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DALLAS - Dec. 10, 2019 - Federal regulations may keep lung cancer patients out of clinical trials simply because these patients are on medications that might affect the electrical system of the heart. Drilling into the details quickly turns up reasons to think these regulations may be preventing a substantial proportion of patients from participating in clinical trials. There may be alternatives, and researchers and physicians should explore them.

These are the conclusions of a team of researchers from UT Southwestern Medical Center that included members of the Harold C. Simmons Comprehensive Cancer Center. Their findings, published in the journal Clinical Lung Cancer in November, might help break down barriers for patients to participate in important, potentially lifesaving clinical trials. The barriers currently exclude thousands of patients.

"This issue comes up all the time in my practice," said Dr. David Gerber, who treats lung cancer patients and is a Professor of Internal Medicine and Population and Data Sciences. He is one of the study's authors and has been studying clinical trial eligibility criteria for a decade.

Clinical trial eligibility criteria are designed to limit risks to study participants. But, according to Dr. Gerber, these criteria may be excessive in places.

"The criteria are not as thoughtful as they could be," Dr. Gerber said. "We keep cutting and pasting from earlier studies, basically doing the same things over and over without justifying them or deciding if they're rational."

Using a database of more than 280,000 Veterans Health Administration patients with lung cancer, the study found that more than 25 percent of lung cancer patients were prescribed medications with potential cardiac risk, and almost 10 percent were taking multiple such medications. Dr. Gerber noted that even if these medications are not having cardiac effects on patients, simply receiving the medications may bar patients from clinical trials. Furthermore, when cardiac effects are noted, the actual risk to patients is often measured over a 40-year period. Because most lung cancer patients are over 70 years old, a 40-year range of possible risks may be less relevant.

"Lung cancer is a serious and possibly life-threatening condition," Dr. Gerber said. "When we design clinical trials, we need to consider potential benefits as well as theoretical risks."

Dr. Carlos L. Arteaga, Director of the Simmons Cancer Center and Associate Dean of Oncology Programs, said studies like Dr. Gerber's are urgently needed because less than 2 percent of adult cancer patients in the U.S. are enrolled in clinical trials that can benefit the patient and advance scientific knowledge. He said clinical trials for lung cancer are particularly important because lung cancer is the leading cause of cancer deaths in Texas and the nation.

"Studying barriers to clinical trials can be as important as creating a new clinical trial itself. Patients can't benefit from trials they can't access," said Dr. Arteaga, also Professor of Internal Medicine who holds The Lisa K. Simmons Distinguished Chair in Comprehensive Oncology. "Dr. Gerber's work is one of the first steps in making clinical trials more accessible."

Dr. Mark Link, a cardiologist and Professor of Internal Medicine who worked on the study, said the seemingly excessive caution around the drugs stems largely from a medical crisis in the late 1990s. A new drug created to treat gastric motility disorders such as diarrhea, vomiting, and severe constipation showed positive effects on the gastrointestinal tract but serious threats to the heart.

"This new drug was widely used and very effective. It worked extremely well, but then the reports started coming in of QTc prolongation of this drug, and it was taken off the market," said Dr. Link, who holds the Laurence and Susan Hirsch/Centex Distinguished Chair in Heart Disease.

QTc prolongation is the blip on an electrocardiogram, the iconic machine on the medical TV shows that charts each heartbeat with a beep and a fever chart line. The space between the highest peaks on the EKG line is known as the QTc interval. It is the moment the heart is preparing to beat again. It's a crucial step in cardiac health - in staying alive - so the threats caused by the gastric motility disorder drug prompted the FDA to zero in on other drugs that affect QTc prolongation. The fallout included strict rules stating that patients taking drugs that prolong - or even might prolong - QTc intervals cannot enter clinical cancer trials.

The most common QTc-prolonging medications that the study found to be potential barriers to clinical trials included antibiotics, psychiatric medications, and cardiac medications.

DES PLAINES, IL -- A study to evaluate the effect of an Electronic Medication Complete Communication (EMC2) Opioid Strategy on patients' safe use of and knowledge about opioids found that the EMC2 tools improved demonstrated safe dosing, but these benefits did not translate into actual use based on medication dairies. The study findings are published in the December 2019 issue of Academic Emergency Medicine (AEM), a journal of the Society for Academic Emergency Medicine (SAEM).

The lead author of the study is Danielle M. McCarthy MD, MS, vice chair for research in the department of emergency medicine and associate professor of emergency medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.

The investigators implemented the best practices effort of "take, stop, wait" prescribing language, together with the added boost of text messaging, to educate patients on how to reduce overuse of opioids. Intervention improved demonstrated safe dosing of opioids, and the text-messaging intervention resulted in improved patient knowledge, however there was no influence of the intervention on actual safe medication use among the portion of the sample returning medication diaries.

The findings support the notion that possessing knowledge about medication risks is likely necessary but not sufficient to ensure safe use, as medication-taking behaviors are often influenced by complex factors (e.g. health literacy, self-efficacy, and attitudes) in addition to knowledge.

The authors suggest that future emergency department interventions may opt to focus on post-discharge communication as the greatest increases in knowledge in this sample were among patients receiving the text-messaging portion of the intervention.

Jason Haukoos, MD, professor of emergency medicine and director of emergency medicine research at the University of Colorado School of Medicine Anschutz Medical Campus, commented:

"The work performed by this investigative team as part of the ED EMC2 pragmatic clinical trial advances our thinking about best practices of opioid prescribing from the emergency department. Critical to combating the opioid epidemic, integration of an electronic multi-faceted intervention aimed at physicians, pharmacists, and patients, as studied in this trial, may improve the safe use of opioids. Although challenged by the single centered approach, the results are compelling and should now be extended as part of a larger, multi-centered initiative."

About 32 percent of older, sicker patients enrolled on a leukemia clinical trial experienced serious side effects from a treatment that combined a chemotherapy and an immunotherapy drug, leading investigators to pause the trial and the U.S. Food and Drug Administration to eventually pull the combination from the current study.

Released today at the 61st American Society of Hematology (ASH) Annual Meeting, the findings serve as both triumph and warning. The randomized, two-arm trial design allowed investigators to catch the toxicity signal early, just eight months after the first patient enrolled. The trial also illustrates the tension currently facing cancer researchers, as eligibility criteria for clinical trials are loosened and as evidence mounts that immunotherapies can cause serious side effects, particularly for patients, many of them older, managing other illnesses like diabetes.

"Our findings highlight special concerns that cancer physicians must consider as we enroll vulnerable populations," said Annette Hay, M.D., a hematologist at Queen's University in Canada who, along with Sarit Assouline, M.D., of McGill University Jewish General Hospital, co-leads this section of the leukemia trial. "We also see the importance of vigilance and close collaborations, including with the FDA, to ensure patient safety."

The results stem from a trial run by the SWOG Cancer Research Network, a cancer clinical trials network funded by the National Cancer Institute (NCI) through the National Institutes of Health. Hay presented them in a poster session today in Orlando, Florida at the ASH Annual Meeting, the world's largest conference devoted to blood diseases and blood cancers like lymphoma.

The study, S1612, is a unique collaboration between the Canadian Cancer Trials Group, where Hay and Assouline are members, and SWOG, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group. All four groups are funded by NCI through their National Clinical Trials Network. S1612 launched in December 2018 to test treatments for acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), a bone marrow disorder sometimes referred to as "pre-leukemia."

Hay and the other investigators set out to minimize trial exclusions and allow older, less-fit adults to join. That's because a majority of people who get AML and MDS are over the age of 60 when they're diagnosed. However, these older adults have not been well-represented in trials because so many are barred from joining. To make trials more representative, and to make their results more generalizable, the American Society of Clinical Oncology and the Friends of Cancer Research called for more inclusive trial criteria in a series of articles published in 2017 in the Journal of Clinical Oncology. In 2018, the FDA and NCI both issued new enrollment guidelines for industry- and publicly-funded cancer trials, respectively, which allow patients with organ dysfunction or a past cancer diagnosis, among others, to be considered for enrollment.

There is an urgent need for new AML and MDS treatments. While the chemotherapy azacitidine is standard, few patients respond well to it. Hay and her collaborators wanted to add new drugs into the mix, including the immunotherapy nivolumab. Knowing that toxicities could result, especially in older, sicker patients, the team designed the trial to ensure maximum safety. Patients would be randomly selected to join one of three groups - patients who get azacitidine only, patients who get azacitidine and nivolumab, and patients who get azacitidine and midostaurin, a new type of targeted drug. By including a control group - patients only getting standard treatment - researchers could better spot problems with patients getting combinations.

In October 2018, after 78 patients enrolled, enrollment was suspended. At the time, researchers had found that four patients died due to side-effects from the azacitidine and nivolumab treatment, compared with one patient who died due to side effects from azacitidine only. While the number of early deaths didn't reach statistical significance, they sent a possible toxicity signal to the study leadership. After a review of safety data, and consultation with the FDA, researchers tightened the eligibility requirements for patients who could get assigned to the azacitidine and nivolumab combination, and boosted side effect surveillance. In October 2019, the FDA removed the nivolumab combination from the trial.

In 2020, S1612 will reopen with the control group, the azacitidine and midostaurin group, and a new arm - in which patients will be treated with a combination of two chemotherapy agents - decitabine and cytarabine. In addition, the research team plans to continue to evaluate azacitidine and nivolumab in older, less fit adults, and are working to determine the appropriate population and refining the toxicity profile in order to move forward.

"There is a message here for us in cancer research," Hay said. "As we broaden our trial eligibility criteria, we may be including patients who may not only have cancer but two, three, even five other diseases. So they may experience significant side effects from trial treatment, especially drugs that stimulate the immune system. It's important to incorporate frailty screening tools in trial design."

Lancaster University researchers have discovered, for the first time, how a genetic alteration that increases the risk of developing Autism and Tourette's impacts on the brain.

Their research also suggests that ketamine, or related drugs, may be a useful treatment for both of these disorders.

Autism affects an estimated 2.8 million people in the UK while Tourette's Syndrome - a condition that causes a person to make involuntary sounds and movements called tics -affects an estimated 300,000 people in the UK. The treatments available for both disorders are limited and new treatments are urgently required. Recent research has also shown that these disorders are genetically linked.

People with a genetic deletion known as chromosome 2p16.3 deletion often experience developmental delay and have learning difficulties. They are also around 15 times more likely to develop Autism and 20 times more likely to develop Tourette's Syndrome, but the mechanisms involved are not completely understood.

Using brain imaging studies, neuroscientists have shown that deletion of the gene impacted by 2p16.3 deletion (Neurexin1) impacts on the function of brain regions involved in both conditions. A key finding is that this genetic deletion disrupts a brain area known as the thalamus, compromising its ability to communicate with other brain areas.

Lead researcher Dr Neil Dawson of Lancaster University said: "We currently have a very poor understanding of how the 2p16.3 deletion dramatically increases the risk of developing these disorders.

However, we know that the 2p16.3 deletion involves deletion of the Neurexin1 gene, a gene that makes a protein responsible for allowing neurons to communicate effectively."

Deletion of the Neurexin1 gene affects brain areas involved in Autism and Tourette's including the thalamus, a collection of brain regions that play a key role in helping other brain areas communicate with each other. Changes were also found in brain regions involved in processing sensory information and in learning and memory.

Importantly, the researchers also found that the ability of the thalamic brain regions to communicate with other brain areas was impaired by the genetic deletion. They then tested the ability of a low dose of the drug ketamine, a drug used clinically at higher doses as an anesthetic, to normalize the alterations in brain function induced by the genetic deletion.

Dr Dawson said: "Intriguingly our data suggest that ketamine can restore some aspects of the brain dysfunction that results from 2p16.3 deletion and suggests that ketamine, or other related drugs, may be useful in treating some of the symptoms seen in Autism and Tourette's. The brain circuits affected suggest that these drugs may be particularly useful for the cognitive and motor problems experienced by people with these disorders."

Interestingly, ketamine was shown to normalise activity in the thalamic regions found to be hyperactive as a result of the genetic deletion and re-established the ability of these regions to communicate with other brain areas. This suggests that ketamine, or related drugs, may be a useful treatment for people with 2p16.3 deletion or with Autism and Tourette's Syndrome, although more research is needed.

Dr Dawson urges caution to those who may be thinking of using ketamine therapeutically.

"While this data gives us important new information on the brain circuits affected by 2p16.3 deletion and of the potential usefulness of ketamine to help people with Autism and Tourette's much more research needs to be conducted to prove its clinical potential. We know that ketamine impacts on the activity of several brain regions in addition to the thalamus, and the effects in these other regions are likely to cause unwanted side-effects. In addition, long-term ketamine treatment may have negative consequences that are not yet fully understood. We also think ketamine may not be the best therapeutic option due to its relatively short lifespan in the body.

"However, the findings of this study give us important clues regarding the types of drugs that may be useful in the treatment of these disorders, and we are using this information to actively pursue the validation of these drugs for the potential treatment of these disorders."

Physicians use standard disease classifications based on symptoms or location in the body to help make diagnoses. These classifications, called nosologies, can help doctors understand which diseases are closely related, and thus may be caused by the same underlying issues or respond to the same treatments.

An important part of understanding disease is estimating its heritability, that is, what percentage of disease variation in individuals is due to inherited genetic variants versus environmental causes like exposure to pollution, infections or trauma. Traditionally, to calculate the heritability of a given disease, researchers needed expensive data sets containing all kinds of medical and genetic data plus detailed knowledge of family relationships. In a new study, data scientists from the University of Chicago estimated heritability and mapped out relationships among thousands of diseases using data from electronic health records.

The study, published December 3, 2019 in Nature Communications, calculated statistical curves of each disease's prevalence over an average lifetime, showing which tend to strike earlier or later in life. The researchers also created "disease embeddings," or groupings of diseases that show how closely they are related to each other based on diagnostic codes and notes in the health record. Using similarities in these curves and patterns revealed by the disease embeddings, researchers could then estimate heritability and genetic correlations between diseases.

"It used to be that every new estimate of heritability or genetic and environmental correlations between diseases was a big deal," said Andrey Rzhetsky, PhD, a data scientist at UChicago who is the paper's senior author. "Here we were able to estimate thousands of heritability values and hundreds of thousands of correlations, doing what used to be very expensive and slow at a very large scale."

Early onset vs late onset

To build the team's statistical models, postdoctoral researcher Gengjie Jia, PhD, the paper's first author, used data from Truven MarketScan, a database of de-identified health claims of 151 million people in the United States over 11 years. They also included data from the Danish National Patient Registry (5.6 million people over 21 years) and the Swedish National Health Registry (9.4 million people over 44 years). They then created disease prevalence curves that plot the percentage of people who have a disease at each age.

The curves document statistically significant changes in a condition's prevalence over the average lifespan. Different extremes and shapes of the curves show whether a disease is more prevalent at younger (early onset) or older (late onset) ages. The researchers can also identify dips or spikes in the curve that may be a sign of environmental trigger events that can influence disease, such as puberty, changes in diet, trauma or exposure to infections.

The team also built "disease embeddings," or relationships between diseases, using a neural network model to analyze several different factors around when a disease appears in a medical record. This analysis was modeled after natural language processing that defines a word's underlying semantics by analyzing its surrounding words. In a health record, a disease is like a word, and the historical record of conditions they develop over a lifetime form a sentence. For example, "headaches" might later be followed by "migraines" as physicians narrow down a diagnosis. Therefore, when you plot them on a two-dimensional map, headaches would appear closer to migraines than, say, stomach cramps.

"The system is learning from real sequences in the patient data by optimizing 20 parameters for each disease," Rzhetsky said. "From that context, given a patient's past health history, the network is trying to anticipate what comes next. You can think about it like what happens in the doctor's mind as they make a diagnosis."

Identifying new patterns

As they studied the data, several patterns started to emerge. In the U.S. data, early onset diseases outnumbered late onset conditions, but were less prevalent in the population. This could be because routine newborn screening and monitoring of children tends to identify more diseases, or because diseases with a strong genetic component tend to strike earlier and cause more deaths.

When two diseases are closely correlated by genetics alone, the shapes of their prevalence curves are likely to be very different. If they are linked only by environmental factors, they are much more similar, but the curves are most similar when both environmental and genetic correlations are high.

The researchers also saw that some diseases that would appear to be closely related, like psychiatric conditions, clustered into different groups based on mean onset age. Attention deficit hyperactivity disorder and autism, for example, are early onset, whereas schizophrenia, bipolar disorder and depression tend to be late onset.

Jia said that this initial run with such large health datasets validates their approach to classifying diseases based on similarity of the shapes of the curves. While at a high level, the result matched commonly accepted classifications and associations between groups of diseases, it did identify some surprises. For example, parasitic infections were found to align with an array of noninfectious diseases, such as neurofibromatosis, tympanic membrane disorders of the ear, osteogenesis imperfecta (brittle bone disease) and congenital eye anomalies.

The disease prevalence curves, standardized across age and sex, have never previously been systematically compared like this study does (click here to see a searchable database of sex-and-country-stratified prevalence curves for over 500 diseases). Now, the team hopes to refine these tools and use them to help fill in the gaps for understudied conditions.

"Our estimates can be used for deciding where to allocate research resources," Rzhetsky said. "Does this disease have a stronger genetic or environmental component? We did this through a whole spectrum of diseases, so it's a general tool that can be applied to other conditions as they arise."

BOSTON - While most U.S. infant and preschool-aged international travelers are eligible for measles-mumps-rubella (MMR) vaccination prior to departure, almost 60 percent of eligible young travelers were not vaccinated during pretravel consultation, researchers at Massachusetts General Hospital (MGH) have found. In a study published in JAMA Pediatrics, the team reported that most eligible pediatric international travelers were not vaccinated due to clinician decision or guardian refusal, despite recommendations from the Advisory Committee on Immunization Practices (ACIP).

"At a time when the global resurgence of measles is evident in the U.S., our results show that clinicians too frequently miss opportunities to vaccinate eligible pediatric travelers with MMR," says Emily Hyle, MD, investigator in the Division of Infectious Diseases at MGH, and lead author of the study. "Children represent less than 10 percent of U.S. international travelers but account for nearly half of known measles importations that trigger additional measles infections and outbreaks in the U.S." Even young travelers to places not considered high risk for disease should be vaccinated, she adds, noting that Europe accounted for 30 percent of imported measles cases to the U.S. from 2001 to 2016.

ACIP recommends that children in the U.S. receive two lifetime MMR vaccine doses as part of routine vaccination. The first is given between 12 and 15 months and the second between 4 and 6 years of age. However, due to the increased risk of measles exposure for international pediatric travelers, ACIP recommends that infants (6 to 12 months) receive one MMR vaccination prior to departure (which does not count toward the two lifetime doses), and that preschool-aged travelers (1 to 6 years) should receive both lifetime vaccine doses before departure.

To assess how well ACIP recommendations were achieved, the research team evaluated consultations of pediatric travelers at the Global TravEpiNet (GTEN) sites, a multisite consortium around the country supported by the Centers for Disease Control and Prevention (CDC). Among more than 14,000 pediatric international travelers who sought pretravel health consultations from 2009-2018, 92 percent of infants and 60 percent of preschool-aged children were eligible for pretravel MMR vaccinations, yet 44 percent of those infants and 57 percent of preschool children were not vaccinated, often because clinicians failed to recognize the child's eligibility. "This underscores the knowledge gaps that exist about MMR vaccination, even among clinicians with expertise in travel medicine," says Regina LaRocque, MD, MPH, investigator in the MGH Division of Infectious Diseases, and senior author of the study.

Measles is a viral illness associated with fever, cough, coryza and conjunctivitis followed by a rash that can result in hospitalization, severe neurologic disease and death. Although measles continues to circulate widely internationally, a safe and effective MMR vaccine as part of routine childhood vaccinations has led to control of measles in the U.S. For the past 20 years, importations of measles from U.S. travelers or foreign visitors have been responsible for most measles outbreaks in the U.S., though they have been rare. However, measles is on the rise again in the U.S. due to under-vaccination. More than 1,200 measles cases were reported in the U.S. in 2019, which was the greatest number since 2000.

"Children who are most likely to need MMR vaccination before international travel are aged 6 months to school-age because they won't have yet received their complete MMR vaccinations routinely," explains Hyle. "Measles poses serious health risks to people who are infected while abroad, as well as to those in communities to which they return. These risks can be greatly reduced or even eliminated via MMR vaccination prior to departure. Our study suggests the urgent need for greater awareness of the benefits of MMR vaccination for international travelers by pediatricians, as well as by guardians who may fail to recognize measles as a serious illness."

Patients with ALS (amyotrophic lateral sclerosis) often suffer from type 2 diabetes. This phenomenon has since long remained mechanistically enigmatic. Now, researchers at Karolinska Institutet in Sweden have identified a molecular mechanism linking these two diseases. The study is published in the scientific journal PNAS.

The researchers found that immunoglobulin G (IgG) antibodies in the blood of ALS patients target the calcium channel in the cell membrane of the insulin-secreting beta cells in the pancreas.

"This leads to an unphysiological calcium (Ca2+) influx and consequent beta cell death," says Dr. Yue Shi, first author of the study and Postdoctoral researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet.

Altered humoral immunity, i.e. the presence of autoantibodies targeting the body's own cells, is a known phenomenon in type 1 diabetes. The new study highlights the presence of autoantibodies as a pathogenic mechanism in a subgroup of patients with type 2 diabetes.

"We now demonstrate that IgG from ALS patients with type 2 diabetes behave like cytotoxic autoantibodies, suggesting that altered humoral immunity can serve as a critical pathogenic mechanism in the development of diabetes," says Dr. Shao-Nian Yang, Associate professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and senior author of the study. "This may lay the foundation for a new immunotherapy strategy for patients suffering from both ALS and diabetes."

The researchers believe that the presence of autoantibodies may be a generalised phenomenon for other neurodegenerative diseases as well. Similar to ALS patients, a proportion of patients with disorders like Alzheimer's disease, Parkinson's disease and multiple sclerosis also suffer from type 2 diabetes.

"Interestingly, pancreatic beta cells and neurons are equipped with similar types of calcium channels and share a series of physiological and pathological mechanisms for their function/dysfunction and survival/death, such as Ca2+-dependent exocytosis and Ca2+-triggered cell death," says Professor Per-Olof Berggren, Director of the Rolf Luft Research Center, Karolinska Institutet, and senior author of the study. "The extent to which the pathogenic mechanism that we discovered in patients with both ALS and type 2 diabetes may be generalised to other neurodegenerative diseases associated with diabetes will be the focus for future studies."

Los Angeles - Cancer immunology drugs, which harness the body's immune system to better attack cancer cells, have significantly changed the face of cancer treatment. People with aggressive cancers are now living longer, healthier lives. Unfortunately, cancer immunology therapy only works in a subset of patients.

Now, a new study from scientists at the UCLA Jonsson Comprehensive Cancer Center helps explain why some people with advanced cancer may not respond to one of the leading immunotherapies, PD-1 blockade, and how a new combination approach may help overcome resistance to the immunotherapy drug.

The UCLA study, published today in the inaugural issue of the new scientific journal Nature Cancer, showed that genetic and pharmacological inhibition of the oncogene PAK4 overcomes resistance to anti-PD-1 therapy in preclinical models.

"One of the main reasons patients do not respond to PD-1 blockade is because the T cells never make it into the tumor to attack the cancer cells," said lead author Gabriel Abril-Rodriguez, a doctoral candidate in the departments of pharmacology and medicine in the David Geffen School of Medicine at UCLA. "We found that biopsies of patients who did not respond to PD-1 blockade showed an overexpression of PAK4, so that led us to believe it played a role in suppressing the immunotherapy treatment."

PAK4 has been known previously to be involved in cell migration and proliferation. The new research from UCLA demonstrates that high expression of this oncogene also correlates with a lack of immune cells migrating into the tumors to destroy the cancer cells.

Using biopsies from people with advanced melanoma who received the immune checkpoint blocking antibody pembrolizumab, UCLA researchers performed RNA sequencing to characterize the phenotype of the tumors. They saw that the tumors that did not respond to PD-1 blockade had a high expression of PAK4 and were not infiltrated by immune cells, meaning that the immune cells had not found their way to the tumor to attack the cancer cells.

The team then inhibited PAK4 in cell lines by either using a drug inhibitor or a gene editing technique called CRISPR-Cas9. The scientists found that deleting PAK4 increased the migration of tumor-specific immune cells and sensitized tumors to PD-1 blockade immunotherapy, reversing the resistance.

"Developing new and improved combination treatments like this one for people who do not initially respond to anti-PD-1 treatment is the next step forward in our efforts to make immunotherapy work better for more people," said Dr. Antoni Ribas, the study's senior author, a professor of medicine at the Geffen School and director of the Jonsson Cancer Center's Tumor Immunology Program. "The results from this study could also be expanded to other tumor types that are notoriously resistant to PD-1 blockade, such as pancreatic cancer."

The PAK4 inhibitor used in the study is already being tested in a phase one trial. The combination treatment with anti-PD-1 will be tested in a clinical trial setting in the near future.

(New York, NY - December 9, 2019) - Mount Sinai researchers have designed an innovative experimental therapy that may be able to stop the growth of triple-negative breast cancer, the deadliest type of breast cancer, which has few effective treatment options, according to a study published in Nature Chemical Biology in December.

The therapy is known is MS1943. In a cancer cell line and mouse models, it degraded a protein called EZH2 that drives the growth of triple-negative breast cancer.

Research teams led by Jian Jin, PhD, Director of the Mount Sinai Center for Therapeutics Discovery, and Ramon Parsons, MD, PhD, Director of The Tisch Cancer Institute at Mount Sinai, developed MS1943 as a first-in-class small-molecule agent that selectively degrades EZH2. They also showed that agents that inhibit the enzymatic activity of EZH2 but do not degrade EZH2 did not work in triple-negative breast cancer.

MS1943 effectively reduced EZH2 protein levels in a variety of cancer cell lines, including a triple-negative breast cancer cell line, leading to the death of these triple-negative breast cancer cells.

"Our findings suggest that EZH2 selective degraders such as MS1943 may provide an emerging therapeutic approach for the treatment of triple-negative breast cancer," said Dr. Jin, who is also Co-leader of the Cancer Clinical Investigation Program at The Tisch Cancer Institute, Mount Sinai Professor in Therapeutics Discovery, and Professor of Pharmacological Sciences, and Oncological Sciences, at the Icahn School of Medicine at Mount Sinai. "The EZH2 selective degrader reported in this study is also an invaluable tool to test therapeutic hypotheses in other cancers."

A prescription of short-term exercise for patients with advanced prostate cancer could help to reduce the side-effects of hormone therapy, according to new research from the University of East Anglia.

Researchers from the Norfolk and Norwich University Hospital (NNUH) and UEA led a trial which involved patients who were due to start androgen deprivation therapy (ADT).

Fifty patients took part in the research study, with half of the participants taking part in two supervised exercise sessions a week for three months at specialist exercise science facilities at UEA.

The trial aimed to reduce the adverse side-effects of hormone therapy such as weight gain and an increased risk of heart problems and assessed participants' health three months after their exercise programme.

The findings, which have been published in the British Journal of Urology International (BJUI), showed that the three month programme of aerobic and resistance training intervention prevented adverse changes in cardiopulmonary fitness and fatigue for those taking part in the trial.

Prof John Saxton, from UEA's Norwich Medical School, said: "Structured exercise programmes have much to offer people living with common cancers. Hormone treatments for prostate cancer are known to have undesirable side-effects, which increase a man's susceptibility to cardiovascular disease.

"This research shows that some of the harmful side-effects of hormone therapy are reduced in men who begin to exercise regularly around the same time that these drugs are prescribed.

"Our findings have important implications for the quality of prostate cancer survival," he added.

Wilphard Ndjavera, Clinical Fellow for Urology at NNUH, said: "All the patients really enjoyed the sessions and the results have suggested that exercise does work to reduce these harmful side effects of treatment. It is one of only two studies in the world to look at this."

"After the supervised exercise was withdrawn, differences in cardiopulmonary fitness and fatigue were not sustained, but the exercise group showed higher quality of life and reduced cardiovascular risk compared to the control group."

"These findings have important implications for clinicians concerned with the management of ADT-related side-effects."

Ever since the German midfielder, Christoph Kramer suffered a black-out in the final of the 2014 Football World Cup there has been a growing number of debates around the question of sport-related concussion. The emphasis here is on correct diagnosis. There are plenty of symptoms but these can be ambiguous. Researchers of the Department of Neurology, Psychosomatics and Psychiatry of the Institute for Exercise Therapy and Movement-Oriented Prevention and Rehabilitation have now been able to find evidence for their hypothesis, that non-verbal hand movement behaviour offers additional information concerning the state of health of the athletes, but specifically with respect to possible post-concussion symptoms.

Dr. Ingo Helmich and his team compared the hand movements of symptomatic and asymptomatic athletes after concussion. The findings show that non-verbal behaviour and hand movements differ between the two groups, in that symptomatic athletes are more likely to perform so-called "motion quality presentation gestures" which provide information on the athletes' post-concussion motor sensory experience.

The study provides evidence of significant non-verbal gestures and behaviour differences between people with and without concussion which can serve as behavioural markers for sports-related concussions and so improve diagnosis.

Taking a baby aspirin every day to prevent a heart attack or stroke should no longer be recommended to patients who haven't already experienced one of these events.

That's according to a new study published in Family Practice.

Nearly one-quarter of Americans over the age of 40 have reported taking aspirin daily even if they don't have a history of heart disease or stroke.

That's a problem, says study author University of Georgia researcher Mark Ebell.

As a physician and epidemiologist at UGA's College of Public Health, Ebell's work evaluates the evidence underpinning clinical practice and health behaviors. The current recommendation for taking aspirin as the primary form of heart attack or stroke prevention is limited to adults aged 50 to 69 who have an increased cardiovascular risk.

"We shouldn't just assume that everyone will benefit from low-dose aspirin, and in fact the data show that the potential benefits are similar to the potential harms for most people who have not had a cardiovascular event and are taking it to try to prevent a first heart attack or stroke," said Ebell.

Aspirin was first found to reduce the risk of fatal and nonfatal heart attacks 30 years ago, and subsequent studies found evidence that aspirin may also reduce risk of stroke and colon cancer.

But aspirin use has always carried risks, said Ebell, namely bleeding in the stomach and brain.

More recent studies have begun to suggest that potential harms of taking aspirin may outweigh the benefits by today's medical standards.

"If you look back in the 1970s and '80s when a lot of these original studies were done, patients were not taking statin drugs to control cholesterol, their blood pressure was not as well controlled, and they weren't getting screenings for colorectal cancer," said Ebell.

Ebell and his colleague Frank Moriarty of the Royal College of Surgeons in Ireland compared aspirin studies using patient data from 1978 to 2002 to four large-scale aspirin trials occurring after 2005, when statin use and colorectal cancer screenings had become more widespread.

They found that for 1,000 patients treated for five years, there were four fewer cardiovascular events and seven more major hemorrhages. Ebell was particularly alarmed by the number of brain bleeds experienced by aspirin users.

"About 1 in 300 persons who took aspirin for five years experienced a brain bleed. That's pretty serious harm. This type of bleeding can be fatal. It can be disabling, certainly," he said. "One in 300 is not something that the typical doctor is going to be able to pick up on in their practice. That's why we need these big studies to understand small but important increases in risk."

Ebell cautions people who are concerned about their cardiovascular risk, but who haven't had a heart attack or stroke, to talk with their doctors about other ways to prevent a major event.

These days, he says, treatment for blood pressure, cholesterol and diabetes are more aggressive, and the rate of other risk factors like smoking has dropped.

"There are so many things that we're doing better now that reduce cardiovascular and colorectal cancer risk, which leaves less for aspirin to do," he said.

A common virus that is harmless to most individuals may produce an important biomarker in determining the prognosis of brain cancer patients, according to a recent study published by a student researcher at the University of Cincinnati.

Patients with glioblastomas or malignant brain tumors, face a difficult future. The disease is fatal, and only about 5 percent of patients are alive five years after their diagnosis, explains Haidn Foster, a third-year medical student at the UC College of Medicine and first author of a recent study of glioblastoma patients in the scholarly journal Neuro-Oncology Advances.

The study looked at health outcomes of 188 glioblastoma patients and found that individuals who tested positive for an antibody indicating Human cytomegalovirus (HCMV) exposure lived an average of 404 days after their cancer diagnosis compared to an average of 530 days for patients who were never infected by HCMV, said Foster.

A life expectancy difference of four months is an important consideration for patients and their physicians. "For glioblastoma patients time is precious and treatment that would prolong life by a few weeks or months is considered a victory," said Foster.

"The question we asked, "Did having a prior HCMV infection, indicated by the presence of this antibody we could detect in patients' blood, correlate with poorer overall survival in glioblastoma patients?" said Foster. "It turned out this correlation did exist,and it was independent of other factors such as patient age or the extent of tumor resection."

Foster's work was performed in collaboration with a research laboratory led by Dr. Charles Cobbs, director of the Ben & Catherine Ivy Center for Advanced Brain Tumor Treatment at the Swedish Neuroscience Institute in Seattle, Washington. Cobbs first discovered the presence of cytomegalovirus in glioblastoma brain tumors in 2002.

"We believe that human cytomegalovirus is a possible contributor to the aggressiveness of human glioblastoma tumors," said Cobbs. "These are highly malignant tumors, and there is significant evidence, albeit controversial, that HCMV is present in a high percentage of these tumors."

Cobbs said collaborators at Harvard Medical School have shown that in animal models that mice that are latently infected with the virus can reactivate the virus when they develop brain tumors. The virus will then promote a much more aggressive growth state of the tumor and promote more rapid death.

"There is evidence from researchers in Germany who have shown that when glioblastoma patients receive standard treatment with radiation and chemotherapy, people who have a latent infection with this virus will often reactivate the virus systemically, and this can cause a fatal encephalitis which is preventable if identified and treated with antiviral drugs," explained Cobbs.

"The work that Haidn independently proposed and performed will hopefully contribute to a growing body of work that suggests that this virus, which is considered to have no significant pathological impact in people who have normal immune systems, may actually be a dangerous pathogen that can promote and accelerate the growth and malignancy of a common brain tumor and possibly other cancer types," said Cobbs.

Treatment of glioblastoma patients has typically consisted of surgical removal of the tumor followed by six weeks of radiation plus a chemotherapy drug called temozolomide, said Cobbs. Survival rates for glioblastoma patients on average range from 12 to 18 months.

Glioblastoma patients in the study had given their consent and were all treated by Cobbs. Just over half or 97 patients had never been exposed to HCMV, while the remaining 91 patients did test positive to HCMV exposure.

"The majority of the United States population has been infected with cytomegalovirus, but it's generally not harmful for most individuals, " said Foster. "For people who are immunosuppressed or have naturally lower immunity, however, such as infants, AIDS patients or transplant patients, the virus can cause significant disease."

Cobbs said the study led by Foster highlights the possibility that having a prior infection and a presumed latent infection with CMV may somehow predispose patients to have a more aggressive course with glioblastoma.

"This could potentially be due to either a viral infection of the tumor itself, as shown with a mouse model from our collaborators at Harvard Medical School, or potentially systemic effects of reactivation of the virus during radiation and chemotherapy, which in and of itself could be an independent factor in promoting encephalitis and other life-threatening complications," said Cobbs.

The study was funded by several sources including the Ben & Catherine Ivy Foundation and the National Institutes of health.

"We suggest, given the result of his paper, that more oncologists do HCMV testing for their patients with glioblastoma because the absence of viral antibodies indicates patients may have a better overall life expectancy," said Foster. "Moreover, there is growing early evidence to suggest that antivirals and virus-targeted immunotherapies could improve outcomes for patients infected by HCMV."

A new paper in Family Practice, published by Oxford University Press, found that the widespread use of statins and cancer screening technology may have altered the benefits of aspirin use. Researchers concluded that aspirin no longer provides a net benefit as primary prevention for cardiovascular disease and cancer.

Nearly half of adults 70 years and older have reported taking aspirin daily even if they don't have a history of heart disease or stroke. Overall, an estimated 40% of adults in the United States take aspirin for primary prevention of cardiovascular diseases, making it one of our most commonly used medications

Researchers conducted the first review of aspirin's role in cardiovascular prevention 30 years ago, reporting a reduction in risk for both fatal and non-fatal heart attacks. Subsequent reports also found a reduction in cancer deaths for patients taking aspirin for five or more years, but no reduction in cardiovascular related deaths or strokes, and consistently displayed a significant risk of major bleeding complications.

Most of these aspirin trials were set in Europe and the United States and recruited patients prior to 2000. Since then, cholesterol-lowering drugs have gone into widespread use, accompanied by better management of hypertension, less tobacco use, and widespread adoption of colorectal cancer screening.

Researchers compared these older studies with four recent large scale trials of aspirin. Broadly, participants in the newer trials resembled the contemporary population that would use aspirin for primary prevention. In comparison, they were older, somewhat less likely to smoke, and more likely to have type 2 diabetes than patients in the older trials.

Like older studies, the recent trials of aspirin for primary prevention found no mortality benefit and a significant increase in the risk of major haemorrhages. However, they failed to find evidence for the two important benefits of aspirin: a reduction in the risk of cancer deaths and a reduced risk of non-fatal heart attacks. For every 1000 patients who took aspirin for five years there were four fewer major cardiovascular events but 7 more episodes of major haemorrhage and no change to overall cardiovascular mortality.

With the widespread use of statins and population wide cancer screenings today, aspirin may no longer reduce the overall risk of cancer death or heart attack when given as primary prevention.

"The good news is that the incidence of cardiovascular disease and colorectal cancer are decreasing due to better control of risk factors and screening, but that also seems to reduce the potential benefit of aspirin."

Although HIV infection rates are high among the transgender community in Russia, many transgender people know very little about the virus, as well as their own health status. In Russia's first study to examine transgender people as an at-risk social group for HIV transmission, demographers attribute these high infection rates to the community's social stigmatization and isolation, as well as a lack of access to medical services. The study's findings have been published in the HSE journal, Demographic Review.

Invisible and Isolated

In Russia, there are more than a million known cases of HIV. Worldwide, according to UNAIDS estimates, this number is 37.9 million. The risk of HIV infection is greatest for individuals who engage in male-to-male sexual contact, use intravenous drugs, work in the sex trade, as well as those being held in the Russian penitentiary system.

Another at-risk demographic group is the transgender community. The term 'transgender' is an umbrella term that refers to people whose gender identity differs from what is usually associated with the sex that was assigned to them at birth.

The term may refer to individuals who have undergone surgery or hormone treatment to bring their bodies into alignment with their gender identity, as well as individuals who have not undergone any medical treatment. The term also includes individuals who are nonbinary, i.e., those who do not identify with either biological sex. Currently, nonbinary gender is officially recognized in only a few countries (including India, Canada, Australia, and some US states).

Transgender people are perhaps the most isolated and invisible social group. In Russia, as in most countries of the world, their official numbers are unknown, and there are no statistics. Conducting even an approximate transgender community 'census' is difficult: transgender Russians generally do not respond to survey attempts due to society's unacceptance and stigmatization of the community.

For this same reason, transgender people form one of the most vulnerable social groups: transgender citizens feel excluded from society. When transgender people transition, they often lose their jobs and are shunned by their families. They are forced to move and apply for new documents (passport, birth certificate, as well as a new social security account, insofar as the retirement age in Russia is determined by gender). Consequently, transgender people feel like outcasts. They develop problems with substance abuse and fall victim to sexual violence. Transgender people also find it difficult to find employment, which causes some of them to resort to sex work.

These conditions, on the one hand, make transgender people especially vulnerable to HIV (in Russia, the transmission of the virus through sexual contact has increased, though in many regions of the country, the main form of transmission remains intravenous drug use). On the other hand, these conditions make it difficult to estimate the number of people infected with the virus and provide treatment. 'Making contact with the transgender community from the outside is very difficult, and it is even more difficult when promoting prevention awareness,' the researchers write. Confidential conversation is possible only with a 'peer-to-peer' approach, i.e., when a transgender person can talk with a fellow member of the community.

Researchers used the 'peer-to-peer' approach in telephone interviews with a sample of transgender people. The sample consisted of 224 individuals who have undergone corrective surgery at a sex correction clinic in Moscow.

Among those surveyed, almost three quarters (72%) had transitioned from male to female (mtf), and 28% had transitioned from female to male (ftm). The average age of those surveyed was 29.3 years. The researchers measured participants' HIV awareness by using the UNAIDS questionnaire.

Indifference and Misconceptions

The survey confirmed a high HIV infection rate. Of the 224 respondents, almost half (105) reported that they are HIV-positive. The other half of respondents (112) reported that they 'were not interested in learning their status.' This, however, say the researchers, 'does not mean that these respondents are not HIV-positive.' Of the sample, seven respondents reported that they know they are HIV negative.

These figures show that transgender people are poorly informed about the Human Immunodeficiency Virus. Moreover, respondents not only showed a lack of awareness about the disease, but reported a lack of interest in knowing their own HIV status.

'A significant portion of those we surveyed do not care if they have the virus or not,' the authors note.

Respondents demonstrated a lack of awareness about how HIV is transmitted:

29% of respondents believe that HIV is not transmitted through shared use of syringes, needles, and rinse water.

13% believe that one can contract HIV by sharing baths, toilets, dishes, or towels with someone who has the virus.

13% believe that HIV can be transmitted through kissing.

17% believe that mosquitoes can become carriers of the virus and that it can be spread through mosquito bites.

9% feel confident that they can identify a person who is HIV positive based on their appearance.

9% of respondents do not distinguish between HIV and AIDS.

'If we summarize all of the incorrect answers we received to the survey's basic questions about what HIV is, then we can conclude that about half of the respondents do not know certain facts about the immunodeficiency virus and, more significantly, have misconceptions about it, which is considerably worse,' the researchers say.

Transmission

Among HIV-positive respondents, 12% believe they contracted the virus sexually, and 44% cite shared syringe use. 38% believe that they contracted virus during a blood transfusion.

Respondents most likely did not always answer the question about how they contracted the disease truthfully. 'It is likely that drug use is the true source of transmission rather than a blood transfusion performed at a clinic, because if that many people contracted HIV in medical clinics, that would be a public health crisis,' the researchers note. The Russian Ministry of Health investigates every reported case of infection at a medical institution. 'We don't know of any investigations of cases that concern blood transfusions performed on transgender individuals,' the authors say.

Lack of Awareness

For the largest portion of respondents, the main source of information about the virus is the Internet: over a third of respondents (34%) cited the Web as their main source of information. Television as a source comes in second place at 29%. The press, as well as family and friends, were each cited by 14% of respondents. Other sources were named by 9% of participants. Of these other sources, school and university lectures were cited by less than 1% of respondents.

'In theory, schools and universities are places where young people (most of the respondents) should be able to receive reliable information about HIV in the first place,' the researchers suggest. 'However, young people aren't receiving it at these places.' Furthermore, the researchers says, 'there is reason to doubt the adequacy of information' from the Internet or the media, which is disseminated by sources who themselves do not have sufficient knowledge about the virus and how it is transmitted.

The researchers also asked respondents how they think the problem of low public HIV awareness should be solved. Most identified the same sources from which they themselves learned about HIV, while also emphasizing the importance of schools and universities hosting awareness events and educational lectures.

In general, respondents think it should be up to the government to raise awareness. 'The traditions of state paternalism are strong, and the first thing that many respondents say is "the government should",' the authors observe.

Risks and Consequences

Over two thirds of the HIV-positive respondents report undergoing antiretroviral therapy, while one third does not. The researchers purposely did not study the reasons behind this. However, they note, this indicates that these individuals are either 'unable or unwilling to undergo treatment.'

The study also reveals that, of those surveyed, one out of every three does not tell their partner that they have HIV.

This has serious consequences. 'If the couple is in a long-term relationship, the probability of transmission is high, and this can be considered intentionally transmitting a sexually transmitted disease,' the researchers say.

Given the isolation of the transgender community, organizations that work with the community should address these problems, the researchers say. 'For starters, efforts should be made to include transgender people in the general Russian healthcare system, so that they are not afraid to go to the doctor and seek help.' And for this, measures need to be taken to stop the stigmatization of transgender people in Russian society.