Body

One of the first studies to investigate the outcome of COVID-19 infection in patients with blood cancer has been conducted by clinical researchers from Queen Mary University of London and Barts Health NHS Trust.

People with blood cancer are expected to be amongst those at increased risk of COVID-19 infection due to a weakened immune system from the effects of their cancer and the nature of the cancer treatment they receive.

Immunosuppression in blood cancer patients is also predicted to lead to more severe outcomes following infection. However, the present study found that even if patients were actively having intensive treatment for blood cancer that weakened their immune system, they usually recovered from COVID-19 as long as they were otherwise fit and well.

The study, published in the British Journal of Haematology, looked at 35 adult patients with blood cancer who had tested positive for COVID-19 and monitored them for a minimum of 14 days. At the end of the observation period, 60 per cent of patients had recovered from COVID-19 infection.

The observations revealed that age was the most significantly associated factor with COVID-19 infection outcome, with almost all of the patients who died being aged 70 years or older at the time of COVID-19 diagnosis. Patients who died also had significantly more co-existing health conditions, such as hypertension, chronic kidney disease or diabetes, than those who recovered from the virus.

Lead author of the study, Dr John Riches from Queen Mary University of London said: "Although this is a small and preliminary study, it is a first step in understanding the risk posed by COVID-19 to patients with blood cancers. At the current time, all patients with certain blood cancers are being advised to 'shield' to try to minimise the risk of getting the virus. However, this study suggests that the risk of COVID-19 to younger patients with few or no medical conditions aside from their blood cancer is less than the risk to older patients with lots of other medical conditions."

The data showed no correlation between blood cancer treatment and outcome following COVID-19 infection, and suggest that while patients with blood cancers have poorer outcomes than the general population after COVID-19, the majority still survive. While this is the largest study to date to examine the clinical outcome of COVID-19 infection in patients with blood cancer, the findings will need to be confirmed in large national and international registry studies.

When obesity occurs, a person's own fat cells can set off a complex inflammatory chain reaction that can further disrupt metabolism and weaken immune response--potentially placing people at higher risk of poor outcomes from a variety of diseases and infections, including COVID-19.

A study laying out the details of this newly revealed cellular process was led by scientists at Cincinnati Children's and the University of Cincinnati College of Medicine and was published online June 2, 2020, in Nature Communications.

The team reports that type I interferons, a class of substances produced by immune cells also are produced by fat cells called adipocytes. These interferons drive a constant low-level, chronic immune response that amplifies "vigor" to a cycle of inflammation within white adipose tissue (WAT). More commonly known as white fat, this is the type of fat that expands to form most of the unwanted bulges around our thighs, arms and bellies.

This inflammation, in turn, appears to drive a cascade of cellular responses that promotes obesity-related disease, especially type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).

"Our novel study reveals how Type I Interferon sensing by adipocytes uncovers their dormant inflammatory potential and exacerbates obesity-associated metabolic derangements. Further, our findings highlight a previously underappreciated role for adipocytes as a contributor to the overall inflammation in obesity," says Senad Divanovic, PhD, corresponding author and a researcher in the Division of Immunobiology at Cincinnati Children's.

HEALTH RISKS OF OBESITY INCLUDE POOR INFECTION OUTCOMES

Obesity affects more than 600 million people worldwide--and the US has the highest average adult body mass index (BMI) of all high-income countries. By 2030, roughly half of the U.S. population could become obese.

Long known as a major risk factor for type 2 diabetes, NAFLD, cardiovascular disease, and diverse cancers, obesity also has been linked with elevated susceptibility and risk of developing serious complications to infection.

Obesity also was an independent risk factor for severity and mortality in the 2009 H1N1 influenza pandemic, and is a risk for hospital admission and poor outcomes among those infected in the current COVID-19 pandemic.

Many studies have shown that obesity is much more complicated than simply eating too much or not getting enough exercise. Previous work has shown that obesity also reflects the outcome of various disruptions to how the body converts food into energy for our cells.

However, only recently have scientists begun to suspect that these excess calories could reshape fat cell behavior to affect the immune system.

ADIPOCYTES REVEALED AS NEW TARGET FOR TYPE 1 INTERFERONS

The new study shows how type 1 interferons operate along an axis of interaction with IFNa receptors (IFNAR) to trigger a vicious cycle of inflammation. Among the effects: changes in expression of several genes associated with inflammation, glycolysis and fatty acid production.

For example, mice fed an obesity-inducing diet displayed an augmented type I IFN signature including increases in Ifnb1, Ifnar1, Oas1a, and Isg15 gene expression, the team reported.

Importantly, many of the metabolic changes documented in mice were found to be conserved in human adipocytes.

This activity was unexpected, because until now most scientists have studied type 1 interferons in relation to viral infections and immune cell function.

"Our observations suggest that the type I Interferon axis can alter adipocyte core inflammatory programming to converge them closer to that of an inflammatory immune cell. Additionally, type I Interferons modify the metabolic circuit of adipocytes, which to our knowledge is the first depiction of immune-mediated modulation of adipocyte core metabolism," Divanovic says.

WHAT'S NEXT?

Further investigation continues into the specific mechanisms that type I Interferons employ to modify adipocyte core metabolism. In addition, researchers continue to study the full extent of how adipocytes can "mimic" inflammatory immune cell capabilities.

"These findings directly impact an extensive number of patients, both adult and pediatric," Divanovic says.

Beyond diabetes and NAFLD, the interplay between obesity and the immune system appears to increase risk of preterm birth and may reduce the body's ability to fight off infections--including viruses such as COVID-19.

"Academic emergency departments never deny emergency care to any person." That is the statement put forth in a commentary from the Board of Directors of the Society for Academic Emergency Medicine and the Senior Editorial Board of Academic Emergency Medicine journal. The commentary, to be published in the June issue of Academic Emergency Medicine, was written in response to recent news stories stating that patients with symptoms of COVID?19 were "turned away" from emergency departments. The commentary addresses these serious allegations, with an attempt to provide the perspective of academic emergency departments (EDs) around the nation.

In the COVID-19 environment, acute unscheduled care in emergency departments has changed. Subsequently, hospital responses designed to protect patients from COVID-19 might give patients the impression that less was done in the emergency care setting. Combined with unprecedented social isolation policies and uncertainties surrounding access to and accuracy of diagnostic testing, available therapies, and mortality estimates, understandable fear and confusion can quickly transform to anger.

The commentary strongly asserts the legal, historical, and ethical obligation of academic emergency departments to provide safe evaluation and care to anyone, anytime. Notably, under the Federal Emergency Medical Treatment and Labor Act (EMTALA), no ED that receives funding from Medicaid or Medicare can "turn away" any patient. Every patient must receive a medical screening examination to determine that no emergent medical condition exists prior to discharge. This applies for all 120 million patients who visit an ED each year regardless of the ability to pay, race, ethnicity, creed, gender, sexual orientation, physical ability, or any other human factor.

D. Mark Courtney, MD, professor of emergency medicine and executive vice chair of academic affairs at UT Southwestern Medical Center, commented:

"I used this article to talk to a group of 30 medical students via a video conference platform on the current state and future of emergency medicine. These are the future pipeline of doctors who will be providing care for us 5, 10, 20 years from now. They wanted to know how emergency care has changed in this pandemic and why? They pointed to things they had seen on Twitter and wondered. I told them to check out this article and to realize that they were joining a group of doctors who had both a legal, historical, and ethical basis for providing safe evaluation and care to the sickest of the sick as well as those less ill but filled with fear and uncertainty. That the leaders of our academic society and journal came together to write this article is a strong statement to how committed and unified we are to be there 24/7 for all."

Lung cancers account for approximately 25 percent of all cancer deaths. Even among those who do not smoke, 1 in 15 men and 1 in 17 women are expected to develop lung cancer in their lifetime, according to the American Cancer Society. Lung cancer has confounded scientists who strive to develop better therapies for this aggressive and deadly disease.

About 15 percent of lung cancers are classified as small cell lung cancer. Recent studies have indicated that four major subtypes of small cell lung cancer exist, yet approaches to tailor treatment of these subtypes have not yet become standard of care. Today in the journal Cancer Cell, scientists outline new findings about the origins of these lung cancer subtypes, paving the way for a new foundation to study this disease.

Trudy Oliver, PhD, a lung cancer researcher at Huntsman Cancer Institute (HCI) and associate professor of oncological sciences at the University of Utah (U of U), is working to improve our ability to fight this disease. Prior work in her lab helped create a mouse model of small cell lung cancer, providing researchers with a sophisticated tool to better understand how this disease progresses and to analyze potential treatment approaches. According to Oliver, "Small cell lung cancer has historically been treated as a single disease, which has been an unsuccessful approach for most patients. Thanks to rapid advances in the field, we now understand that each type of small cell lung cancer has specific traits--including traits that may help us understand better ways to tailor treatment for patients."

U of U graduate student Abbie Ireland, a member of Oliver's team and first author on the study, developed a new assay that allowed the team to follow single cells from tumor samples and observe how they change over time. Ireland and colleagues found that the major subtypes of small cell lung cancer are not so discretely different after all. Rather than thinking of them as distinct diseases, the team found that one tumor subtype can evolve to become a different subtype. And further, a tumor may have cells representing multiple subtypes at any given time.

"Human development involves multiple stages--infancy, adolescence, and adulthood. While we are humans at each of those stages, we have unique characteristics and behaviors at each stage," says Oliver. "Our data suggest that small cell lung cancer is the same way, that it changes at different stages and displays unique characteristics and behaviors in each stage." Oliver's team believes this means small cell lung cancer will have unique vulnerabilities as it evolves. To treat these sophisticated tumors may require a therapeutic approach that acknowledges the tumors are a "moving target" and that treatments need to evolve over time with the tumor. It is also possible these cancers will require combinations of drugs that can target multiple subtypes of the tumor at the same time.

This finding may also aid in understanding other cancers known to have subtypes, such as breast cancer or glioblastoma. The team speculates that subtypes in other cancers may also represent stages of tumor evolution.

Through a collaboration with HCI lung cancer physicians, Oliver was able to access samples of tumors donated by 21 patients who had surgeries at HCI. Tumor samples of small cell lung cancer are very difficult to obtain, and this opportunity to study tumor traits from tumors donated by patients was important to advance insights into this disease. Ireland and her colleagues analyzed tumors for markers of small cell lung cancer subtypes and found that many tumors had markers of more than one subtype, consistent with their ability to change subtype or evolve. Additionally, through a collaboration at Washington University in St. Louis, the team studied one human tumor at the single-cell level using a relatively new, advanced technology called single-cell RNA sequencing.

Oliver's group further showed that a gene called MYC, which is known to promote tumor growth in many cancers, appears to be responsible for driving the evolution of small cell lung tumors.

"Together, the results of these human tissue analyses revealed that small cell lung cancer tumors indeed harbor multiple subtypes," says Oliver. Oliver posits this may explain why so many therapies have failed for small cell lung cancer in clinical trials. Since the tumor is naturally evolving, there may need to be multiple, simultaneous treatments in order to be effective.

Oliver's team now plans to investigate how the evolution of tumors may affect response to various therapies.

Scientific evidence suggests that cancer can metastasize to other organs when either a single cell or a cluster of cells detaches from the original tumor and travels through the blood to another location, where it grows into a new tumor. Clusters seem to have a higher metastatic potential than single cells, and a report published in Nature Cancer shows new insights into what contributes to the clusters' selective advantage.

The researchers found that clusters of tumor cells are more resistant than single tumor cells to being killed by natural killer (NK) cells, immune cells that specialize in surveillance and destruction of tumor cells. Being more resistant to NK cell-mediated destruction led to a disproportionally higher representation of cluster metastasis. The findings suggest that enhancing the natural ability of NK cells to eliminate circulating cancer cell clusters may provide a complementary approach to cancer therapy.

"We were working with different animal models investigating why tumor clusters seemed to be better at forming lung metastases than single cells, when we unexpectedly discovered that the clusters' ability to metastasize appeared to be associated with the presence of competent NK cells," said first author Hin Ching Flora Lo, graduate student in Baylor's Integrative Molecular and Biomedical Sciences Graduate Program. She is a member of the lab of Dr. Xiang Zhang, professor of molecular and cellular biology and the Lester and Sue Smith Breast Center at Baylor.

The researchers determined that activated NK cells can eliminate both single cell and cluster metastasis, but they are more efficient at eliminating the former. The clusters have a selective advantage and, as a result, their contribution to metastasis is higher than that of single cancer cells.

"We also explored what mediated the clusters' resistance to NK cell killing and discovered that cancer clusters seem to tone down the activity of NK cells against them," Lo said. "Clusters display on the cell surface more molecules that inhibit the activity of NK cells and fewer that increase their activity. As a result, when NK cells bind to clusters to destroy them, the combined effect is reduced killing activity."

This phenomenon may represent an additional survival advantage complementary to other previously known characteristics of cancer clusters, such as being resistant to chemotherapy.

"Our study highlights the importance of NK cells in immunotherapy. Activated NK cells act fast, and efficiently kill tumor cells. They use a killing mechanism that is similar to the mechanism T cells use, but recognition of the tumor cells is different. That's one of the reasons we think that enhancing NK-mediated killing ability may provide a complementary approach in immunotherapy," said Zhang, a member of Baylor's Dan L Duncan Comprehensive Cancer Center and a McNair Scholar.

Several months into the pandemic, most Americans are familiar with the physical toll COVID-19 takes on those who contract it. But what about the mental and emotional implications of stress caused by the pandemic itself?

A new study by researchers from the University of Connecticut provides the first snapshot of the immediate impact of COVID-19 on Americans' stress levels, coping strategies, and adherence to public health guidelines.

For the study, which was published in the Journal of General Internal Medicine, the team surveyed over 1,000 English-speaking individuals, 18 years of age or older, living in the United States. Responses were collected in early April 2020, giving the researchers a unique view of how Americans are handling their new reality.

"Almost overnight, the rapid emergence of the COVID-19 pandemic in the United States and subsequent state and federal prevention measures dramatically altered daily behavior," says Crystal Park, professor of in the Department of Psychological Sciences. "This unique, early study and our planned future work will let us see how Americans navigate all of these changes, and how their response to this stress evolves over time."

In the study, the UConn researchers present baseline data on COVID-19-related stressors in three categories: stress related to the virus itself, stress related to changes in daily routines caused by the pandemic, and financial or resource-related stress. These measures allowed them to examine the circumstance-specific stressors of COVID-19 rather than global stress that could have other causes.

Based on previous work during SARS outbreaks and the early months of the COVID-19 pandemic, the researchers created an assessment of 23 COVID-19 stressors and their degree of stressfulness. The survey showed that Americans have high stress exposure from COVID-19, and that some demographic groups appear particularly vulnerable to stress effects. Reading or hearing about the severity and contagiousness of COVID-19 was the most common stressor, with almost 97% of survey respondents experiencing it. Uncertainty about the duration of social distancing requirements and changes to social and daily personal care routines also ranked high on the list of stressors with between 80% and 88% of those surveyed experiencing them.

While fears related to the virus itself were the most common, the survey showed that respondents were more acutely concerned about the financial consequences caused by the pandemic. Of the stressors experienced, respondents ranked loss of job security or income as the most stressful, followed by risk of a loved one's illness.

The researchers also looked at the methods Americans reported using to cope with these stressors. Distraction, seeking emotional social support, and active coping were the most commonly reported strategies. Younger participants, sexual minorities, and those with greater financial instability generally reported greater use of less helpful strategies, including substance use, behavioral disengagement, and humor.

Because of the unprecedented nature of the COVID-19 pandemic, the researchers say it's hard to determine which strategies will be healthy for managing stress over the weeks and months ahead.

"Distraction or avoidance is usually considered to be an unproductive coping strategy for most challenging situations and can lead to negative outcomes," says Beth Russell, associate professor of Human Development and Family Sciences and director of the Center for Applied Research in Human Development (CARHD). "But in this instance where people don't have much control over making the disease itself better, we can do small things to help ourselves and others - seek connections through telemediated emotional support, for example - and find ways to let the time pass. We'll see in the long run how those strategies help people's mental health."

The survey also showed very high rates of compliance with social distancing and federal Centers for Disease Control and Prevention (CDC) guidelines. Approximately 95% of respondents avoided eating out at bars or restaurants and visiting nursing homes, although these behaviors are likely impacted by policies enacted at the state and municipal levels. Almost 90% of respondents had stopped discretionary travel and were keeping the recommended six-feet distance from others. Approximately 75% of respondents reported adhering to CDC guidelines related to hygiene, like avoiding touching their faces and regularly cleaning and disinfecting surfaces. Some of the reported behaviors showed a potentially worrisome lack of adherence to critical CDC guidelines though, particularly for men and younger adults.

The role demographics play in stress, coping, and adherence to guidelines will be the focus of future studies by the team. Those results will be important for clinicians and policymakers as they develop the most effective health interventions to stem the anticipated long-term mental health impacts, they say.

"As we focus on developing treatments and vaccines, it is critical that we also understand the social aspects of this virus," says Michael Fendrich, associate dean for research in UConn's School of Social Work and co-author of the paper. "Understanding how Americans experience and respond to COVID-19 stressors and how this varies by socio-demographic characteristics can help to more effectively target prevention measures across various groups."

The team is continuing to monitor Americans' response to stress from the COVID-19 pandemic in future longitudinal waves of this study, which they hope will inform effective health behavior interventions to stop its spread.

ANN ARBOR, Mich. - Adults and children with type 1 diabetes will spend an average of $2,500 a year out-of-pocket for health care - but insulin isn't always the biggest expense - new research suggests.

While out-of-pocket costs for insulin was substantial, it accounted for just 18% of total out-of-pocket expenses for health care, according to the findings in JAMA Internal Medicine.

In fact, insulin accounted for less out-of-pocket spending than diabetes-related supplies, such as insulin pumps, syringes, and continuous glucose monitors.

"Insulin is the difference between life and death for patients with type 1 diabetes, and efforts to make it more affordable are critical," says lead author Kao-Ping Chua, M.D., Ph.D., a pediatrician and researcher at Michigan Medicine's C.S. Mott Children's Hospital and the Susan B. Meister Child Health Evaluation and Research Center.

"However, our study shows that even if insulin were free, families would still have substantial out-of-pocket costs for other health care. Policymakers should improve the affordability of all care for type 1 diabetes."

Eight percent of patients in the study spent at least double the average with more than $5,000 in out-of-pocket costs, possibly because they were enrolled in high-deductible health plans or had particularly great health needs, authors say.

Families of children spent the most on diabetes-related supplies, with annual out-of-pocket costs averaging $823 for pediatric patients compared to $445 for adult patients. The study found that 4 in 5 children used insulin pumps, continuous glucose monitors, or both, compared with just over half of adults.

"These technologies can improve quality of life and improve diabetes control for all patients, but can be especially important to the families of children with type 1 diabetes," Chua says.

Chua notes that many adults are comfortable checking their glucose and injecting insulin manually. But for young children who may be leery of needles or adolescents who forget to take insulin, automating the process of glucose monitoring and insulin delivery can be particularly beneficial for diabetes management.

Diabetes devices have been proven to improve diabetes control and reduce risks of hypoglycemia - a condition in which blood glucose drops dangerously low.

The Michigan-led study is based on national data of 65,199 patients ages 1-64 in 2018 who received private employer-sponsored insurance coverage. This included 7,842 children. The dataset did not include patients covered by Medicare or Medicaid or those without insurance.

Chua says the study's findings are particularly timely given recent efforts to cap out-of-pocket costs for insulin. Several states and insurers imposed monthly caps on these costs earlier in 2020. The Centers for Medicare and Medicaid Services just announced that many elderly Medicare beneficiaries will soon pay no more than $35 for a one-month supply of insulin.

"These are important first steps," says Chua. "But policymakers also must look at the bigger picture and ensure that they are reducing the financial burden of health care for diabetes patients more broadly."

One way to do this, says Chua, is to follow the example of a 2019 IRS rule that allows patients in high-deductible health plans to receive coverage for insulin, diabetes testing, and glucometers before deductibles are met. He believes this policy should be extended to all plans and to more services.

"It's crucial to remove barriers to accessing high-value care that improves outcomes," Chua says.

Health care affordability for patients with type 1 diabetes is especially concerning, because of economic hardships from the COVID-19 pandemic, Chua says.

"Many people with private insurance have lost their jobs and insurance coverage," he says. "This may put health care like insulin and diabetes-related supplies out of reach."

What The Study Did: How the COVID-19 pandemic is associated with national enrollment in cancer clinical trials is investigated in this study.

Authors: Joseph M. Unger, Ph.D., of the SWOG Statistics and Data Management Center and the Fred Hutchinson Cancer Research Center in Seattle, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.10651)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

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About JAMA Network Open: JAMA Network Open is the new online-only open access general medical journal from the JAMA Network. On weekdays, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.

Synlogic, Inc., (Nasdaq: SYBX) a clinical stage company applying synthetic biology to beneficial microbes to develop novel, living medicines, today announced the publication in Nature Communications of preclinical data supporting its first clinical immuno-oncology program, SYNB1891, which is being evaluated in a Phase 1 clinical trial in patients with advanced solid tumors or lymphoma. Data described in the publication demonstrate that SYNB1891 treatment cleared tumors and stimulated antitumor immunity in preclinical models of cancer.

"The targeted delivery and dual immune stimulatory activity of SYNB1891 offer distinct advantages over other approaches," said Aoife Brennan, M.B., Ch. B., Synlogic's president and chief executive officer. "The preclinical data published today highlight the transformative potential of SYNB1891. Together with the early experience in the clinic demonstrating feasibility and tolerability in the initial cohorts of the clinical trial, these data provide support for the continued development of SYNB1891 as a potential therapeutic option to expand the benefits of immunotherapy to more patients with cancer."

The publication titled, "Immunotherapy with an engineered bacteria by targeting the STING pathway for anti-tumor immunity," details the engineering and characterization of SYNB1891. The work describes preclinical studies that demonstrate anti-tumor activity and generation of immunological memory by SYNB1891 in mouse models of cancer, as well as its robust activation of human antigen presenting cells (APCs) that are key to the generation of an anti-tumoral immune response.

SYNB1891 is an engineered strain of E. coli Nissle, that produces cyclic di-AMP (CDA), a stimulator of the STING (STimulator of INterferon Genes) pathway. This mechanism can play a critical role in the initiation of an anti-tumor immune response via activation of APCs and presentation of tumor antigens. The bacterial chassis of SYNB1891 also stimulates the innate immune system by several other mechanisms, including via Toll-like receptors (TLRs), potentially adding to the magnitude of the overall immune response. A notable advantage of SYNB1891 is that the STING agonist is not released by the bacteria until they have been engulfed by the target cells (APCs) and so there is less risk of deleterious effects on other immune cells such as T-cells. Also, while SYNB1891 has been engineered with safety features that are designed to prevent its replication unless supplemented with specific nutrients, the bacteria remain active for several days within the injected tumor to stimulate a local immune response.

Intra-tumorally administered SYNB1891 is being evaluated as a monotherapy in an ongoing Phase 1 open-label, multicenter, dose escalation clinical trial (NCT04167137) in patients with advanced solid tumors or lymphoma. Synlogic expects to release data from the monotherapy arm of this study in late 2020. After establishing a maximum tolerated dose for SYNB1891 as monotherapy, Synlogic expects to initiate a second arm of the trial in which subjects will receive escalating dose levels of SYNB1891 in combination with a fixed dose of the checkpoint inhibitor, atezolizumab (Tecentriq®), to establish a recommended dose for the combination regimen.

New research conducted by the University of Liverpool and AKL Research and Development Ltd (AKLRD), published in Inflammopharmacology, highlights the potential benefits of a new drug treatment on the human body's immune response in inflammation.

In a number of inflammatory conditions, such as osteoarthritis, rheumatoid arthritis and, more recently, COVID-19, major complications and extensive tissue damage can occur when the immune system becomes excessively and uncontrollably activated. Finding new ways to selectively control this over-activity could have major clinical benefits.

Neutrophils

To be healthy, we need an effective immune response, otherwise we would succumb to overwhelming infection, even by everyday bacteria. However, sometimes our immune system can become hyperactive and cause damage through inflammation, even in the absence of any infection. This can sometimes be extreme. Indeed, many rheumatic diseases such as rheumatoid arthritis and osteoarthritis are caused by inflammation. The quest has always been to find ways to selectively block the harmful effects of an overactive immune system, without paying the price of blocking our ability to fight infections.

Neutrophils are the most abundant immune cells in our blood. They are rapidly dispatched to sites of infection, where they fulfil their life-saving antimicrobial functions by destroying infectious organisms and producing signalling proteins called cytokines, that help co-ordinate the recruitment and activity of other immune system cells to the battle against the infection. There is much evidence from work in Liverpool to show that these cells are important players behind many rheumatic diseases

Cytokine storms and COVID-19

In some situations, if the levels of cytokines are too high, they can trigger an extreme inflammatory reaction called a cytokine storm. These storms cause overwhelming inflammation that leads to blocked or ruptured blood vessels. This can affect the entire circulatory system. Cytokine storms can cause immense damage, multiple organ failure, sepsis, and even death and, appear to play a major role in severe COVID-19 disease.

For many decades scientists and clinicians have understood the potential benefit of suppressing neutrophils, but any attempt to do this without weakening the immune response to infection has failed.

APPA

APPA* is a novel drug under development by AKLRD for use in osteoarthritis, a major disabling problem world-wide that is caused by low grade inflammation. The first part of its formal clinical evaluation in Liverpool, led by rheumatologist Professor Robert Moots, has recently been successfully completed. Now, in partnership between Liverpool and AKLRD, the impact of the drug on neutrophils has been examined and published.

The study found that APPA clearly demonstrated anti-inflammatory potential but without weakening host defence to infection.

Robert Moots, Professor of Rheumatology at the University of Liverpool and Director for Research and Development at Aintree University Hospital, said: "We have shown that APPA has the potential to dampen down that bad inflammation that causes rheumatic diseases - but not impact on the crucial antimicrobial function of neutrophils. We have been waiting for too many years for such a selective drug".

"Our results suggest a prime role for APPA in helping safely modify aggressive immune response, not only in the arthritis that I treat every day, but even, potentially, in COVID-19."

Professor Steve Edwards, a neutrophil scientist on the project at University of Liverpool said: "Therapeutically targeting the harmful effects of neutrophils in inflammation, without interfering with their ability to fight off infections, has been a long-term goal of many scientists worldwide. At last, we may be able now to realise this goal."

David Miles, CEO of AKLRD said: "These exciting results underpin the favourable clinical results observed in patients with Osteoarthritis, whilst also suggesting APPA has an important role to play in treating a broad range of conditions where inflammation is involved".

(New York) June 01, 2020 - Genetic testing for cancer risk can significantly improve the prevention or treatment of hereditary cancers, but studies have shown that people who might have a genetic risk often don't get tested. A collaborative Stand Up To Cancer 'Dream Team' of researchers co-funded by Ovarian Cancer Research Alliance and the National Ovarian Cancer Coalition have tested a possible solution through a clinical trial aimed at making genetic testing more accessible.

The trial, called MAGENTA (Making GENetic Testing Accessible), engaged nearly 4,000 women from all 50 US states. It is the first large, randomized study to assess different combinations of remote pre- and post-test genetic counseling for cancer risk. The results, which were presented recently at the American Society of Clinical Oncology's annual meeting, showed that genetic testing can be provided remotely and that genetic counseling before and after testing can be skipped without causing increased distress to patients undergoing genetic testing from their home.

"The MAGENTA trial results are especially relevant now given the fact that the coronavirus pandemic is necessitating the timely and effective delivery of virtual healthcare," said Elizabeth Swisher, MD, co-leader of the Dream Team and director of the Division of Gynecologic Oncology at UW School of Medicine. "There are many benefits to this new design, so I do see genetic testing for medical purposes headed in this direction, regardless of the pandemic."

The trial began in 2016 and ended in 2020. All of the women who participated in the trial had a family history of breast or ovarian cancer or had a family member with a known genetic mutation. Each participant underwent genetic testing for 19 genes associated with inherited cancer risk. Testing was done using a saliva kit provided by Color Genomics, which was mailed to each trial participant's home and then returned by standard mail.

"Ovarian Cancer Research Alliance is so pleased to have played a pivotal role in this important and timely project," said Audra Moran, President and CEO of Ovarian Cancer Research Alliance. "Better understanding your risk of ovarian cancer is one of the most important things a woman can do to empower herself against the disease. We hope the results of this study will lead to easier access to potentially life-saving genetic testing for more people."

Trial participants were split into four groups. In every group, women watched an educational video on genetic testing for cancer risk before completing their test. In the standard group women had mandatory genetic counseling by phone before and after testing. In the other three groups women skipped the pre-test counseling, the post-test counseling or both. In all four groups, anyone with a positive test result had genetic counseling delivered by a telephone appointment.

The study recently completed analysis of the first three-month follow-up survey to determine if the remote counseling methods caused negative feelings such as distress or anxiety for trial participants. Analysis of 12 and 24-month checkup surveys will follow.

Results from the three-month follow-up survey showed that the electronic genetic education methods were effective and skipping personalized counseling did not increase patients' distress. If applied broadly, this can allow medical practitioners to more efficiently provide genetic testing.

Furthermore, skipping pre-test counseling resulted in more follow-through in completing the testing than traditional genetic counseling. Lastly, the approach increased access by eliminating common barriers associated with scheduling and attending several in-person counseling and testing appointments at a medical center or clinic.

"These trial results are not only tangible but empowering for women with inherited risk for ovarian cancer," said Melissa Aucoin, CEO of the National Ovarian Cancer Coalition. "With the vast majority of women diagnosed in late stages, improving preventative measures can have a significant impact on the future of ovarian cancer. We applaud the Dream Team for delivering progress."

"The majority of individuals meeting the U.S. Preventative Services Task Force guidelines for genetic testing have not received genetic testing or counseling," said Karen Lu, MD, principal investigator of the study and professor and chair of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center. "The results of this study demonstrate that using online and remote methods for preventative testing and genetic counseling can be an option to help break down barriers and expand the availability of preventative cancer care."

One family's story

Before Roni Scheller passed away from ovarian cancer at age 59, she encouraged the women in her family to participate in genetic testing. Her two sisters, Pamela and Kyle, as well as her cousin Dalin, all enrolled in the MAGENTA clinical trial.

Dalin and Kyle tested negative. Pamela tested positive for a genetic mutation that significantly increases her risk of breast and colorectal cancer. After discussing the risks and benefits of treatment options with her physician, she decided to have her breasts and ovaries removed as a preventative measure. She is also very diligent about getting regular screening tests for colorectal cancer.

"The whole process felt very empowering to me," said Pamela. "Knowing what my risks were and being able to direct my concerns into action removed the constant 'maybes' and 'what ifs' that I was feeling before the test."

The MAGENTA trial provided all the tools to make the process convenient and smooth, Pamela explained. She doesn't have any regrets and feels like knowing her genetic information gives her peace of mind.

"I feel lucky to live in these times when modern medicine can provide answers. And of course Dalin, Kyle and I will be forever grateful to my sister Roni for encouraging us to participate in the MAGENTA trial," said Pamela.

"This trial is an important validation that it's possible to engage more patients in clinical trials using remote methods," said Sung Poblete, PhD, RN, CEO of Stand Up To Cancer. "It's exciting to see how successful this trial was and how well the remote counseling methods were received by participants."

The current practice of testing most pregnant women for thyroid stimulating hormone (TSH) may be leading to overdiagnosis and overtreatment, according to new research in CMAJ (Canadian Medical Association Journal).

The study of more than 188 000 women in Alberta found that TSH testing was performed in more than half (111 522 or 59%) of all pregnant women who did not have thyroid disease before pregnancy. Testing was most commonly done around gestational week 5-6.

"The practice of TSH testing early in the first trimester may be resulting in overdiagnosis and unnecessary thyroid hormone therapy during and after pregnancy," writes Dr. Lois Donovan, an endocrinologist at the Cumming School of Medicine, University of Calgary, with coauthors.

The challenge with TSH screening in pregnancy is that it identifies many women with very minor elevations in TSH, which is known as subclinical hypothyroidism. The best evidence shows no benefit for the mother or child from treatment of pregnant women with subclinical hypothyroidism.

In 5050 (4.5%) pregnancies with TSH testing, women were started on thyroid hormone therapy; most (99%) received levothyroxine. Almost half of them (44.6%) continued with the treatment after giving birth, and almost one-third (31.5%) received 2 or more prescriptions in the first postpartum year.

"This raises concerns about overmedicalization during pregnancy, given that minor, untreated TSH elevation usually normalized, as indicated by repeat measurement," write the authors. "The frequent postpartum continuation of thyroid hormone therapy for those who started it during pregnancy adds to this concern."

Evidence-based clinical practice guidelines are needed to provide clinicians with the appropriate approach to decide whether and when TSH testing is required in pregnancy and when it is necessary to continue treatment in the postpartum period.

Researchers at Uppsala University and Uppsala University Hospital have developed a new method to measure levels of the medication hydroxychloroquine in patients with the rheumatic disease systemic lupus erythematosus (SLE). The analysis method may also be useful in other areas, such as in the treatment of COVID-19. The study is being published in Arthritis Research and Therapy.

Hydroxychloroquine was originally used to treat malaria but has also proven effective with SLE and rheumatoid arthritis (RA). Today it is recommended to all SLE patients since it protects against flares of the disease. Tests are now being conducted to see if it can also be used to treat COVID-19.

A disadvantage of hydroxychloroquine is its side effects which can be avoided, however, if the dosage is adjusted for each patient.

To achieve the protective effect against flares in SLE while also minimising the risk of side effects, Uppsala researchers have now developed a method that can be used in the medical care system to measure hydroxychloroquine levels in the blood of SLE patients. The method is based on high-resolution mass spectrometry and has been used at Uppsala University Hospital since December 2019.

First, the researchers went through available data on hydroxychloroquine measurements. They saw that results from measurements on whole blood, plasma and serum were not comparable with each other.

"It was shown that there were major differences between different reports, and there seemed to be very large individual differences," says Kim Kultima, Associate Professor at the Department of Medical Sciences at Uppsala University and also active at Clinical Chemistry and Pharmacology at Uppsala University Hospital.

For this reason, his research team conducted a study together with the research team in rheumatology that compared the levels of hydroxychloroquine in plasma, serum and whole blood in SLE patients. They concluded that the levels in whole blood were about twice as high as in serum and plasma. Whole blood analyses were also the most dependable.

"One striking result, and a very important insight, was that levels in whole blood for patients prescribed the same dosage could differ by up to 15 times between individuals. This indicates a large individual variation in how the medication is metabolised."

One problem pointed out by the study is that the services for electronic information on medicinal products in Sweden (FASS) provides concentrations of hydroxychloroquine in plasma. The researchers judge that these values provide an inaccurate and inappropriate picture for monitoring medication levels in patients.

"We also have to be very careful about drawing hasty conclusions about whether hydroxychloroquine is effective with COVID-19. What we know today is that the analysis method will hopefully lead to better data for providing the right dosages to SLE patients who are prescribed the medication."

In collaboration with doctors at the Infectious Disease Clinic and within intensive care at Uppsala University Hospital, there are plans and preparations in place to be able to measure the levels of the medication in the blood of COVID-19 patients if the substance proves effective.

Bottom Line: Among patients with both colorectal cancer and diabetes in Korea, those who had a high adherence to their oral diabetes medication had a significantly reduced risk of overall mortality compared with those with lower adherence.

Journal in Which the Study was Published: Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research

Authors: Senior author Aesun Shin, MD, PhD, professor in the Department of Preventive Medicine at Seoul National University College of Medicine; and first author Sunho Choe, MD, resident physician in the Department of Preventive Medicine at Seoul National University College of Medicine

Background: "It is estimated that only 60 percent of those with diabetes are taking their antidiabetic medications as directed," said Shin. "We wanted to study whether adhering to diabetes medications has an impact on survival among patients with colorectal cancer."

The association between diabetes and increased incidence of colorectal cancer is well established, noted Choe. Further, the use of the antidiabetic medication metformin has been repeatedly shown to improve colorectal cancer survival among those with diabetes, he said. "However, it is estimated that the majority of patients take additional antidiabetic medications along with metformin, and how the combination of these medications affects the prognosis of colorectal cancer remains underexplored," he added.

"We wanted to improve upon prior studies that evaluated how the use of metformin alone impacted colorectal cancer outcomes," Shin said. "To that end, we compared survival outcomes among colorectal cancer patients who had different levels of adherence to all of their prescribed oral antidiabetics."

How the Study was Conducted: To conduct this retrospective cohort study, the researchers used information from the National Health Information Database, which has claims data for those who have national health insurance in Korea, from 2002 to 2016. Individuals who had diabetes and were diagnosed with colorectal cancer in this time frame were included in the study, resulting in a total study population of 33,841 participants. Patients were followed for an average of 4.7 years.

To estimate patients' adherence to their oral antidiabetic medications, the researchers used prescription data to calculate the patients' proportion of days covered (PDC), which is defined as the number of days with medications on hand divided by the number of days in a specified time interval. Adherence to prescribed injectable medications, including insulin, was not measured. The researchers categorized oral medication adherence into two groups for comparison: patients with high adherence had a PDC of at least 80 percent, while patients with low adherence had a PDC of less than 80 percent.

Results: Overall, the researchers found that over 80 percent of patients were taking more than one oral antidiabetic medication. Further, less than 23 percent of patients were in the high-adherence category. Compared with patients with high adherence, those with low adherence to their oral antidiabetic medication had a nearly 20 percent increase in their risk of overall mortality, in both crude and adjusted models. High adherence to oral antidiabetic medication was found to have a protective effect for all colorectal cancer subgroups, with the most pronounced effect observed among patients with distal colon cancer.

"Based on our data, less than 25 percent of patients were taking their diabetes medications as prescribed, suggesting that over 75 percent of diabetic patients with colorectal cancer could benefit by adhering to these prescriptions," said Shin.

The researchers did not have access to some clinical information, including cancer stage, which is an important factor in comparing prognoses between different groups. In lieu of cancer stage, the researchers stratified the study population based on type of cancer treatment received. Patients who had early-stage disease likely received surgery alone, while patients with late-stage disease likely received palliative therapy, such as chemotherapy or radiotherapy without surgery, Shin explained.

The researchers found that patients who received surgery, surgery plus radiotherapy, or surgery plus chemotherapy had a protective benefit if they had high adherence to oral antidiabetic medications. Patients who received surgery with both radiotherapy and chemotherapy or patients who received radiotherapy or chemotherapy without surgery did not have a protective benefit even if they had a high adherence.

Lymphoma is a type of blood cancer that develops from lymphocytes (a type of white blood cell). It has many subtypes. A rare subtype, called intravascular large B-cell lymphoma (or IVLBCL) is notably hard to diagnose accurately because the cancerous lymphocytes grow inside small blood vessels, instead of at lymph nodes, and there is no perceptible swelling/enlargement of lymph nodes. There is also no effective treatment: the disease tends to affect the elderly, for whom standard high-dose chemotherapy may have serious side-effects, and patients are at a high risk of developing subsequent central nervous system (CNS) disorders even with treatment. A novel treatment protocol with fewer side-effects and which also tackles secondary CNS involvement is needed, and this is exactly what a group of scientists, led by researchers from Nagoya University and Mie University, Japan, attempted to test in a new clinical trial.

All of this being said, however, the rarity of this disease has made testing new combinations of drugs difficult. A previous "retrospective" study involving the analysis of medical records of patients who had undergone standard chemotherapy combined with a drug called "rituximab" showed that this line of treatment is more promising than standard treatment alone, but it does not solve the problem of secondary CNS involvement. "We considered that rituximab-containing chemotherapies combined with treatment for the secondary CNS problems could lead to further improvement in the clinical outcome," remarks Dr Kazuyuki Shimada of Nagoya University. With this consideration, Dr Shimada and team conducted a Phase 2 multicenter clinical trial, where they administered their proposed treatment to 38 enrolled patients (aged 20 to 79 years and without CNS disorders at the time of cancer diagnosis) and monitored their conditions over the long term. The results are published in their paper in The Lancet Oncology.

Overall, their treatment protocol appears to be promising: 76% of the enrolled patients reached the primary goal of two-year survival without disease progression and 92% reached two-year overall survival. The disease affected the CNS in only 3% of patients. What's more, the toxicity of the treatment was found to be low, and all adverse effects were manageable, with very few serious complications.

Aptly summarizing their achievement, Dr Shimada says: "To the best of our knowledge, this is the first 'prospective' trial of any treatment in patients with IVLBCL. It appears that the proposed treatment protocol might be effective in patients without apparent central nervous system involvement at the time of diagnosis."

An important advantage of the proposed treatment protocol is that it employs a combination of conventional drugs and uses no novel agents. This means that although further study is necessary, this protocol can be adopted in clinical practice in the very near future. As Dr Shimada explains: "Given the rarity of this disease, a large-scale Phase 3 prospective trial is not feasible. In such a scenario, the results of our trial provide a safe and effective treatment option that can function as a historic control for future prospective trials."

The findings of this clinical trial are certainly quite promising. With only minor refinements to the proposed treatment protocol, patients with IVLBCL could have an edge in their fight against cancer.