One of the primary ways physicians diagnose urinary tract infections is with a test that detects bacteria in urine. A new enhanced test, developed at Loyola University Chicago, detects significantly more bacteria than the standard test, according to a study presented at a meeting of the American Society for Microbiology in New Orleans. Urinary tract infections (UTIs) are among the most common reasons for visits to doctors’ offices and emergency departments. A UTI is an infection in the urinary system, usually involving the bladder and urethra. Women are at higher risk. Symptoms include a strong urge to urinate, a burning sensation when urinating, pelvic pain and urine that appears cloudy or discoloured. Antibiotics often are the first-line treatment. The current test for urinary tract infections is called a standard culture. In a lab, a sample of urine is added to a growth medium that promotes the growth of bacteria that may be in the urine. Two growth media are used and samples are incubated for 24 hours in room air. The new test, called enhanced quantitative urine culture (EQUC), uses a higher volume of urine. In addition to room air, samples are incubated in air containing a high concentration of carbon dioxide and in an anaerobic (absence of oxygen) environment. Samples are incubated for 48 hours in three growth media. The study enrolled 150 urogynaecologic patients, half of whom reported symptoms of UTIs. Urine samples from the patients were subjected to both the standard culture and the EQUC tests. In 69 of the 75 women reporting UTI symptoms, the EQUC test detected one or more bacteria species, for a total of 110 species. Using the standard culture, only 50 percent of these bacteria species were identified. The standard culture identified most of the E. coli bacteria, but only 24 percent of the non-E. coli bacteria. Loyola researchers will soon launch a clinical trial to investigate whether using the EQUC method could improve the clinical care of women with UTIs. The trial will enroll 225 women who have UTI symptoms. Seventy five women will receive the standard culture plus EQUC and 150 women will receive the standard culture alone.
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As more biomarker-based studies open, such testing will increase opportunities to match patients with clinical trials. Nearly three-quarters of patients with advanced cancer could be referred to a potential targeted treatment based on the results of a comprehensive analysis of their tumour’s genetic landscape, a new analysis finds. The study suggests the value of so-called next generation sequencing, a sophisticated method of evaluating the DNA and RNA of a tumour to help direct treatment. In a report on the first 500 patients with advanced solid tumours to go through the University of Michigan Comprehensive Cancer Center’s sequencing program, 72 percent qualified for a clinical trial based on a genetic marker in their tumour. Although not all of those patients were able to enroll in a trial based on other eligibility factors and trial location, the number who did enroll doubled from about 5 percent of patients in 2012 to 11 percent in 2016. Increased trial enrollment occurred as several major national biomarker-based studies opened. “Availability of biomarker trials is crucial for being able to act on these results. Over time, we became better at matching patients to clinical trials as more of these basket trials opened,” says Erin Cobain, M.D., clinical lecturer of haematology/oncology at the University of Michigan Medical School. As part of the sequencing program, patients with stage 4 cancer undergo a biopsy and provide a blood sample to test their normal DNA. Patients also receive genetic counselling. Results of the sequencing are discussed by a team of oncologists, genetics specialists, pathologists, bioinformatics specialists and genetic counsellors, among others, at a precision medicine tumour board. This group discusses all results and assesses the feasibility of pursuing treatment options based on the genomic findings. Genetic sequencing involves looking at all of the DNA and RNA expressed within a tumor. Scientists comb through this enormous amount of data to identify anomalies that may prove to be targets for existing approved or experimental therapies. In addition, the program sequences patients’ normal genome. This means it’s able to identify hereditary genetic variations, or those inherited from a mother or father and potentially passed down to children. Researchers found these hereditary variations in 11 percent of patients, none of which had been previously identified through family history. “That was a major surprise — that 11 percent of patients had a genetic change that increases cancer risk is much higher than we would expect. This has significant impact not only on the patients, but also on their families, who may carry a genetic susceptibility to cancer,” Cobain says. MI-ONCOSEQ requires a fresh biopsy, whereas many commercial sequencing tools can use frozen tissue samples. This ensures the U-M researchers can perform a more comprehensive analysis. Commercial tests analyse only about 350 genes while MI-ONCOSEQ’s more thorough analysis of both DNA and RNA covers at least 1,700 genes. This means many anomalies were identified that would not have been found on panel-based tests. Because MI-ONCOSEQ is run as a research study, patients do not pay for sequencing. Cobain cites an example of a patient with cholangiocarcinoma, a cancer of the bile duct. Sequencing revealed a novel gene fusion that would not have been identified through panel-based tests. The patient was able to enroll on a clinical trial targeting the gene fusion and had an excellent response to that therapy. “This would not have been found by a commercial assay,” Cobain says. “Sequencing is beginning to have a real impact on treatment recommendations. It’s important to consider this testing early in the patient’s clinical course in order to improve our ability to act on the results and impact the patient’s course.”
Michigan University labblog.uofmhealth.org/rounds/genetic-sequencing-can-influence-treatment-for-advanced-cancer
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The first analysis of nearly 19,000 de-identified genomic records from the American Association for Cancer Research (AACR) international data-sharing initiative known as AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) has been published. In addition to the genomic analysis, the report includes examples of how the AACR Project GENIE genomic data can be used to facilitate clinical research, including: Analysis showing that more than 30 percent of the samples had mutations that are clinically actionable, meaning that they are suggestive of a specific treatment that is either already approved by the U.S. Food and Drug Administration or is being tested in clinical trials. Analysis showing that the rate at which patients with samples in the AACR Project GENIE registry would match with arms of the NCI-MATCH trial reflected the actual accrual rates for the trial. Details of two additional studies underway that are linking certain genetic characteristics of metastatic breast cancer with clinical and pathological features of the tumors, as well as with patient outcomes. “There has been a lot of discussion about the potential of data-sharing initiatives to accelerate the pace of progress against cancer,” said Charles L. Sawyers, MD, FAACR, who is the AACR Project GENIE Steering Committee chairperson and an author on the paper. “This paper shows that AACR Project GENIE has made the first steps to delivering on this promise. “We are particularly excited by the clinical actionability analysis,” continued Sawyers, who is also chairperson of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, and a Howard Hughes Medical Institute investigator. “Prior studies looking at how often tumour genome sequencing identifies a clinically actionable mutation have yielded variable results, leading some to question its clinical utility. The huge number of samples in our study and the high rate of clinical actionability give us confidence that tumour genome sequencing can have an important role in clinical care.” AACR Project GENIE is a multi-phase, multi-year, international data-sharing project that was launched by the AACR in partnership with eight global academic leaders in clinical cancer genomics in November 2015. Just over a year later, in January 2017, the AACR Project GENIE consortium made public nearly 19,000 de-identified genomic records collected from patients who were treated at the eight international institutions participating in the first phase of the project. “This paper describes the AACR Project GENIE consortium and provides a landscape overview of the first public GENIE data release,” said Ethan Cerami, PhD, director of the Knowledge Systems Group and lead scientist in the Department of Biostatistics and Computational Biology at the Dana-Farber Cancer Institute in Boston, and an author on the paper. “By showing that we can share data across multiple institutions in the United States, Canada, and Europe to obtain results none of the institutions could have obtained alone, we have put AACR Project GENIE at the forefront of data-sharing efforts to accelerate scientific discovery and ultimately improve patient care.”
American Association for Cancer Research www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1059#.WTSKEmSGP5Y
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Reporting results, researchers seek ways to develop regenerative therapies for muscle disorders by getting stem cells to fuse and form functioning skeletal muscle tissues. A detour on the road to regenerative medicine for people with muscular disorders is figuring out how to coax muscle stem cells to fuse together and form functioning skeletal muscle tissues. A study published reports scientists identify a new gene essential to this process, shedding new light on possible new therapeutic strategies. Led by researchers at the Cincinnati Children’s Hospital Medical Center Heart Institute, the study demonstrates the gene Gm7325 and its protein – which the scientists named “myomerger” – prompt muscle stem cells to fuse and develop skeletal muscles the body needs to move and survive. They also show that myomerger works with another gene, Tmem8c, and its associated protein “myomaker” to fuse cells that normally would not. In laboratory tests on embryonic mice engineered to not express myomerger in skeletal muscle, the animals did not develop enough muscle fibre to live. "These findings stimulate new avenues for cell therapy approaches for regenerative medicine,” said Douglas Millay, PhD, study senior investigator and a scientist in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s. “This includes the potential for cells expressing myomaker and myomerger to be loaded with therapeutic material and then fused to diseased tissue. An example would be muscular dystrophy, which is a devastating genetic muscle disease. The fusion technology possibly could be harnessed to provide muscle cells with a normal copy of the missing gene.” One of the molecular mysteries hindering development of regenerative therapy for muscles is uncovering the precise genetic and molecular processes that cause skeletal muscle stem cells (called myoblasts) to fuse and form the striated muscle fibres that allow movement. Millay and his colleagues are identifying, deconstructing and analysing these processes to search for new therapeutic clues. Genetic degenerative disorders of the muscle number in the dozens, but are rare in the overall population, according to the National Institutes of Health. The major categories of these devastating wasting diseases include: muscular dystrophy, congenital myopathy and metabolic myopathy. Muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common form is Duchenne MD. A previous study authored by Millay in 2014 identified myomaker and its gene through bioinformatic analysis. Myomaker is also required for myoblast stem cells to fuse. However, it was clear from that work that myomaker did not work alone and needed a partner to drive the fusion process. The current study indicates that myomerger is the missing link for fusion, and that both genes are absolutely required for fusion to occur, according to the researchers. To find additional genes that regulate fusion, Millay’s team screened for those activated by expression of a protein called MyoD, which is the primary initiator of the all the genes that make muscle. The team focused on the top 100 genes induced by MyoD (including GM7325/myomerger) and designed a screen to test the factors that could function within and across cell membranes. They also looked for genes not previously studied for having a role in fusing muscle stem cells. These analyses eventually pointed to a previously uncharacterized gene listed in the database – Gm7325. The researchers are building on their current findings, which they say establishes a system for reconstituting cell fusion in mammalian cells, a feat not yet achieved by biomedical science.
Interactions among proteins that relay information from one immune cell to another are weakened in the blood of brain cancer patients within five years before the cancer is diagnosed, said lead researcher Judith Schwartzbaum of The Ohio State University. That information could one day lead to earlier diagnosis of brain cancer, said Schwartzbaum, an associate professor of epidemiology and member of Ohio State’s Comprehensive Cancer Center. The study focused on gliomas, which make up about 80 percent of brain cancer diagnoses. Average survival time for the most common type of glioma is 14 months. Symptoms vary and include headaches, memory loss, personality changes, blurred vision and difficulty speaking. On average, the cancer is diagnosed three months after the onset of symptoms and when tumours are typically advanced. “It’s important to identify the early stages of tumour development if we hope to intervene more effectively,” Schwartzbaum said. “If you understand those early steps, maybe you can design treatments to block further tumour growth.” While widespread blood testing of people without symptoms of this rare tumour would be impractical, this research could pave the way for techniques to identify brain cancer earlier and allow for more-effective treatment, Schwartzbaum said. Schwartzbaum evaluated blood samples from 974 people, half of whom went on to receive a brain-cancer diagnosis in the years after their blood was drawn. The samples came from Norway’s Janus Serum Bank. Because of previous research – including her own on the relationship between allergies and brain cancer – Schwartzbaum was interested in the role of cytokines, proteins that communicate with one another and with immune cells to spark immune responses. Schwartzbaum’s previous work found that allergies appeared to offer protection against brain cancer. In this study, Schwartzbaum evaluated 277 cytokines in the blood samples and found less cytokine interaction in the blood of people who developed cancer. “There was a clear weakening of those interactions in the group who developed brain cancer and it’s possible this plays a role in tumour growth and development,” Schwartzbaum said. Cytokine activity in cancer is especially important to understand because it can play a good-guy role in terms of fighting tumour development, but it also can play a villain and support a tumour by suppressing the immune system, she said. In addition to discovering the weakening of cytokine interactions in the blood of future cancer patients, the researchers found a handful of cytokines that appear to play an especially important role in glioma development. The results of this study must be confirmed and further evaluated before it could translate to changes in the earlier diagnosis of brain cancer, but the discovery offers important insights, Schwartzbaum said. “It’s possible this could also happen with other tumours – that this is a general sign of tumour development,” she said.
Ohio State Universityhttps://news.osu.edu/news/2015/09/09/a-hint-of-increased-brain-tumor-risk-5-years-before-diagnosis/
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Epigenetic changes present at birth – in genes related to addiction and aggression – could be linked to conduct problems in children, according to a new study by King’s College London and the University of Bristol. Conduct problems (CP) such as fighting, lying and stealing are the most common reason for child treatment referral in the UK, costing an estimated £22 billion per year. Children who develop conduct problems before the age of 10 (known as early-onset CP) are at a much higher risk for severe and chronic antisocial behaviour across the lifespan, resulting in further social costs related to crime, welfare dependence and health-care needs. Genetic factors are known to strongly influence conduct problems, explaining between 50-80 per cent of the differences between children who develop problems and those who do not. However, little is known about how genetic factors interact with environmental influences – especially during foetal development – to increase the risk for later conduct problems. Understanding changes in DNA methylation, an epigenetic process that regulates how genes are ‘switched on and off’, could aid the development of more effective approaches to preventing later conduct problems. The study used data from Bristol’s Avon Longitudinal Study of Parents and Children (ALSPAC) to examine associations between DNA methylation at birth and conduct problems from the ages of four to 13. The researchers also measured the influence of environmental factors previously linked to early onset of conduct problems, including maternal diet, smoking, alcohol use and exposure to stressful life events. They found that at birth, epigenetic changes in seven sites across children’s DNA differentiated those who went on to develop early-onset versus those who did not. Some of these epigenetic differences were associated with prenatal exposures, such as smoking and alcohol use during pregnancy. One of the genes which showed the most significant epigenetic changes, called MGLL, is known to play a role in reward, addiction and pain perception. This is notable as previous research suggests conduct problems are often accompanied by substance abuse, and there is also evidence indicating that some people who engage in antisocial lifestyles show higher pain tolerance. The researchers also found smaller differences in a number of genes previously associated with aggression and antisocial behaviour, including MAOA. Dr Edward Barker, senior author from King’s College London, said: ‘We know that children with early-onset conduct problems are much more likely to engage in antisocial behaviour as adults, so this is clearly a very important group to look at from a societal point of view. ‘There is good evidence that exposure to maternal smoking and alcohol is associated with developmental problems in children, yet we don’t know how increased risk for conduct problems occurs. These results suggest that epigenetic changes taking place in the womb are a good place to start.’
King’s College London www.kcl.ac.uk/ioppn/news/records/2017/06-June/Epigenetic-changes-at-birth-could-explain-later-behaviour-problems.aspx
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Researchers from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, together with colleagues from Gelesis and the University of Copenhagen, presented preliminary data demonstrating that study participants with high fasting plasma glucose lost more weight than those with low fasting plasma glucose when following a high-fibre, low-glycemic load diet. The data suggest that fasting plasma glucose levels — also called blood sugar levels — could be helpful in determining the type of diet that is most effective for weight management for people with pre-diabetes or diabetes. “Fasting blood sugar is easily measured and our findings suggest that it could serve as a useful measure in advising some patients on the type of diet that is most beneficial for their weight loss,” said senior author Sai Krupa Das, Ph.D., scientist in the Energy Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston. “The biggest benefits of the high-fibre, low-glycemic diet were seen in people with high fasting blood sugar levels. Study participants with higher blood sugar levels lost more weight on a high-fibre, low-glycemic diet than those on the same diet with lower blood sugar levels, suggesting that it might be possible to optimize weight loss approaches based on a simple clinical measure,” she continued. Das is the senior author on the Healthy Weight for Living Study which found that workplace-based weight programs could be an effective approach for people with significant weight loss goals. Data from that study was used in this new analysis. Participants in the six month study who were overweight or with obesity and who had high fasting blood glucose lost a greater percentage of body weight (-9.4 percent) compared to those with low fasting blood glucose (-4.1 percent). Notably, 79 percent of participants with high fasting blood glucose had lost five percent of their body weight compared to 50 percent with low fasting blood glucose. In addition, 36 percent in the high group, vs. 8 percent in the low group lost 10 percent of their body weight. “The difference in response among those with high fasting blood sugar and lower fasting blood sugar is important. It might be time to consider glycemic status when advising patients on the best strategy for weight loss,” said study author Susan B. Roberts, Ph.D., director of the Energy Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.
Tufts University now.tufts.edu/news-releases/fasting-glucose-marker-greater-weight-loss-high-fiber-low-glycemic-diet
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A new diagnostic developed by Alberta scientists will allow men to bypass painful biopsies to test for aggressive prostate cancer. The test incorporates a unique nanotechnology platform to make the diagnostic using only a single drop of blood, and is significantly more accurate than current screening methods. The Extracellular Vesicle Fingerprint Predictive Score (EV-FPS) test uses machine learning to combine information from millions of cancer cell nanoparticles in the blood to recognize the unique fingerprint of aggressive prostate cancer. The diagnostic, developed by members of the Alberta Prostate Cancer Research Initiative (APCaRI), was evaluated in a group of 377 Albertan men who were referred to their urologist with suspected prostate cancer. It was found that EV-FPS correctly identified men with aggressive prostate cancer 40 percent more accurately than the most common test—Prostate-Specific Antigen (PSA) blood test—in wide use today. "Higher sensitivity means that our test will miss fewer aggressive cancers," said John Lewis, the Alberta Cancer Foundation’s Frank and Carla Sojonky Chair of Prostate Cancer Research at the University of Alberta. "For this kind of test you want the sensitivity to be as high as possible because you don’t want to miss a single cancer that should be treated." According to the team, current tests such as the PSA and digital rectal exam (DRE) often lead to unneeded biopsies. Lewis says more than 50 per cent of men who undergo biopsy do not have prostate cancer, yet suffer the pain and side effects of the procedure such as infection or sepsis. Less than 20 per cent of men who receive a prostate biopsy are diagnosed with the aggressive form of prostate cancer that could most benefit from treatment. It’s estimated that successful implementation of the EV-FPS test could eventually eliminate up to 600-thousand unnecessary biopsies, 24-thousand hospitalizations and up to 50 per cent of unnecessary treatments for prostate cancer each year in North America alone. Beyond cost savings to the health care system, the researchers say the diagnostic test will have a dramatic impact on the health care experience and quality of life for men and their families.
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It is almost axiomatic in medicine that the study of rare disorders informs the understanding of more common, widespread ailments. Researchers from the Perelman School of Medicine at the University of Pennsylvania who study an inherited disorder of skin, hair follicles, nails, sweat glands, and teeth called hypohidrotic ectodermal dysplasia (HED) have identified a mechanism that may also be disrupted in male pattern baldness, a more common condition. About one in 5,000 to 10,000 people are thought to have HED, although this may be an underestimate of its actual prevalence as this condition is not always diagnosed correctly. HED is most frequently caused by mutations in the EDA, EDAR, EDARRAD and WNT10A genes. In addition to its association with HED, mutations in WNT10A are the most common genetic defect observed in people who are born missing one or more teeth, but do not display other characteristics of the disease. These milder WNT10A mutations occur surprisingly frequently, in about 1 to 2 percent of the population. Interestingly, a variant of the WNT10A gene associated with lower levels of its protein’s expression has been linked to a greater likelihood of male pattern baldness, according to a recent genome-wide association study. “By analysing mice with the WNT10A mutation, as well as tissues from human patients with WNT10A mutations, we found that WNT10A regulates the proliferation, but not the maintenance, of stem cells in hair follicles,” said Sarah Millar, PhD, vice chair for Basic Research in the Department of Dermatology. “Together with a previously published genome-wide association study, our findings suggest that lower levels of WNT10A may contribute to male pattern baldness in some individuals.” The team made mouse models for WNT10A-associated HED by deleting the Wnt10a gene. The mutant mice displayed the same symptoms as HED patients with severe loss of function mutations in the WNT10A gene. Long-term absence of WNT10A leads to miniaturization of hair follicle structures and enlargement of the associated sebaceous glands, a phenomenon that is also observed in male pattern baldness. Millar’s group and her clinical collaborators, including Emily Chu, MD, PhD, an assistant professor of Dermatology and John McGrath, MD, from King’s College, London, also discovered that cracking and scaling of palm and foot sole skin in WNT10A patients is due to decreased expression of a structural protein called Keratin 9, which is specifically expressed in these regions of skin and contributes to its mechanical integrity. “Our studies took us back and forth between human patients and our mouse model,” said Millar. “Our goal was to find what happened to cellular components affected by the WNT10A mutation to make better treatments.” Millar’s group showed that decreased proliferation and Keratin 9 expression in the absence of WNT10A resulted from failure of signalling through a well-characterized pathway that stabilizes a protein called beta-catenin, allowing it to enter the cell nucleus and activate gene transcription. These findings indicate that small molecule drugs that activate the beta-catenin pathway downstream of WNT10A could potentially be used to treat hair thinning and palm and sole skin defects in WNT10A patients. These agents may also be useful for preventing hair loss in a subgroup of people with male pattern baldness.
Penn Medicine www.pennmedicine.org/news/news-releases/2017/june/inherited-rare-skin-disease-informs-treatment-of-common-hair-disorders
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Tens of thousands of cancer patients each year may benefit from an immunotherapy regimen called PD-1 blockade, based on results from a new clinical study. The findings establish genetic markers that help physicians identify which patients might respond to the therapy, which had been approved previously for a select few classes of cancer. "What we describe in this paper applies to about 4% of patients with advanced cancer, regardless of the tumour type," said Bert Vogelstein of Johns Hopkins University, a senior author on the paper. In an 86-patient clinical trial encompassing 12 different kinds of cancers, Dung Le and colleagues at Johns Hopkins University demonstrated that the immunotherapy drug pembrolizumab (an anti-PD-1 antibody) was effective against multiple types of tumours. All of the patients had cancers with defects in a genome maintenance pathway called mismatch repair (MMR). "One patient, a young graduate student, was scheduled to go into hospice for terminal care two days prior to receiving the test result that showed he had an MMR-deficient tumour," said Vogelstein. "Shortly after beginning treatment, he went into remission. Since then he’s been able to finish his Ph.D., get married and live a happy and productive life." PD-1 blockade doesn’t directly destroy tumours, but instead aids the immune system in targeting cancer cells — which can suppress the body’s defences in order to thrive. Until recently, PD-1 blockade therapies were approved for only a select few classes of cancers, such as melanoma and lung cancer. Yet in a historic May 2017 decision , the United States Food and Drug Administration ruled that tumour genetics, rather than tissue of origin, could be used as a clinical indicator for pembrolizumab therapy. "This is the first approval for a treatment that is tissue agnostic, which means clinicians can use pembrolizumab for any tumour with mismatch repair deficiency," said Le. As many as 60,000 cancers every year might harbour MMR mutations that would render them susceptible to PD-1 blockade, according to Le and colleagues’ analysis of genome sequencing data from 12,019 cancers representing 32 distinct tumor types. PD-1 blockade takes advantage of the fact that MMR defects make cancer genomes inherently unstable, giving them a potential Achilles’ heel. "Tumours that have more chaotic genomes produce more proteins that are recognized by the immune system," said Geoff Lindeman, a breast cancer researcher at Walter and Eliza Hall Institute of Medical Research, who was not involved in the study. Different types of cancers experience various levels of genomic chaos. Most tumors harbor roughly 50 genetic alterations whereas skin and lung cancers tend to have mutation counts well in the hundreds, arising from exposure to environmental DNA-damaging agents like UV light or cigarette smoke. Problems with MMR can push tumors towards thousands of mutations per cell. Yet even with such high mutational loads, cancer can still escape from the immune system. "Tumors find ways to switch off the immune cells," said Vogelstein. "Checkpoint inhibitors like anti-PD-1 can re-awaken these immune cells for an extra weapon in the ongoing war between cancer and the immune system." Though the trial is still ongoing, 11 patients were able to stop taking the therapy; they have remained disease-free with no evidence of recurrence for an average of 8.3 months.
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Enhanced test for urinary tract infections detects more bacteria than standard test
, /in E-News /by 3wmediaOne of the primary ways physicians diagnose urinary tract infections is with a test that detects bacteria in urine.
A new enhanced test, developed at Loyola University Chicago, detects significantly more bacteria than the standard test, according to a study presented at a meeting of the American Society for Microbiology in New Orleans.
Urinary tract infections (UTIs) are among the most common reasons for visits to doctors’ offices and emergency departments. A UTI is an infection in the urinary system, usually involving the bladder and urethra. Women are at higher risk. Symptoms include a strong urge to urinate, a burning sensation when urinating, pelvic pain and urine that appears cloudy or discoloured. Antibiotics often are the first-line treatment.
The current test for urinary tract infections is called a standard culture. In a lab, a sample of urine is added to a growth medium that promotes the growth of bacteria that may be in the urine. Two growth media are used and samples are incubated for 24 hours in room air.
The new test, called enhanced quantitative urine culture (EQUC), uses a higher volume of urine. In addition to room air, samples are incubated in air containing a high concentration of carbon dioxide and in an anaerobic (absence of oxygen) environment. Samples are incubated for 48 hours in three growth media.
The study enrolled 150 urogynaecologic patients, half of whom reported symptoms of UTIs. Urine samples from the patients were subjected to both the standard culture and the EQUC tests. In 69 of the 75 women reporting UTI symptoms, the EQUC test detected one or more bacteria species, for a total of 110 species. Using the standard culture, only 50 percent of these bacteria species were identified. The standard culture identified most of the E. coli bacteria, but only 24 percent of the non-E. coli bacteria.
Loyola researchers will soon launch a clinical trial to investigate whether using the EQUC method could improve the clinical care of women with UTIs. The trial will enroll 225 women who have UTI symptoms. Seventy five women will receive the standard culture plus EQUC and 150 women will receive the standard culture alone.
EurekAlert
www.eurekalert.org/pub_releases/2017-06/luhs-etf053017.php
Genetic sequencing can influence treatment for advanced cancer
, /in E-News /by 3wmediaAs more biomarker-based studies open, such testing will increase opportunities to match patients with clinical trials.
Nearly three-quarters of patients with advanced cancer could be referred to a potential targeted treatment based on the results of a comprehensive analysis of their tumour’s genetic landscape, a new analysis finds.
The study suggests the value of so-called next generation sequencing, a sophisticated method of evaluating the DNA and RNA of a tumour to help direct treatment.
In a report on the first 500 patients with advanced solid tumours to go through the University of Michigan Comprehensive Cancer Center’s sequencing program, 72 percent qualified for a clinical trial based on a genetic marker in their tumour.
Although not all of those patients were able to enroll in a trial based on other eligibility factors and trial location, the number who did enroll doubled from about 5 percent of patients in 2012 to 11 percent in 2016. Increased trial enrollment occurred as several major national biomarker-based studies opened.
“Availability of biomarker trials is crucial for being able to act on these results. Over time, we became better at matching patients to clinical trials as more of these basket trials opened,” says Erin Cobain, M.D., clinical lecturer of haematology/oncology at the University of Michigan Medical School.
As part of the sequencing program, patients with stage 4 cancer undergo a biopsy and provide a blood sample to test their normal DNA. Patients also receive genetic counselling.
Results of the sequencing are discussed by a team of oncologists, genetics specialists, pathologists, bioinformatics specialists and genetic counsellors, among others, at a precision medicine tumour board. This group discusses all results and assesses the feasibility of pursuing treatment options based on the genomic findings.
Genetic sequencing involves looking at all of the DNA and RNA expressed within a tumor. Scientists comb through this enormous amount of data to identify anomalies that may prove to be targets for existing approved or experimental therapies.
In addition, the program sequences patients’ normal genome. This means it’s able to identify hereditary genetic variations, or those inherited from a mother or father and potentially passed down to children.
Researchers found these hereditary variations in 11 percent of patients, none of which had been previously identified through family history.
“That was a major surprise — that 11 percent of patients had a genetic change that increases cancer risk is much higher than we would expect. This has significant impact not only on the patients, but also on their families, who may carry a genetic susceptibility to cancer,” Cobain says.
MI-ONCOSEQ requires a fresh biopsy, whereas many commercial sequencing tools can use frozen tissue samples. This ensures the U-M researchers can perform a more comprehensive analysis. Commercial tests analyse only about 350 genes while MI-ONCOSEQ’s more thorough analysis of both DNA and RNA covers at least 1,700 genes.
This means many anomalies were identified that would not have been found on panel-based tests. Because MI-ONCOSEQ is run as a research study, patients do not pay for sequencing.
Cobain cites an example of a patient with cholangiocarcinoma, a cancer of the bile duct. Sequencing revealed a novel gene fusion that would not have been identified through panel-based tests. The patient was able to enroll on a clinical trial targeting the gene fusion and had an excellent response to that therapy.
“This would not have been found by a commercial assay,” Cobain says. “Sequencing is beginning to have a real impact on treatment recommendations. It’s important to consider this testing early in the patient’s clinical course in order to improve our ability to act on the results and impact the patient’s course.”
Michigan University
labblog.uofmhealth.org/rounds/genetic-sequencing-can-influence-treatment-for-advanced-cancer
First analysis of AACR Project GENIE data published
, /in E-News /by 3wmediaThe first analysis of nearly 19,000 de-identified genomic records from the American Association for Cancer Research (AACR) international data-sharing initiative known as AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) has been published.
In addition to the genomic analysis, the report includes examples of how the AACR Project GENIE genomic data can be used to facilitate clinical research, including:
Analysis showing that more than 30 percent of the samples had mutations that are clinically actionable, meaning that they are suggestive of a specific treatment that is either already approved by the U.S. Food and Drug Administration or is being tested in clinical trials.
Analysis showing that the rate at which patients with samples in the AACR Project GENIE registry would match with arms of the NCI-MATCH trial reflected the actual accrual rates for the trial.
Details of two additional studies underway that are linking certain genetic characteristics of metastatic breast cancer with clinical and pathological features of the tumors, as well as with patient outcomes.
“There has been a lot of discussion about the potential of data-sharing initiatives to accelerate the pace of progress against cancer,” said Charles L. Sawyers, MD, FAACR, who is the AACR Project GENIE Steering Committee chairperson and an author on the paper. “This paper shows that AACR Project GENIE has made the first steps to delivering on this promise.
“We are particularly excited by the clinical actionability analysis,” continued Sawyers, who is also chairperson of the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center in New York, and a Howard Hughes Medical Institute investigator. “Prior studies looking at how often tumour genome sequencing identifies a clinically actionable mutation have yielded variable results, leading some to question its clinical utility. The huge number of samples in our study and the high rate of clinical actionability give us confidence that tumour genome sequencing can have an important role in clinical care.”
AACR Project GENIE is a multi-phase, multi-year, international data-sharing project that was launched by the AACR in partnership with eight global academic leaders in clinical cancer genomics in November 2015. Just over a year later, in January 2017, the AACR Project GENIE consortium made public nearly 19,000 de-identified genomic records collected from patients who were treated at the eight international institutions participating in the first phase of the project.
“This paper describes the AACR Project GENIE consortium and provides a landscape overview of the first public GENIE data release,” said Ethan Cerami, PhD, director of the Knowledge Systems Group and lead scientist in the Department of Biostatistics and Computational Biology at the Dana-Farber Cancer Institute in Boston, and an author on the paper. “By showing that we can share data across multiple institutions in the United States, Canada, and Europe to obtain results none of the institutions could have obtained alone, we have put AACR Project GENIE at the forefront of data-sharing efforts to accelerate scientific discovery and ultimately improve patient care.”
American Association for Cancer Research
www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1059#.WTSKEmSGP5Y
One gene closer to regenerative therapy for muscular disorders
, /in E-News /by 3wmediaReporting results, researchers seek ways to develop regenerative therapies for muscle disorders by getting stem cells to fuse and form functioning skeletal muscle tissues.
A detour on the road to regenerative medicine for people with muscular disorders is figuring out how to coax muscle stem cells to fuse together and form functioning skeletal muscle tissues. A study published reports scientists identify a new gene essential to this process, shedding new light on possible new therapeutic strategies.
Led by researchers at the Cincinnati Children’s Hospital Medical Center Heart Institute, the study demonstrates the gene Gm7325 and its protein – which the scientists named “myomerger” – prompt muscle stem cells to fuse and develop skeletal muscles the body needs to move and survive. They also show that myomerger works with another gene, Tmem8c, and its associated protein “myomaker” to fuse cells that normally would not.
In laboratory tests on embryonic mice engineered to not express myomerger in skeletal muscle, the animals did not develop enough muscle fibre to live.
"These findings stimulate new avenues for cell therapy approaches for regenerative medicine,” said Douglas Millay, PhD, study senior investigator and a scientist in the Division of Molecular Cardiovascular Biology at Cincinnati Children’s. “This includes the potential for cells expressing myomaker and myomerger to be loaded with therapeutic material and then fused to diseased tissue. An example would be muscular dystrophy, which is a devastating genetic muscle disease. The fusion technology possibly could be harnessed to provide muscle cells with a normal copy of the missing gene.”
One of the molecular mysteries hindering development of regenerative therapy for muscles is uncovering the precise genetic and molecular processes that cause skeletal muscle stem cells (called myoblasts) to fuse and form the striated muscle fibres that allow movement. Millay and his colleagues are identifying, deconstructing and analysing these processes to search for new therapeutic clues.
Genetic degenerative disorders of the muscle number in the dozens, but are rare in the overall population, according to the National Institutes of Health. The major categories of these devastating wasting diseases include: muscular dystrophy, congenital myopathy and metabolic myopathy. Muscular dystrophies are a group of more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. The most common form is Duchenne MD.
A previous study authored by Millay in 2014 identified myomaker and its gene through bioinformatic analysis. Myomaker is also required for myoblast stem cells to fuse. However, it was clear from that work that myomaker did not work alone and needed a partner to drive the fusion process. The current study indicates that myomerger is the missing link for fusion, and that both genes are absolutely required for fusion to occur, according to the researchers.
To find additional genes that regulate fusion, Millay’s team screened for those activated by expression of a protein called MyoD, which is the primary initiator of the all the genes that make muscle. The team focused on the top 100 genes induced by MyoD (including GM7325/myomerger) and designed a screen to test the factors that could function within and across cell membranes. They also looked for genes not previously studied for having a role in fusing muscle stem cells. These analyses eventually pointed to a previously uncharacterized gene listed in the database – Gm7325.
The researchers are building on their current findings, which they say establishes a system for reconstituting cell fusion in mammalian cells, a feat not yet achieved by biomedical science.
Cincinnati Children’s Hospital
www.cincinnatichildrens.org/news/release/2017/regenerative-therapy
Five years before brain cancer diagnosis, changes detectable in blood
, /in E-News /by 3wmediaInteractions among proteins that relay information from one immune cell to another are weakened in the blood of brain cancer patients within five years before the cancer is diagnosed, said lead researcher Judith Schwartzbaum of The Ohio State University.
That information could one day lead to earlier diagnosis of brain cancer, said Schwartzbaum, an associate professor of epidemiology and member of Ohio State’s Comprehensive Cancer Center.
The study focused on gliomas, which make up about 80 percent of brain cancer diagnoses. Average survival time for the most common type of glioma is 14 months.
Symptoms vary and include headaches, memory loss, personality changes, blurred vision and difficulty speaking. On average, the cancer is diagnosed three months after the onset of symptoms and when tumours are typically advanced.
“It’s important to identify the early stages of tumour development if we hope to intervene more effectively,” Schwartzbaum said. “If you understand those early steps, maybe you can design treatments to block further tumour growth.”
While widespread blood testing of people without symptoms of this rare tumour would be impractical, this research could pave the way for techniques to identify brain cancer earlier and allow for more-effective treatment, Schwartzbaum said.
Schwartzbaum evaluated blood samples from 974 people, half of whom went on to receive a brain-cancer diagnosis in the years after their blood was drawn. The samples came from Norway’s Janus Serum Bank.
Because of previous research – including her own on the relationship between allergies and brain cancer – Schwartzbaum was interested in the role of cytokines, proteins that communicate with one another and with immune cells to spark immune responses. Schwartzbaum’s previous work found that allergies appeared to offer protection against brain cancer.
In this study, Schwartzbaum evaluated 277 cytokines in the blood samples and found less cytokine interaction in the blood of people who developed cancer.
“There was a clear weakening of those interactions in the group who developed brain cancer and it’s possible this plays a role in tumour growth and development,” Schwartzbaum said.
Cytokine activity in cancer is especially important to understand because it can play a good-guy role in terms of fighting tumour development, but it also can play a villain and support a tumour by suppressing the immune system, she said.
In addition to discovering the weakening of cytokine interactions in the blood of future cancer patients, the researchers found a handful of cytokines that appear to play an especially important role in glioma development.
The results of this study must be confirmed and further evaluated before it could translate to changes in the earlier diagnosis of brain cancer, but the discovery offers important insights, Schwartzbaum said.
“It’s possible this could also happen with other tumours – that this is a general sign of tumour development,” she said.
Ohio State Universityhttps://news.osu.edu/news/2015/09/09/a-hint-of-increased-brain-tumor-risk-5-years-before-diagnosis/
Epigenetic changes at birth could explain later behaviour problems
, /in E-News /by 3wmediaEpigenetic changes present at birth – in genes related to addiction and aggression – could be linked to conduct problems in children, according to a new study by King’s College London and the University of Bristol.
Conduct problems (CP) such as fighting, lying and stealing are the most common reason for child treatment referral in the UK, costing an estimated £22 billion per year. Children who develop conduct problems before the age of 10 (known as early-onset CP) are at a much higher risk for severe and chronic antisocial behaviour across the lifespan, resulting in further social costs related to crime, welfare dependence and health-care needs.
Genetic factors are known to strongly influence conduct problems, explaining between 50-80 per cent of the differences between children who develop problems and those who do not. However, little is known about how genetic factors interact with environmental influences – especially during foetal development – to increase the risk for later conduct problems. Understanding changes in DNA methylation, an epigenetic process that regulates how genes are ‘switched on and off’, could aid the development of more effective approaches to preventing later conduct problems.
The study used data from Bristol’s Avon Longitudinal Study of Parents and Children (ALSPAC) to examine associations between DNA methylation at birth and conduct problems from the ages of four to 13.
The researchers also measured the influence of environmental factors previously linked to early onset of conduct problems, including maternal diet, smoking, alcohol use and exposure to stressful life events.
They found that at birth, epigenetic changes in seven sites across children’s DNA differentiated those who went on to develop early-onset versus those who did not. Some of these epigenetic differences were associated with prenatal exposures, such as smoking and alcohol use during pregnancy.
One of the genes which showed the most significant epigenetic changes, called MGLL, is known to play a role in reward, addiction and pain perception. This is notable as previous research suggests conduct problems are often accompanied by substance abuse, and there is also evidence indicating that some people who engage in antisocial lifestyles show higher pain tolerance. The researchers also found smaller differences in a number of genes previously associated with aggression and antisocial behaviour, including MAOA.
Dr Edward Barker, senior author from King’s College London, said: ‘We know that children with early-onset conduct problems are much more likely to engage in antisocial behaviour as adults, so this is clearly a very important group to look at from a societal point of view.
‘There is good evidence that exposure to maternal smoking and alcohol is associated with developmental problems in children, yet we don’t know how increased risk for conduct problems occurs. These results suggest that epigenetic changes taking place in the womb are a good place to start.’
King’s College London
www.kcl.ac.uk/ioppn/news/records/2017/06-June/Epigenetic-changes-at-birth-could-explain-later-behaviour-problems.aspx
Fasting glucose as a marker for greater weight loss on a high-fibre, low-glycemic diet
, /in E-News /by 3wmediaResearchers from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, together with colleagues from Gelesis and the University of Copenhagen, presented preliminary data demonstrating that study participants with high fasting plasma glucose lost more weight than those with low fasting plasma glucose when following a high-fibre, low-glycemic load diet.
The data suggest that fasting plasma glucose levels — also called blood sugar levels — could be helpful in determining the type of diet that is most effective for weight management for people with pre-diabetes or diabetes.
“Fasting blood sugar is easily measured and our findings suggest that it could serve as a useful measure in advising some patients on the type of diet that is most beneficial for their weight loss,” said senior author Sai Krupa Das, Ph.D., scientist in the Energy Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston.
“The biggest benefits of the high-fibre, low-glycemic diet were seen in people with high fasting blood sugar levels. Study participants with higher blood sugar levels lost more weight on a high-fibre, low-glycemic diet than those on the same diet with lower blood sugar levels, suggesting that it might be possible to optimize weight loss approaches based on a simple clinical measure,” she continued.
Das is the senior author on the Healthy Weight for Living Study which found that workplace-based weight programs could be an effective approach for people with significant weight loss goals. Data from that study was used in this new analysis.
Participants in the six month study who were overweight or with obesity and who had high fasting blood glucose lost a greater percentage of body weight (-9.4 percent) compared to those with low fasting blood glucose (-4.1 percent). Notably, 79 percent of participants with high fasting blood glucose had lost five percent of their body weight compared to 50 percent with low fasting blood glucose.
In addition, 36 percent in the high group, vs. 8 percent in the low group lost 10 percent of their body weight.
“The difference in response among those with high fasting blood sugar and lower fasting blood sugar is important. It might be time to consider glycemic status when advising patients on the best strategy for weight loss,” said study author Susan B. Roberts, Ph.D., director of the Energy Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.
Tufts University
now.tufts.edu/news-releases/fasting-glucose-marker-greater-weight-loss-high-fiber-low-glycemic-diet
New blood test uses nanotechnology to predict aggressive prostate cancer accurately
, /in E-News /by 3wmediaA new diagnostic developed by Alberta scientists will allow men to bypass painful biopsies to test for aggressive prostate cancer. The test incorporates a unique nanotechnology platform to make the diagnostic using only a single drop of blood, and is significantly more accurate than current screening methods.
The Extracellular Vesicle Fingerprint Predictive Score (EV-FPS) test uses machine learning to combine information from millions of cancer cell nanoparticles in the blood to recognize the unique fingerprint of aggressive prostate cancer. The diagnostic, developed by members of the Alberta Prostate Cancer Research Initiative (APCaRI), was evaluated in a group of 377 Albertan men who were referred to their urologist with suspected prostate cancer. It was found that EV-FPS correctly identified men with aggressive prostate cancer 40 percent more accurately than the most common test—Prostate-Specific Antigen (PSA) blood test—in wide use today.
"Higher sensitivity means that our test will miss fewer aggressive cancers," said John Lewis, the Alberta Cancer Foundation’s Frank and Carla Sojonky Chair of Prostate Cancer Research at the University of Alberta. "For this kind of test you want the sensitivity to be as high as possible because you don’t want to miss a single cancer that should be treated."
According to the team, current tests such as the PSA and digital rectal exam (DRE) often lead to unneeded biopsies. Lewis says more than 50 per cent of men who undergo biopsy do not have prostate cancer, yet suffer the pain and side effects of the procedure such as infection or sepsis. Less than 20 per cent of men who receive a prostate biopsy are diagnosed with the aggressive form of prostate cancer that could most benefit from treatment.
It’s estimated that successful implementation of the EV-FPS test could eventually eliminate up to 600-thousand unnecessary biopsies, 24-thousand hospitalizations and up to 50 per cent of unnecessary treatments for prostate cancer each year in North America alone. Beyond cost savings to the health care system, the researchers say the diagnostic test will have a dramatic impact on the health care experience and quality of life for men and their families.
Medicalexpress
medicalxpress.com/news/2017-06-blood-nanotechnology-aggressive-prostate-cancer.html
Inherited, rare skin disease informs treatment of common hair disorders
, /in E-News /by 3wmediaIt is almost axiomatic in medicine that the study of rare disorders informs the understanding of more common, widespread ailments. Researchers from the Perelman School of Medicine at the University of Pennsylvania who study an inherited disorder of skin, hair follicles, nails, sweat glands, and teeth called hypohidrotic ectodermal dysplasia (HED) have identified a mechanism that may also be disrupted in male pattern baldness, a more common condition.
About one in 5,000 to 10,000 people are thought to have HED, although this may be an underestimate of its actual prevalence as this condition is not always diagnosed correctly. HED is most frequently caused by mutations in the EDA, EDAR, EDARRAD and WNT10A genes. In addition to its association with HED, mutations in WNT10A are the most common genetic defect observed in people who are born missing one or more teeth, but do not display other characteristics of the disease. These milder WNT10A mutations occur surprisingly frequently, in about 1 to 2 percent of the population. Interestingly, a variant of the WNT10A gene associated with lower levels of its protein’s expression has been linked to a greater likelihood of male pattern baldness, according to a recent genome-wide association study.
“By analysing mice with the WNT10A mutation, as well as tissues from human patients with WNT10A mutations, we found that WNT10A regulates the proliferation, but not the maintenance, of stem cells in hair follicles,” said Sarah Millar, PhD, vice chair for Basic Research in the Department of Dermatology. “Together with a previously published genome-wide association study, our findings suggest that lower levels of WNT10A may contribute to male pattern baldness in some individuals.”
The team made mouse models for WNT10A-associated HED by deleting the Wnt10a gene. The mutant mice displayed the same symptoms as HED patients with severe loss of function mutations in the WNT10A gene. Long-term absence of WNT10A leads to miniaturization of hair follicle structures and enlargement of the associated sebaceous glands, a phenomenon that is also observed in male pattern baldness.
Millar’s group and her clinical collaborators, including Emily Chu, MD, PhD, an assistant professor of Dermatology and John McGrath, MD, from King’s College, London, also discovered that cracking and scaling of palm and foot sole skin in WNT10A patients is due to decreased expression of a structural protein called Keratin 9, which is specifically expressed in these regions of skin and contributes to its mechanical integrity.
“Our studies took us back and forth between human patients and our mouse model,” said Millar. “Our goal was to find what happened to cellular components affected by the WNT10A mutation to make better treatments.”
Millar’s group showed that decreased proliferation and Keratin 9 expression in the absence of WNT10A resulted from failure of signalling through a well-characterized pathway that stabilizes a protein called beta-catenin, allowing it to enter the cell nucleus and activate gene transcription.
These findings indicate that small molecule drugs that activate the beta-catenin pathway downstream of WNT10A could potentially be used to treat hair thinning and palm and sole skin defects in WNT10A patients. These agents may also be useful for preventing hair loss in a subgroup of people with male pattern baldness.
Penn Medicine
www.pennmedicine.org/news/news-releases/2017/june/inherited-rare-skin-disease-informs-treatment-of-common-hair-disorders
Studies open up possibility of immunotherapy for more cancer patients
, /in E-News /by 3wmediaTens of thousands of cancer patients each year may benefit from an immunotherapy regimen called PD-1 blockade, based on results from a new clinical study. The findings establish genetic markers that help physicians identify which patients might respond to the therapy, which had been approved previously for a select few classes of cancer.
"What we describe in this paper applies to about 4% of patients with advanced cancer, regardless of the tumour type," said Bert Vogelstein of Johns Hopkins University, a senior author on the paper.
In an 86-patient clinical trial encompassing 12 different kinds of cancers, Dung Le and colleagues at Johns Hopkins University demonstrated that the immunotherapy drug pembrolizumab (an anti-PD-1 antibody) was effective against multiple types of tumours. All of the patients had cancers with defects in a genome maintenance pathway called mismatch repair (MMR).
"One patient, a young graduate student, was scheduled to go into hospice for terminal care two days prior to receiving the test result that showed he had an MMR-deficient tumour," said Vogelstein. "Shortly after beginning treatment, he went into remission. Since then he’s been able to finish his Ph.D., get married and live a happy and productive life."
PD-1 blockade doesn’t directly destroy tumours, but instead aids the immune system in targeting cancer cells — which can suppress the body’s defences in order to thrive.
Until recently, PD-1 blockade therapies were approved for only a select few classes of cancers, such as melanoma and lung cancer. Yet in a historic May 2017 decision , the United States Food and Drug Administration ruled that tumour genetics, rather than tissue of origin, could be used as a clinical indicator for pembrolizumab therapy.
"This is the first approval for a treatment that is tissue agnostic, which means clinicians can use pembrolizumab for any tumour with mismatch repair deficiency," said Le.
As many as 60,000 cancers every year might harbour MMR mutations that would render them susceptible to PD-1 blockade, according to Le and colleagues’ analysis of genome sequencing data from 12,019 cancers representing 32 distinct tumor types.
PD-1 blockade takes advantage of the fact that MMR defects make cancer genomes inherently unstable, giving them a potential Achilles’ heel.
"Tumours that have more chaotic genomes produce more proteins that are recognized by the immune system," said Geoff Lindeman, a breast cancer researcher at Walter and Eliza Hall Institute of Medical Research, who was not involved in the study.
Different types of cancers experience various levels of genomic chaos. Most tumors harbor roughly 50 genetic alterations whereas skin and lung cancers tend to have mutation counts well in the hundreds, arising from exposure to environmental DNA-damaging agents like UV light or cigarette smoke. Problems with MMR can push tumors towards thousands of mutations per cell.
Yet even with such high mutational loads, cancer can still escape from the immune system.
"Tumors find ways to switch off the immune cells," said Vogelstein. "Checkpoint inhibitors like anti-PD-1 can re-awaken these immune cells for an extra weapon in the ongoing war between cancer and the immune system."
Though the trial is still ongoing, 11 patients were able to stop taking the therapy; they have remained disease-free with no evidence of recurrence for an average of 8.3 months.
AAAS
www.aaas.org/news/studies-open-possibility-immunotherapy-more-cancer-patients