miércoles, 20 de septiembre de 2017

Simple blood test provides new treatment choices to lung cancer patients

Simple blood test provides new treatment choices to lung cancer patients

News-Medical

Simple blood test provides new treatment choices to lung cancer patients

University Hospitals Birmingham NHS Foundation Trust and Roche Diagnostics introduce
pioneering approach to lung cancer diagnosis
A simple test which can detect gene mutations in tumor DNA from blood samples is giving new choices to lung cancer patients with faster diagnosis and improved access to life changing drugs.
Traditionally, lung cancer diagnosis has relied solely on lung biopsies, an invasive procedure which many patients are too unwell to tolerate.  However the new cobas® EGFR Mutation Test v2 CE-IVD test from Roche Diagnostics enables the use of a liquid biopsy from blood to be used alongside or instead of the lung biopsy (when the lung biopsy cannot be performed) to identify genetic abnormalities in the EGFR gene associated with lung cancer.
The test is highly specific and its results can be used to predict a patient’s response to treatment, allowing doctors to rapidly prescribe tailored treatments in line with NHS England’s goal to ensure personalised treatment and care for everyone diagnosed with cancer.
University Hospital Birmingham NHS Foundation Trust (UHB), has introduced the test to its renowned cancer diagnostics laboratory. The new testing service gives more patients access to life-saving treatments with fewer side-effects than classic chemotherapy, improving quality of life for patients.
The Trust’s new service has been highly commended for adopting the pioneering approach by the West Midlands Academic Health Science Network’s innovation awards.
Dr Phillipe Taniere, Consultant Histopathologist at UHB which runs the Queen Elizabeth Hospital Birmingham, said:
Identifying mutations in blood samples has historically been a challenge due to the low frequency of cancerous cells in the sample. However this new, powerful technology from Roche Diagnostics has made it possible to take a simple blood sample and rapidly identify EGFR mutations in tumours’ DNA. We are delighted to be providing such an advanced service to our patients and leading the way in diagnostic capabilities in the region and the UK.
Brigitte Fernandes-McAlear, Director of Molecular, Tissue and Sequencing, Roche Diagnostics, said:
University Hospital Birmingham NHS Foundation Trust has made Roche’s breakthrough innovation a reality for doctors and patients, ensuring rapid genetic analysis of cancer and personalized therapy. It’s essential that pioneering diagnostic approaches such as these are adopted across the cancer care pathway to treat patients with the medicines they so urgently need.

Pharmaceutical compound from leaves of coralberry may help combat asthma

Pharmaceutical compound from leaves of coralberry may help combat asthma

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Pharmaceutical compound from leaves of coralberry may help combat asthma

The coralberry could offer new hope for asthmatics: researchers at the University of Bonn have extracted a new kind of active pharmaceutical ingredient from its leaves to combat this widespread respiratory disease. In mice, it almost completely inhibits the characteristic contraction of the airways. The plant itself is not exotic: it can be found in any well-stocked garden center. The study is published in the renowned journal Science Translational Medicine.
The coralberry is no outstanding beauty most of the year. This however changes in the winter months: it then forms striking, bright red berries, which make it a popular ornamental plant during this time. Nevertheless, the scientists involved in the study are interested in the plant for another reason: the leaves of the coralberry contain a substance with the cryptic name FR900359. It is assumed that this could be suitable as a medication against certain diseases, despite the fact that Ardisia crenata (its botanical name) has so far been largely disregarded by science.
Researchers at the Institutes of Physiology I, Pharmaceutical Biology and Pharmaceutical Chemistry at the University of Bonn, together with asthma specialists from Nottingham (United Kingdom), have now published a study that could change this. They found that FR900359 is very effective at preventing the bronchial muscles from contracting. Asthmatics regularly suffer from these pronounced contractions preventing adequate ventilation of the lungs. The resulting shortness of breath can be life-threatening.
More effective than common medicines
The new compound relieves these spasms - and is supposedly more effective and has a more prolonged action than the most common asthma drug salbutamol. "However, we have so far only tested the substance in asthmatic mice," explains junior professor Dr. Daniela Wenzel. Wenzel is doing research in respiratory diseases at the Institute of Physiology I at the University of Bonn; she was the leader of the study.
The idea to test FR900359 came from the Institute of Pharmaceutical Biology: there, the scientists managed to isolate and characterize the active pharmaceutical substance from the leaves of the coralberry. "This compound inhibits critical signaling molecules in our cells, the Gq proteins," explains Wenzel. Gq proteins exert key functions in many processes in the body - including control of the airway tone.
Normally, interaction of various signaling pathways induces narrowing of the airways. Inhibition of individual signaling pathways can reduce the contraction of the respiratory tract. However, this does not make it possible to completely prevent such contractions in patients with severe asthma. The various contracting signals converge on Gq proteins and trigger airway spasm. "When we inhibit the activation of Gq proteins with FR900359, we achieve a much greater effect," emphasizes Dr. Michaela Matthey from the Institute of Physiology.
This worked exceptionally well in asthmatic mice in the study. "We were able to prevent the animals from reacting to allergens such as house dust mite with a narrowing of the bronchia," Wenzel is pleased to report. There were hardly any side effects, as the active pharmaceutical ingredient could be applied via inhalation to the respiratory tract and thus only reached the systemic circulation in small quantities. However, it is not known whether the substance is also suitable for use in people. Although the scientists have already been able to show that human bronchial muscle cells in a petri dish and isolated human airways react in a similarly promising manner, further tests, which could take years, are required prior to its application in people.
Nevertheless, the work is already a great success. This is no coincidence: the German Research Foundation (DFG) funds the research group "G protein signal cascades: creating new pharmaceutical concepts with molecular probes and active pharmaceutical ingredients" at the University of Bonn. The aim is to pharmaceutically influence central signaling molecules such as the Gq proteins to identify novel substances for the treatment of certain diseases. Physiologists and pharmacists at the University collaborate closely within the research group; the current study is the result of this successful scientific interaction.

Sodium channels play important role in keeping tiny lung capillaries from leaking, worsening pneumonia

Sodium channels play important role in keeping tiny lung capillaries from leaking, worsening pneumonia

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Sodium channels play important role in keeping tiny lung capillaries from leaking, worsening pneumonia





Sodium channels in the cells that line the tiny capillaries in our lungs play an important role in keeping those capillaries from leaking and potentially worsening conditions like pneumonia, scientists report.
The TIP peptide, a synthetic version of the tip of the cancer-killing immune molecule tumor necrosis factor, appears to strengthen that barrier function, according to the study in the journal Frontiers in Immunology.
TIP's protection works even in the face of pneumolysin, a toxin released in large volume in response to antibiotic treatment to kill pneumonia-causing bacterium. The toxin can create tiny holes in the natural barriers of both capillaries as well as air sacs in the lungs. The result can be a second and potentially deadly wave of fluid accumulation in the lungs in about 20 percent of the sickest pneumonia patients.
"We showed that these channels are present in human capillary endothelial cells and that these channels play a really important role in protecting us from pneumolysin," says Dr. Rudolf Lucas, vascular biologist at the Vascular Biology Center at the Medical College of Georgia at Augusta University and the study's corresponding author.
"We also provided more evidence that targeting these channels with the TIP peptide or something similar is a solid strategy for reducing dangerous fluid volume in your lungs," says Lucas. The studies were conducted in the endothelial cells that line human lung capillaries, known to form a tight barrier for the blood vessels.
Tiny capillaries and air sacs, or alveoli, in the lungs have thin walls and close proximity which enable the capillaries to pick up oxygen from the air sacs and carry it forward to the rest of the body. The toxin makes the usually tight lining of the capillaries leaky so blood and other fluid can get into the lung tissue, even into the air sacs. The lungs can become overwhelmed with fluid, and the body doesn't get the oxygen it needs.
Similarly, sodium transport channels in the air sacs are negatively impacted by the toxin.
The function of the epithelial sodium channel, or ENaC, which helps move fluid out of air sacs normally, is even more in demand in the face of pneumonia, but the toxin impairs its ability in both the air sacs and capillaries, the scientists have now shown.
The scientific team working through the complex interchange found that in the capillaries of the lung, an important subunit of ENaC - called ENaC-alpha - is important as well to strengthening the barrier function of the blood vessels. They then showed that the TIP peptide, which they developed and know binds to ENaC-alpha, significantly strengthened the barrier in human endothelial cells exposed to the toxin.
They also found at work in the barrier function, a hybrid of ENaC-alpha and the acid sensing ion channel, known for its pain-mediating contributions in the brain. A troubled lung also becomes acidic, which can activate this acid sensing ion channel. They found their TIP peptide also activates the unique hybrid it makes with ENaC-alpha.
"Patients are being treated with antibiotics, which they need to kill the bugs," Lucas notes. The problem is, once you kill the bugs in large quantities, they can release huge amounts of this toxin into the lungs and these toxins make holes, literally holes in membranes of every cell containing cholesterol."
Pulmonologists and other critical care specialists recognize the subsequent problems that can result from high levels of the pneumolysin toxin, but currently don't have a direct solution, Lucas says. Ventilator support can help push oxygen through the fluid-filled sacs, but carries the risk of letting even more bugs into the lungs as well as physical damage to lung tissue.
There also is currently no way to identify ahead of time which patients will experience this second wave, Lucas says. Children are particularly vulnerable because their immune systems also mount a vigorous attack against the invading bacterium and so even more toxin results from the dying bug. Pneumonia is a top killer of children under age five across the world, according to the World Health Organization, along with preterm birth complications, birth asphyxia, diarrhea, malaria and malnutrition.
The TIP peptide is attracted to the sugar coating at the mouth of the sodium channel.
Lucas led a team of scientists who reported in 2014 that the TIP peptide worked like a doorstop to keep sodium channels inside air sacs open in animal models.
Results of a clinical study led by the University of Vienna, also published this year in the journal Critical Care, showed that patients with more severe pulmonary edema - fluid in their lungs - who required a ventilator to support their breathing were able to better clear fluid from their lungs following inhaled treatment with the Tip peptide. Others did not appear to benefit.

Nurses at risk of chronic lung disease COPD due to regular disinfectant use

Nurses at risk of chronic lung disease COPD due to regular disinfectant use

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Nurses at risk of chronic lung disease COPD due to regular disinfectant use

According to a new study, nurses who are work disinfectants continually through their careers are more likely to develop a chronic lung disease called chronic obstructive pulmonary disease (COPD).
The results come from analysis of health of over 55,000 nurses in the USA in the Nurses’ Health Study II. The results of this study will be presented (11th September 2017) at the European Respiratory Society International Congress held in Milan, by Dr Orianne Dumas (PhD) from INSERM, Villejuif, France.
Image Credit: Sielemann / Shutterstock
Image Credit: Sielemann / Shutterstock
Broadly the study shows that tasks that involve use of disinfectants including cleaning surfaces lead to exposure to certain chemicals. These lead to a 22% to 32% increased risk of developing COPD. For this study Dr Dumas and her colleagues looked deeper into health information from 55,185 female registered nurses enrolled in the US Nurses' Health Study II. This enrollment had begun way back in 1989 and some interesting results and associations have been derived from this group of participants. The Nurses’ Health Study II is regulated by the Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
The team collected information about the nurses who were on their nursing jobs in 2009 and had no history of COP, and followed them up until May 2017. Results showed that at the end of the study, 663 nurses were diagnosed with COPD. They used questionnaires to assess the amount of exposure to disinfectants and other chemicals at their jobs among these participants. Other factors that contribute to COPD were also asked about to rule out other possible contributing factors to this condition. This included information regarding smoking, age, body mass index as well as ethnicity.
Dr Dumas explained the results saying that nurses who are regularly in contact with disinfectants to clean surfaces, are at a significantly higher risk for developing COPD. The association of weekly cleaning instruments with disinfectants and development was weaker compared to those who cleaned surfaces.
A deeper understanding of the matter was sought. Specifically, glutaraldehyde, a strong disinfectant that is usually used to cleanse instruments, was found to be one of the culprits. Others include bleach, hydrogen peroxide, alcohol and quaternary ammonium compounds. These are used for lower level disinfection of the floors and furniture. These were found to raise the risk of COPD by 24 to 32 percent. Dr Dumas noted in the study that 37% of nurses used disinfectants to clean surfaces every week and 19% used disinfectants to clean medical instruments each week.
There is previous scientific evidence that exposure to disinfectants could be linked to breathing problems among users and health care workers. The actual link between use of disinfectants and COPD has not been explored in details previously. This is the first study that establishes this connected explained Dumas. She said that this study could help policy makers and authorities take into consideration the occupational hazards of the healthcare workers and thus appropriately develop guidelines for disinfection and cleaning of healthcare settings including hospitals. She added that this was a preliminary study and a deeper and more detailed study was needed and the research team was looking at the US Centers for Disease Control and Prevention for funding and support.
Source:
Abstract no: OA 1774, "Occupational exposure to disinfectants and COPD incidence in US nurses: a prospective cohort study - European Respiratory Society International Congress 2017

Epigenetic changes triggered by cigarette smoke may be earliest step in lung cancer development

Epigenetic changes triggered by cigarette smoke may be earliest step in lung cancer development

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Epigenetic changes triggered by cigarette smoke may be earliest step in lung cancer development

Scientists at the Johns Hopkins Kimmel Cancer Center say they have preliminary evidence in laboratory-grown, human airway cells that a condensed form of cigarette smoke triggers so-called "epigenetic" changes in the cells consistent with the earliest steps toward lung cancer development.
Epigenetic processes are essentially switches that control a gene's potentially heritable levels of protein production but without involving changes to underlying structure of a gene's DNA. One example of such an epigenetic change is methylation -; when cells add tiny methyl chemical groups to a beginning region of a gene's DNA sequence, often silencing the gene's activation.
"Our study suggests that epigenetic changes to cells treated with cigarette smoke sensitize airway cells to genetic mutations known to cause lung cancers," says Stephen Baylin, M.D., the Virginia and D.K. Ludwig Professor for Cancer Research and professor of oncology at the Johns Hopkins Kimmel Cancer Center. Details of the scientists' experiments are described in the Sept. 11 issue of Cancer Cell.
For two decades, scientists have known some of the genetic culprits that drive lung cancer growth, including mutations in a gene called KRAS, which are present in one-third of patients with smoking-related lung cancers, according to Baylin. Genetic and epigenetic changes also occur when normal cells undergo chronic stress, such as the repeated irritation and inflammation caused by decades of exposure to cigarette smoke and its contents.
Baylin and Johns Hopkins scientist Michelle Vaz, Ph.D., first author on the study, suspected that the interplay of epigenetic and genetic changes may occur when normal lung cells develop into cancer, but, Baylin says, the timing of such changes was unknown.
To create the effect of tobacco smoke on cells, Vaz, Baylin and their colleagues began their studies with human bronchial cells, which line the airways of the lungs, and grew them in a laboratory. Every day for 15 months, the scientists bathed the cells with a liquid form of cigarette smoke, which they say is comparable to smoking one to two packs of cigarettes daily.
The scientists recorded the molecular and genetic changes in the smoke-exposed cells over 10 to 15 months, which the scientists say may be similar to 20 to 30 years of smoking, and compared the changes to bronchial cells that had not been exposed to the liquid smoke.
After 10 days of smoke exposure, the scientists found an overall increase in DNA damage responses to so-called reactive oxygen species within the cells. Reactive oxygen species, also called free radicals, are chemicals that typically contain oxygen, are known to be found in cigarette smoke, and cause DNA damage in cells.
Between 10 days and three months, the cells exposed to smoke had a two- to four-fold increase in the amount of an enzyme called EZH2, which works to dampen the expression of genes. Baylin and other scientists have shown that EZH2 and its effects can precede abnormal DNA methylation in gene start sites.
After EZH2 enzymes rise, their levels taper off, and then, the scientists found two to three-fold increases in a protein called DNMT1, which maintains DNA methylation in the "start" location of a variety of tumor suppressor genes that normally suppress cell growth. When these genes are silenced a barrier is removed that might otherwise stop the cells from growing uncontrollably -; a hallmark of cancer.
A host of other genes, which control many other cellular processes do not show such abnormal DNA methylation after smoke exposure.
Baylin says certain genes that control cell growth get turned down periodically during certain stages of life, including embryogenesis, when organisms are growing and developing rapidly. These genes can normally be turned on when cells need to stop growth and allow cells to mature. Chronic cigarette smoke exposure, as noted in many human cancers, tends to block these cell maturation genes from properly turning on, says Baylin.
At the end of six months, the amount of EZH2 and DNMT1 enzymes had tapered off in the cells exposed to the smoke. However, the impact of the two methylation-regulating enzymes was still seen at 10 to 15 months, when scientists found decreased expression of hundreds of genes -; many of which are key tumor suppressor genes such as BMP3, SFRP2 and GATA4 -; in the smoke-exposed cells and a five- or-more-fold increase in the signaling of the KRAS oncogene that is known to be mutated in smoking-related lung cancers.
However, no mutations were found in the KRAS gene itself or the tumor suppressor genes during the 15-month period of cigarette smoke exposure. These abnormally methylated and silenced genes, says Baylin, would have blocked the increase in KRAS signaling if the genes had been properly activated under smoke-free circumstances.
The scientists also found that the timing of epigenetic and genetic events may be key to lung cancer development. They tested this by inserting mutations into the KRAS gene in the DNA of cells exposed to the cigarette smoke condensate for six months as well as those exposed for 15 months. The scientists found that the inserted mutation transformed cells into cancer in only the 15-month cells, where methylation was fully established, but not in the six-month-exposed cells.
Vaz and Baylin say the results suggest that early epigenetic changes triggered by chronic cigarette smoke exposure can build up over time and make the airway cells increasingly sensitive to responding to mutations that initiate cancer.
They say that smokers can best lower their risk of cancer by quitting altogether, and the sooner a smoker quits, the lower their lung cancer risk may be. Their analysis of data in previous studies done by The Cancer Genome Atlas group have shown that the types of abnormal methylation levels they found are lower in smokers who have quit for more than 10 years than those who have not quit.
It may be possible to use de-methylating drugs, they say, for people with higher than normal risk for lung cancer, such as people who have had surgery for early forms of the disease. Such drugs are currently used in clinical trials for certain types of cancer and are standard therapy for a type of pre-leukemia condition.
The scientists caution that their model, as is the case with any laboratory model, may not be exactly what occurs in people during a lengthy period of smoking, but they say it's a first step in understanding the epigenetic processes that may occur early in the transformation of cells into lung cancer.
The scientists also do not know if their model applies to people who smoke e-cigarettes or other forms of tobacco, as their study used condensates typically found in traditional cigarettes.

Scientists find new strategy for overcoming resistance to drugs in lung cancer patients

Scientists find new strategy for overcoming resistance to drugs in lung cancer patients

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Scientists find new strategy for overcoming resistance to drugs in lung cancer patients

Research at the University of Southern Denmark has revealed that a new combination of clinically tested drugs inhibits the growth of tumors, thereby potentially improving patients' survival.
Scientists at the University of Southern Denmark have found a new strategy for overcoming the resistance, which many lung cancer patients develop towards a recent drug, which can arrest the growth of tumors.
An EGFR tyrosine kinase inhibitor is a targeted drug that is used to block a special signal pathway (EGFR) in the cancer cells, thereby arresting tumor growth. However, often the positive effect does not last. After about a year, the lung cancer cells have found other ways to multiply, so many patients become resistant to the treatment.
"We investigated how the cancer cells evade the treatment. They do this in at least 10 different ways, and there is no denying that it complicates the challenge of finding a subsequent treatment that, in the longer term, can stop tumor growth and improve survival of lung cancer patients," says Professor and Consultant Henrik Ditzel from the Department of Molecular Medicine at the University of Southern Denmark and the Department of Oncology at Odense University Hospital.
Common factors for resistance
His research group can now prove that there is a common mechanism for the cells that develop resistance. The cells upgrade a different signal pathway (AKT), resulting in elevated AKT activity in cell samples from lung cancer patients, who no longer respond to treatment with tyrosine kinase inhibitors.
So scientists (in cell cultures and in mice) tested a combination treatment using an EGFR tyrosine kinase inhibitor and an AKT inhibitor, and the tests showed that the tumor growth was arrested.
According to Henrik Ditzel, it may not be very long before the results, which has just been published in the highly regarded journal, Nature Communications with PhD student Kirstine Jacobsen as first author, can change management of lung cancer patients.
"An approved drug already exists to inhibit AKT activities. So we are aiming very soon at embarking on a clinical study, in which lung cancer patients, whose malignant tumor has increased AKT, will be given a combination treatment using the two known drugs at the same time. In the longer term, we hope that this will prolong the lives of lung cancer patients, if we can combine several treatments - in other words, turning them into a single treatment - instead of administering different treatments in succession," says Henrik Ditzel.
  • Lung cancer is the leading cause of cancer mortality in the world. The study looks at non-small cell lung cancer, which accounts for virtually 80% of all cases of lung cancer.
  • The study was conducted in collaboration with scientists and doctors from Barcelona and San Francisco.

People with severe emphysema may breathe better after EBV therapy, study shows

People with severe emphysema may breathe better after EBV therapy, study shows

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People with severe emphysema may breathe better after EBV therapy, study shows





People with severe emphysema may breathe better after a minimally invasive procedure that places valves in the airways leading to diseased portions of their lungs, according to a randomized, controlled trial published online in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.
In "A Multicenter RCT of Zephyr® Endobronchial Valve Treatment in Heterogeneous Emphysema (TRANSFORM)," European researchers report results from the first multicenter randomized, controlled trial comparing the therapeutic approach developed by Pulmonx Corp. to standard of care. The one-way Zephyr® valve keeps air from entering diseased regions of the lung, allowing healthier regions to expand and function better.
The authors note that previous studies of the valves, which are placed using a bronchoscope, found that for patients with severe emphysema, this minimally invasive therapy represents an alternative to lung volume reduction surgery. Patients undergoing endobronchial valve (EBV) therapy appear to experience similar improvements in lung function, shortness of breath, exercise intolerance and quality of life--without the morbidity and mortality previously associated with surgery.
"EBVs have been shown to work in single center trials, but these studies tend to be performed at centers, and by physicians, with considerable experience, so the results may not be generalizable to other centers," said lead study author Samuel V. Kemp, MD, a respiratory physician and expert in interventional bronchoscopy at Royal Brompton Hospital, in the U.K. "What is interesting about this multicenter trial is that the results are at least as good as the single center studies, even though some of the investigators were new to the technique."
Zephyr® valves have been certified for human use in Europe, but are not widely available to patients in all health care systems. The valves have not been approved in the U.S., though a clinical trial of the technology is underway to support an application to the Food and Drug Administration for approval.
The European study enrolled 97 patients from 17 medical centers. The patients were all ex-smokers over the age of 40 who had severe heterogeneous emphysema (emphysema isolated to certain parts of the lung). Sixty-five were randomly assigned to the EBV arm. On average, they received four valves to cut off diseased portions of their lungs that did not receive collateral ventilation (ventilation of alveoli through passages that bypass the normal airways). The other patients received standard of care based on each medical center's protocols for caring for patients following bronchoscopy.
The researchers found:
  • After three months, 55.4 percent of the EBV group had a ≥ 12 percent improvement (the minimum improvement the authors decided in advance would be clinically significant) in FEV1, the amount of air that can be forcefully exhaled in one second, compared to 6.5 percent of controls.
  • After six months, the percentage of those in the EBV group meeting the minimum FEV1 improvement was 56.3 percent, compared to 3.2 percent of controls.
  • The average increase in FEV1 in the EBV group was nearly 30 percent.
  • After six months, secondary endpoints among those in the EBV group were also clinically and statistically significant, including being able to walk nearly 80 meters longer in six minutes, retaining 750 fewer milliliters of air (residual volume) upon maximum expiratory effort, exhibiting less shortness of breath on the modified Medical Research Council Dyspnea Scale and reporting higher quality of life on the St. George's Respiratory Questionnaire.
  • The most common adverse event in the EBV group was a collapsed lung, which occurred in 29.2 percent of the patients.
After six months, 30 of the 32 participants in the control arm left the study and received EBV therapy. The authors will continue to follow those who received EBVs for up to two years.
"There has been a lot of skepticism about valves, largely owing to poorly designed early trials," Dr. Kemp said. "TRANSFORM proves that EBVs are a safe and effective treatment for appropriately selected patients with severe emphysema.
"For these patients, the benefits of EBVs are far greater than standard medical therapy, so it is important that patients be assessed by a multidisciplinary team to determine if this treatment will help them breathe better."
Dr. Kemp added that for those patients with collateral ventilation, valves are not suitable and patients should be considered for lung volume reduction surgery.