% had been in practice for more than 15 years.

The physicians first took a brief, self-administered questionnaire asking about their own demographic and medical practice characteristics. The results showed that 22 of the participants were in private practice and 20 treated between zero and 20 CKD patients per week, while the remaining 12 saw more than 20 CKD patients per week.

The 90-minute focus group sessions, facilitated by a female general internist and health services researcher with expertise in qualitative methods, generated responses to questions about perceived barriers and aids for caring for CKD patients. Almost 85% of the primary care physicians said they felt comfortable managing patients with early-stage CKD, but not comfortable managing specific complications such as anemia (44%), bone disorders (72%) and excess metabolic acid in the body that damages the kidneys (69%). Most cited a lack of access to clinical resources such as clinical information systems and insufficient patient education material about CKD as reasons for their lack of confidence. Physicians cited a lack of adequate time to spend with patients and identified health care system-level barriers such as poor reimbursement for delivering care to medically complex CKD patients. These challenges contribute to limited visit times and high out-of-pocket costs for patients.

In the focus group discussions, PCPs also identified patient-level barriers to effective management, such as patients having a limited understanding of the implications of CKD and the financial challenges associated with needing medications, tests and other health costs.

Sperati says physicians in the focus group also emphasized a need for CKD guidelines that were easier to implement: 14 of the 31 said that they didn't follow guidelines, typically given by professional societies such as KDIGO. When asked if they had educational tools and resources available to help patients understand and self-manage their day-to-day CKD needs, only 2 of the 32 strongly agreed that they did.

Asked to identify what could help them most, the focus group physicians cited access to automatic estimated glomerular filtration rate (eGFR) reports to screen for low levels of GFR -- a sign of early kidney disease; clear, concise guidelines for treatment; better education; and improved insurance coverage and physician reimbursement for services and care.

"This is very helpful information in identifying what primary care physicians see as barriers but also as potential solutions," says Sperati. "The National Kidney Foundation and others in the nephrology community have worked hard to engage primary care physicians in the management of CKD patients, and this study should help to further refine and strengthen those efforts. The HHS goal will require addressing CKD from many angles simultaneously."

While the primary care physicians studied had geographic and racial/ethnic diversity, Sperati cautioned that more research is needed to determine if the focus group findings reflect the views and practices of a broader group of PCPs, and that his team's study did not seek out or reflect the views of other care providers, such as nurse practitioners and physician assistants, or patients themselves.

Scientists have developed a method to test whether an infection is resistant to common antibiotics.

Beta-lactam antibiotics (such as penicillin) are one of the most important classes of antibiotics, but resistance to them has grown to such an extent that doctors often avoid prescribing them in favour of stronger drugs.

Scientists from the University of York modified an antibiotic from the beta-lactam family so that it can be attached to a sensor, enabling them to detect the presence of bacteria resistant to treatment.

The new method could lead to clinicians being able to rapidly detect whether an infection is treatable with common antibiotics, reserving stronger alternatives for the patients that need them most.

Antimicrobial resistance (AMR) is a major global threat accelerated by the inappropriate use of antibiotics.

Co-author of the study, Callum Silver, a PhD student from the Department of Electronic Engineering, said: "If we continue to use antibiotics in the way we currently do, we may find ourselves in a situation where we can no longer use antibiotics to treat patients - resulting in millions of deaths per year.

"This study paves the way for the development of tests which will give doctors important information on the bacteria they are dealing with so that common antibiotics can be used whenever possible. Resistance to new antibiotics can emerge very quickly after they come into use and so we need to reserve them for when they are really needed.

"The discovery may also help to identify and isolate resistant bacteria, reducing the chances of large outbreaks."

One of the major ways in which bacteria become resistant to treatment is through the production of enzymes that can break down beta-lactam antibiotics, rendering them ineffective.

The researchers were able to test for the presence of these resistance enzymes by attaching the modified antibiotic to a sensor surface which enabled them to see whether or not the drug was broken down.

The researchers used multiple techniques to show that the drug is still accessible to the enzyme, meaning the modified antibiotic could be used to develop things like urine tests for AMR bacteria in patients.

Callum Silver added: "The lack of diagnostic techniques to inform doctors whether or not they are dealing with resistant bacteria contributes to the problem of AMR."

"This modified antibiotic could be applied to a variety of different biosensing devices for use at the point-of-care."

Dr Steven Johnson, Reader in the University's Department of Electronic Engineering, said: "This important study is the result of a close collaboration between physical, chemical and biological scientists at the University of York and lays the foundation for a new diagnostic test for drug resistant infections.

"We are now working with clinicians at York Teaching Hospital NHS Foundation Trust to integrate this modified antibiotic into a rapid diagnostic test for antimicrobial resistance in urinary tract infections."

Much research has pointed to how an unhealthy diet correlates to obesity, but has not explored how diet can bring about neurological changes in the brain. A recent Yale study has discovered that high-fat diets contribute to irregularities in the hypothalamus region of the brain, which regulates body weight homeostasis and metabolism.

Led by Sabrina Diano, the Richard Sackler Family Professor of Cellular & Molecular Physiology and professor of neuroscience and comparative medicine, the study evaluated how the consumption of a high-fat diet -- specifically diets that include high amounts of fats and carbohydrates -- stimulates hypothalamic inflammation, a physiological response to obesity and malnutrition.

The researchers reaffirmed that inflammation occurs in the hypothalamus as early as three days after consumption of a high-fat diet, even before the body begins to display signs of obesity. "We were intrigued by the fact that these are very fast changes that occur even before the body weight changes, and we wanted to understand the underlying cellular mechanism," said Diano who is also a member of the Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism.

The researchers observed hypothalamic inflammation in animals on a high fat diet and discovered that changes in physical structure were occurring among the microglial cells of animals. These cells act as the first line of defense in the central nervous system that regulate inflammation. Diano's lab found that the activation of the microglia was due to changes in their mitochondria, organelles that help our bodies derive energy from the food we consume. The mitochondria were substantially smaller in the animals on a high-fat diet. The mitochondria's change in size was due to a protein, Uncoupling Protein 2 (UCP2), which regulates the mitochondria's energy utilization, affecting the hypothalamus' control of energy and glucose homeostasis.

The UCP2-mediated activation of microglia affected neurons in the brain that, when receiving an inflammatory signal due to the high fat diet, stimulated the animals in the high-fat diet group to eat more and become obese. However, when this mechanism was blocked by removing the UCP2 protein from microglia, animals exposed to a high fat diet ate less and were resistant to gain weight.

The study not only illustrates how high-fat diets affect us physically, but conveys how an unhealthy diet can alter our food intake neurologically. "There are specific brain mechanisms that get activated when we expose ourselves to specific type of foods. This is a mechanism that may be important from an evolutionary point of view. However, when food rich in fat and carbs is constantly available it is detrimental."

Diano's long-standing goal is to understand the physiological mechanisms that regulate how much food we consume, and she continues to perform research on how activated microglia can affect various diseases in the brain, including Alzheimer's disease, a neurological disorder that is associated with changes in the brain's microglial cells and has been shown to have higher incidence among obese individuals.

WHAT:
Sexually transmitted infections, or STIs, pose a significant public health challenge. Globally, more than one million new STI cases are diagnosed each day. In a new article in The Journal of Infectious Diseases, experts from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, suggest that the biomedical research community must refocus its commitment to STI research to surmount this growing global health crisis.

The perspective piece was written by NIAID Director Anthony S. Fauci, M.D., Robert W. Eisinger, Ph.D., special assistant for scientific projects in NIAID's Immediate Office of the Director, and Emily Erbelding, M.D., director of NIAID's Division of Microbiology and Infectious Diseases. The authors note that a variety of STIs are contributing to the public health crisis as cases of gonorrhea, syphilis, and chlamydia are all on the rise. Left untreated, many STIs can cause serious complications. Congenital syphilis can cause stillbirths and health complications in newborns, and gonorrhea and chlamydia can contribute to life-threatening ectopic pregnancies (when a fertilized egg grows outside the uterus). Gonorrhea and syphilis, which are increasing among men who have sex with men and bisexual men, also are associated with an increased risk for HIV transmission and acquisition. Moreover, increasing antimicrobial resistance will make STIs only more difficult to treat, as many existing drugs will become less effective against the microbes that cause gonorrhea and other STIs.

Unfortunately, the authors note, STI research efforts have not adequately addressed the ongoing spread of these diseases. To address this public health threat, biomedical research programs need to be refocused on developing innovative diagnostics, therapeutics, and vaccines for STIs. Healthcare providers need access to faster, low-cost diagnostics to identify both active and asymptomatic STIs. The STI vaccine pipeline also needs to produce effective new candidate vaccines for syphilis, gonorrhea, and chlamydia. As for STI therapeutics, the authors note that research efforts must focus on drug-drug interactions, toxicities and side effects, while keeping ahead of spreading antimicrobial resistance.

NIAID has launched an initiative involving six new STI Cooperative Research Centers that will work to develop vaccines for syphilis, gonorrhea and chlamydia. NIAID also has funded a large clinical trial examining doxycycline post-exposure prophylaxis against STIs in groups at high-risk for HIV and has supported additional novel research efforts. No single entity, however, can tackle the growing public health problem posed by STIs. As the authors note, cooperation among biomedical researchers in the public and private sectors, together with the efforts of community clinics and healthcare providers, will be key to curbing STIs in the years to come.

Scientists at Trinity College Dublin today [Monday September 9] announced a significant advance in our understanding of mild head trauma (concussive brain injury) and how it may be managed and treated in the future. It seems that repetitive impacts - as opposed to single events - cause the all-important damage to blood vessels in the brain.

Mild head trauma has come to the fore in recent years as being associated with collision and combat sports. However, it is also a very common injury in children and young adults and represents a significant challenge to physicians due to the lack of any robust biomarkers or objective imaging approaches to manage the injury.

"This was a hypothesis-driven project whereby we challenged the hypothesis that repetitive head trauma would induce damage to small blood vessels in the brain that we would then be able to image with a novel form of MRI-based brain scans," said Dr Matthew Campbell, Assistant Professor at Trinity.

The study, which was undertaken by the Trinity-led Concussion Research Interest Group (CRIG) used both sensor-enabled mouthguard technology developed by the group of Professor David Camarillo at Stanford University and dynamic contrast-enhanced MRI to confirm the number and severity of head impacts that would lead to the appearance of "leaky" blood vessels within the brain.

Participants of combat and collision sports such as mixed martial arts (MMA) and rugby took part in the clinical research study, which took four years to complete and is part of a wider longitudinal study, which is still ongoing.

Concussive brain injuries

While it is clear that concussive brain injuries cause clinical symptoms such as dizziness, nausea and confusion, these symptoms all occur independent of any adverse findings on CT or MRI scans, and/or without the presence of any clear blood-based biomarkers. Therefore, the clinical management of concussive brain injuries is challenging and needs new technologies to assist in diagnosis and rehabilitation.

Dr Colin Doherty, Consultant Neurologist at St James's Hospital and clinical lead on the study, added: "Our findings, for the first time, suggest that repetitive head trauma can lead to an MRI signal that we can definitively link to the number and severity of impacts to the head. It appears that the repetitive nature of these impacts as opposed to single events are causing damage to the capillaries of the brain."

The study reports that repetitive impacts to the head, not necessarily just concussions, are likely able to induce changes to the micro-vessels of the brain. It is these changes that are then readily visible when using a novel form of MRI-based imaging.

While the study was based on a selected group of MMA fighters and rugby players, the findings could eventually pave the way for more robust and objective return-to-play guidelines and improved player safety in the longer term.

"This study has highlighted the critical importance of continued efforts to study the underlying effects of concussive brain injuries in all sports. It is imperative that the governing bodies take note of these findings and work together to protect athletes now and in the future," added co-author Professor Mick Molloy, former Chief Medical Officer of World Rugby.

Barcelona--Researchers reported today that a prospective trial comparing two screening methods for at-risk lung cancer patients found that a model used by Canadian, Australian and European public health organizations detected more cancers than the screening model used by the United States Preventive Services Task Force (USPSTF). The results were shared today at the IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer.

The National Lung Screening Trial (NLST) showed that lung cancer screening of high-risk individuals with low-dose computed tomography can reduce lung cancer mortality by 20 percent. Other findings such as the Dutch Belgian (NELSON) trial, first reported at WCLC2018 in Toronto, supported those results.

The International Lung Screening Trial (ILST) was established to follow at-risk lung cancer patients over a six-year period to determine if a popular screening selection model, PLCOm2012, and the model used by the USPSTF, were effective in detecting lung cancers in at-risk patients.

The PLCOm2012 is the most widely validated and applied lung cancer risk prediction model and has been shown to perform well multiple times in the United States, Canada, the United Kingdom, Germany and Australia. This model recommends CT screening for patients if they have a six-year risk of more than 1.5 percent. Most current guidelines, including those of the USPSTF and Center for Medicare and Medicaid Services (CMS), recommend screening using variants of the NLST eligibility criteria: smoked 30 pack-years or more, smoking within 15 years, and age 55 to 77/80years.

Participants in the ILST trial received two annual screens and were followed for six years for lung cancer outcomes. Individuals not qualifying by either criteria were not offered screening, but some of them will be followed for lung cancer outcomes.

Of the 5,013 patients screened, 110 were found to have lung cancer. Ninety-nine percent of the cancers were found using PLCOm2012 compared to 77 percent using USPSTF criteria. 24/110 (21.8 percent) cancers were found by PLCOm2012 alone while only 1/110 (0.9 percent) was found by USPSTF criteria alone.

"Our analysis of ILST data indicates that classification accuracy of lung cancer screening outcomes supports the PLCOm2012 criteria over the USPSTF criteria," said lead researcher Stephen Lam, M.D., of the University of British Columbia in Vancouver.

Many patients see their tumors shrink in response to a drug, only to have them come back with a vengeance as they evolve to fend off the treatment. Oncologists want to be able to quickly detect cancer drug resistance as it emerges in their patients and identify another drug the tumors will still respond to.

A new study from a group of researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital (MGH), IBM Research, and other organizations is one step forward in that direction. The researchers examined a new method for sampling tumors known as liquid biopsy -- a blood sample from a patient that contains DNA shed from tumors, called circulating tumor DNA, or ctDNA, which can be isolated and analyzed.

The research team compared the results of both liquid and standard tissue biopsies from patients who were treated for gastrointestinal cancer but developed drug resistance. The findings, published today in Nature Medicine, reveal that liquid biopsies provide a more complete picture of both the genetic diversity of a patient's cancer and how tumors evolve drug resistance at the molecular level. That picture is challenging the view of how cancer drug resistance typically emerges, with important implications for treatment.

"Remarkably, we found that nearly every patient we analyzed had developed not just one, but multiple drug resistance mechanisms simultaneously, and this may be more common than we previously thought," said Gad Getz, co-senior author of the study, director of the Cancer Genome Computational Analysis Group at the Broad and the Paul C. Zamecnik Chair in Oncology at the MGH Cancer Center. "That is a real paradigm shift and will force us to rethink not just the biology of cancer drug resistance but also how we approach it therapeutically in the future."

The results could explain why cancer, once it has developed drug resistance, is so difficult to defeat. The study also suggests possible molecular mechanisms underlying drug resistance, which could point the way to new and more personalized therapeutics.

Tissue biopsies are a mainstay of cancer diagnosis, but they are invasive and provide a glimpse of only one location in a single tumor. Yet tumor cells, even nearby ones, can be genetically distinct from one another. Liquid biopsies, which incorporate information from multiple tumor lesions, are a promising alternative, but are rarely used in the clinic.

To investigate the utility of liquid biopsies in detecting acquired drug resistance in cancer, Getz, co-senior author Ryan Corcoran, an investigator at MGH and Harvard Medical School, and their colleagues, including first authors Aparna Parikh, Ignaty Leshchiner, and Liudmila Elagina, studied 42 patients with different forms of gastrointestinal cancer who were undergoing treatment with targeted drugs. When the patients showed signs of drug resistance, the researchers analyzed their tumors using both liquid and tissue biopsies. They harnessed a suite of computational tools developed at the Broad Institute, known as PhylogicNDT, to analyze the tumor DNA and their resistance mutations. A head-to-head comparison of liquid and tissue biopsies revealed that in nearly 80% of cases, the liquid biopsies unearthed clinically relevant genetic alterations linked to drug resistance that were not identified through standard tissue biopsies.

"This study is the largest to date to directly compare liquid biopsy to tumor biopsy in the setting of cancer resistance," said Corcoran. "Our findings suggest that liquid biopsy may be the preferred clinical modality for assessing how patients' tumors have evolved after they've become resistant to therapy."

Analysis of DNA from several of the patients in the study didn't show clear resistance mechanisms. To learn more about these cases, the IBM researchers on the team developed machine learning algorithms to group patients together according to shared or similar patterns of genetic alterations linked to drug resistance. By doing this, the researchers were able to suggest possible resistance mechanisms for these cases.

The study is part of a five-year collaboration between the Broad Institute and IBM Research to analyze tumors before and after the onset of drug resistance, in order to discover underlying mechanisms driving resistance. The collaboration grew out of a cancer drug resistance and blood biopsy project supported by the Gerstner Family Foundation.

"The IBM, Broad and MGH teams bring complementary expertise and tools to the table while grappling with the difficult problem of extracting meaning from the data, and this interaction has proved to be very fruitful," said Laxmi Parida, IBM Research Fellow, Computational Genomics, and co-PI, along with Getz, on the Broad/IBM collaboration. "The collaboration has been particularly exciting not only due to the exceptional synergy between the teams but also the invaluable data that are being collected for use by the entire research community."

Although this new study turned up some tantalizing findings, the authors emphasize that larger, more comprehensive efforts are needed to fully understand cancer drug resistance. "To really map out the full landscape of cancer resistance mechanisms, we need much larger studies that span a variety of drugs and cancer types," said Getz.

Barcelona--Lung cancer screening efforts have accelerated in the last decade, with researchers showing that low dose CT screening is effective in reducing lung cancer mortality. Now, researchers in Milan report that using a blood test, accompanied by low dose CT screening, is safe and effective. The results were shared today at the IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer.

The National Lung Screening Trial (NLST) showed that lung cancer screening by three annual rounds of low-dose computed tomography (LDCT) reduced lung cancer mortality. The Multicentric Italian Lung Detection (MILD) provided additional evidence that extended intervention beyond five years, with annual or biennial rounds, enhanced the benefit of low-dose CT screening.

Ugo Pastorino, MD, of the Istituto Nazionale dei Tumori Foundation and the lead researcher on the MILD trial, reports on results from a new trial, the bioMILD trial, which tested the additional value of blood microRNA assay at the time of LDCT on a large number of volunteers, with the aim of targeting next LDCT intervals on the basis of individual risk profile.

The bioMILD trial prospectively enrolled 4,119 volunteers at Istituto Nazionale Tumori of Milan with the median age of 60 years, median pack-years 42, current smokers 79% and females 39%. At the end of March 2019, a total of 11,012 LDCTs and 9,156 miRNA tests were performed, with an overall compliance at the 3-year LDCT of 93% and a median follow-up 4.2 years.

Pastorino had previously reported that that microRNA expression profiles in tumors and, for the first time, also in normal lung tissue, are indicative of aggressive lung cancer development and that specific microRNA signatures can be identified in plasma samples of patients up to two years before spiral-CT detection of the disease.

The BioMILD trial offered a lung cancer screening program combining LDCT and blood microRNA assay to heavy smokers (current or former ?10 years) aged 50-75 years. At baseline, LDCT and miRNA were tested independently with blind evaluation. According to LDCT and miRNA profile, different screening intervals were chosen for the following repeats, and participants with double negative LDCT and miRNA were sent to a 3-year interval.

Preliminary analysis showed a significantly higher lung cancer incidence and overall mortality in subjects with positive LDCT and/or miRNA at baseline. No detrimental effects on stage I lung cancer proportion, resection rates, or interval cancer incidence were observed in the group of subjects sent to 3-year LDCT repeat. Sensitivity and specificity analyses of LDCT and miRNA at baseline and subsequent screening rounds will be presented.

"BioMild showed that the combination of microRNA assay and LDCT is a valuable and safe tool to assess individual risk profile and reduce unnecessary LDCT repeats in lung cancer screening," said Dr. Pastorino.

DALLAS, September 9, 2019 -The number of women with high blood pressure (HBP) when they become pregnant or who have it diagnosed during the first 20 weeks of pregnancy has spiked in the United States over the last four decades, especially among black women, according to new research in the American Heart Association's journal Hypertension.

Having high blood pressure before becoming pregnant and during pregnancy poses potential complications for both women and their unborn children, including increased risks of stillbirth or infant death and preeclampsia (life-threatening high blood pressure during pregnancy), stroke, heart failure, cardiomyopathy (heart muscle disease) or kidney failure and death among other risks for the mother.

The researchers defined high blood pressure as 140 mm Hg systolic blood pressure and 90 mm Hg diastolic blood pressure over the course of the study, however, the American Heart Association defines high blood pressure as 130mm Hg systolic blood pressure (the top number in a blood pressure reading) and 80 mm Hg diastolic blood pressure (the bottom number in a blood pressure reading).

"Women who already have high blood pressure and are planning to become pregnant should work closely with their health care provider to closely monitor and manage their blood pressure, especially during pregnancy, to reduce the serious health risks to both themselves and their unborn child," said lead study author Cande V. Ananth, Ph.D., M.P.H., professor and chief of the Division of Epidemiology and Biostatistics in the Department of Obstetrics, Gynecology and Reproductive Sciences at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

In this study, the largest of its kind according to the researchers, the rates of chronic high blood pressure in pregnant women aged 15 to 49 years were evaluated. Chronic high blood pressure was defined as having high blood pressure before becoming pregnant or during the first 20 weeks of pregnancy. Using data from the Center for Disease Control's National Hospital Discharge Survey (NHDS), they analyzed close to 151.5 million childbirth-related hospitalizations from 1970 to 2010 for changes in chronic hypertension, considering factors such as the mother's age, year of delivery and race.

Overall, the researchers found that almost 1 million (0.63%) women in the study experienced chronic high blood pressure during their pregnancy, and the rate increased sharply with the mother's age and year of delivery, shooting up from 0.11% in 1970 to 1.52% in 2010--over a 13-fold increase over the past four decades.

"We found that mothers who were older when they became pregnant were more likely to have chronic hypertension," said Ananth. "Since more women are electing to postpone their first pregnancies, and advanced maternal age is strongly associated with chronic high blood pressure, women should be aware of the risks associated with having high blood pressure during pregnancy."

The results also revealed that chronic high blood pressure during pregnancy:

Affected black women at more than twice the rate of white women.

Increased on average by 6% every year since 1979, with white women showing a slightly higher increase (7%) than black women (4%) each year.

"We originally speculated that the disproportionately higher rates of obesity, smoking, diabetes and vascular disease among black women might explain these racial disparities," said Ananth. However, after adjusting for obesity and smoking rates, the researchers determined that these factors did not influence the upward trend of chronic high blood pressure during pregnancy.

"We were a very surprised that the increasing prevalence of obesity and the declining prevalence of smoking rates had virtually no impact on trends in chronic hypertension during pregnancy," said Ananth. Despite these results, obesity and smoking remain strong risk factors for high blood pressure.

Barcelona-- Selpercatinib was granted Breakthrough Therapy Designation by the U.S. Food & Drug Administration in 2018 after initial data from the clinical trial LOXO-292 Investigated to Block RET-altered Tumors (LIBRETTO-001) showed the therapy demonstrated robust anti-tumor activity in a group of RET fusion-positive non small cell lung cancer patients, as well as strong evidence of durability.

Now, the same researchers, led by Alexander Drilon, M.D., of Memorial Sloan Kettering Cancer Center in New York City, report data on a primary analysis set of 105 NSCLC patients on selpercatinib. The researchers presented their updated data on LIBRETTO-001 today at the IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer. The LIBRETTO-001 trial includes 87 sites in 16 countries.
Patients with RET fusion-positive non-small cell lung cancer comprise up to two percent of all NSCLC cases but there are no targeted therapies currently approved for patients with this form of lung cancer. Selpercatinib (LOXO-292) is an oral and highly selective investigational drug in clinical development for the treatment of patients with cancers that harbor abnormalities in the Rearranged During Transfection gene (RET). Genomic alterations involving RET, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth.

Researchers presented data from the phase 1/2 LIBRETTO-001 trial, where they noted a high response rate in the primary analysis set of NSCLC patients previously treated with platinum-based chemotherapy, with 68 percent achieving responses and a median duration of response of 20.3 months. The intracranial objective response rate was 91 percent (n=10/11) for patients with target lesions in the brain at baseline.
In the safety data set of all 531 patients enrolled to the study, 5 treatment-related AEs occurred in ?15 percent of patients: dry mouth, diarrhea, hypertension, increased AST and increased ALT. Most AEs were grade 1-2. Only 9 of 531 (1.7 percent) patients discontinued LOXO-292 for treatment-related AEs.

"In this large cohort, selpercatinib's response rate, durability, robust intracranial activity and safety show promise. Furthermore, this continues to confirm that RET fusions are clinically targetable alterations, placing them in the company of activating EGFR/ALK/ROS1 alterations. We are encouraged by this data as there is currently an unmet need to provide genomically tailored therapy to patients with RET fusion-positive NSCLCs." Drilon reported.