Body

A regular dose of aspirin to reduce the risk of inherited bowel cancer lasts at least 10 years after stopping treatment, research has revealed.

The international trial - known as CAPP2 - involved patients with Lynch syndrome from around the world and revealed that two aspirins a day, for an average of two and a half years, reduced the rate of bowel cancer by half.

The study, led by experts at the Universities of Newcastle and Leeds, UK, published in The Lancet today, is a planned double blind 10 year follow-up, supplemented in more than half of recruits with comprehensive national cancer registry data for up to 20 years.

Supports national guidance

The findings of the study further strengthens the National Institute for Health and Care Excellence (NICE) recommendation on taking daily aspirin for those at high risk and supports wider use of aspirin to prevent cancer.

Based on the preliminary five year data from the CAPP2 trial, NICE recommended that aspirin should be offered for the prevention of bowel cancer in adults with Lynch syndrome.

Professor Sir John Burn, from Newcastle University and Newcastle Hospitals NHS Foundation Trust, who led the research, said the new findings further support this important guidance.

He said: "I had an idea 30 years ago that people with a genetic predisposition to colon cancer could help us to test whether aspirin really could reduce the risk of cancer.

"Patients with Lynch syndrome are high risk and this offered statistical power to use cancer as an endpoint - they are like the canaries in the mine who warned the miners that there was gas.

"It took a long time to start the trial and to recruit enough people in 16 countries, but this study has finally given us an answer.

"Two aspirins a day for a couple of years gives protection that lasts more than 10 years and the statistical analysis has become much stronger with time.

"For people at high cancer risk, the benefits are clear - aspirin works. Our new international trial, CaPP3, will see if smaller doses work just as well."

Findings showed that when all original recruits were included in the study, those on aspirin had 42% fewer colon cancers. Among those who took the aspirin for a full two years, there were 50% fewer colon cancers.

The study involved 861 patients with Lynch syndrome, which affects about one in 200 people in the population. These people have a genetic problem with DNA repair, making them at much higher risk of cancers such as bowel and womb.

A group of 427 were randomised to aspirin continuously for two years and 434 were allocated to a placebo and then they were all followed for 10 years. Out of those given two aspirins each day (600mg) there were 18 fewer colon cancers, representing a drop of 42.6%.

When all 163 Lynch syndrome cancers are included in the analysis - such as cancer of the endometrium or womb - there was an overall reduced risk of cancer of 24% in those taking aspirin, or 37% in those who took aspirin for the full two years.

Historic background

Between 1999 and 2005 participants began either taking two aspirins every day for two years or a placebo.

At the end of the treatment stage in 2007 there was no overall difference between those who had taken aspirin and those who had not. However, the research team anticipated a longer term effect and designed the study for continued follow-up.

By 2010 there had been 19 new bowel cancers among those who had received aspirin and 34 among those on placebo. The incidence of cancer among the group who had taken aspirin had halved - and the effect began to be seen five years after patients starting taking the aspirin.

Professor Sir John said: "Aspirin has a major preventative effect on cancer but this doesn't become apparent until at least four years later. With the help of these dedicated volunteers we have learned something of value to us all.

"Before anyone begins to take aspirin on a regular basis they should consult their doctor first as aspirin is known to bring with it a risk of stomach complaints, including ulcers and bleeding.

"However, if there is a strong family history of cancer then people may want to weigh up the cost and health benefits of taking aspirin for at least two years."

The team are now leading a new international trial, CaPP3, with more than 1,800 people with Lynch syndrome enrolled to look at whether smaller, safer doses of aspirin can be used to help reduce the cancer risk.

CHAPEL HILL - June 11, 2020 - As the COVID-19 pandemic continues with many thousands of new infections reported each day, there is a need for widely applicable surveillance testing to gain a better understanding of infection rates, especially the number of infections in people with mild or no symptoms, who can still be carriers. UNC School of Medicine scientists and colleagues developed a new kind of antibody test - a simplified experimental assay that could be ramped up to test thousands of blood samples at labs that do not have the resources of commercial labs and large academic medical centers.

The researchers, who published their work in Science Immunology, created a blood test to pinpoint SARS-CoV-2 antibodies that target one unique piece of the SARS-CoV-2 spike protein. That piece is called a receptor binding domain, or RBD. Their RBD-based antibody test can measure the levels of that domain, which they found correlate to the levels of the all-important neutralizing antibodies that provide immunity.

The RBD of the spike protein in SARS-CoV-2 is not shared among other known human or animal coronaviruses. Therefore, antibodies against this domain are likely to be highly specific to SARS-CoV-2, and so these antibodies reveal if an individual has been exposed to the virus that can cause COVID-19. Indeed, when the researchers tested blood collected from people exposed to other coronaviruses, none had antibodies to the RBD of SARS-CoV-2.

"Our assay is extremely specific for antibodies to the virus that causes COVID-19, which is not the case for some currently available antibody tests," said co-senior author Aravinda de Silva, professor of microbiology and immunology and member of the UNC Institute for Global Health and Infectious Diseases. "Our results strongly support the use of RBD-based antibody assays for population-level surveillance and as a correlate of the neutralizing antibody levels in people who have recovered from SARS-CoV-2 infections."

First and co-senior author Prem Lakshmanane, PhD, assistant professor of microbiology and immunology at UNC, said, "We are now further streamlining our test into an inexpensive assay, so that instead of the test taking four to five hours to complete, our assay could be completed in about 70 minutes without compromising quality."

During the UNC-Chapel Hill campus shutdown, Lakshmanane led a team of researchers including Ramesh Jadi, PhD, Bruno Segovia-Chumbez, and Rajendra Raut, PhD - each designated as an emergency employee - to develop the test from scratch. The team designed new antigens and used a large panel of SARS-CoV-2 patients and control human and animal samples. From day nine after the onset of symptoms and thereafter, the UNC assay allowed the researchers to accurately identify RBD-based antibodies to SARS-CoV-2.

World-renowned coronavirus expert Ralph Baric, PhD, Kenan Distinguished Professor of Epidemiology at the UNC Gillings School of Global Public Health, developed an assay to measure neutralizing antibodies in clinical samples. Assays for measuring neutralizing antibodies take about three days to complete and often require special high-containment facilities necessary for safely working with infectious viruses. The de Silva Lab collaborated with David Martinez, PhD, in the Baric laboratory to test if the RBD-based antibody levels in patients correlated with levels of neutralizing antibodies found in the Baric assay.

"We observed a robust correlation between levels of RBD-binding antibodies and SARS-CoV-2 neutralizing antibodies in individual samples," Lakshmanane said. "This means our assay not only identifies people exposed to SARS-CoV-2, but it can also be used to predict levels of neutralizing antibodies and to identify potential donors for plasma therapy."

The UNC-Chapel Hill researchers have received requests from scientists across the country and around the world for assistance with establishing this new assay within their research laboratories to monitor people for SARS-CoV-2 infection.

"We don't see our research as a means to replace commercial tests," said de Silva, a world-renowned arbovirus researcher. "Commercial tests are critical, especially for making decisions about the clinical management of individual patients. But it's too early in the pandemic to know if the commercial assays are suitable for identifying people who experienced very mild or no disease after infection or if the assays tell us anything about protective immunity, as researchers are still learning about this virus."

He added, "It's important for researchers to stay engaged, to monitor antibody responses and other biological details, and to fine tune assays to meet the different needs of individual patients, the public health community, and vaccine developers."

Having trouble getting around on your own--such as difficulty walking, climbing steps, or being able to get in and out of a chair--can lead to physical disability and losing your independence.

According to research, being physically inactive is the strongest risk factor for disability as we age.

We know that physical activity has proven health benefits, especially moderate-to-vigorous physical activity such as walking to the store or many types of gardening. But perhaps surprisingly, we don't know much about the benefits of lighter forms of physical activity or the effects of spreading our physical activity throughout the day. Understanding the benefits of moving more often and engaging in even lighter forms of physical activity is important for older adults' health. These types of physical activity may be easier for older adults to practice regularly, especially those who are frail.

That's why a team of researchers created a study to examine the effects of performing light physical activity and moderate-to-vigorous physical activity on older adults. The researchers were interested in studying how participating in these different intensities of activity, and whether a person spreads their physical activity throughout the day, affects the chances for developing a major mobility disability. The participants in the study were older adults who had challenges with physical function and who participated in the Lifestyle Interventions and Independence for Elders (LIFE) study. The researchers published their study in the Journal of the American Geriatrics Society.

The LIFE study examined whether a long-term exercise program could improve a major mobility disability. For the purposes of the study, the researchers considered that participants had a "major mobility disability" if they were unable to walk 400 meters (about one-quarter of a mile, or five city blocks).

The people in the study ranged in age from 70 to 89 years old. Before the study, participants got less than 20 minutes of exercise a week, were able to walk 400 meters in less than 15 minutes, and were determined to be able to safely participate in the study.

The participants were divided into two groups: an exercise group and a group that received health education with no exercise. By the sixth month of the study, the participants in the exercise group performed an additional 40 minutes a week of moderate to vigorous exercise, which they continued after 12 months and 24 months.

The focus of the exercise program was on aerobic activity (exercises that increase your breathing and heart rate), specifically walking. Participants had a goal of completing 150 weekly minutes of moderate to vigorous exercise paired with brief balance, flexibility, and lower-body strengthening exercises. Participants aimed to exercise five to six days per week, including two weekly center-based exercise sessions. For the few weeks of training, participants advanced from exercising at a light intensity to a walking intensity they felt was at least "moderate."

Of the participants, 818 were randomly assigned to the exercise program and 507 individuals had "accelerometer" information at the beginning of the study. An accelerometer is similar to a pedometer, but it measures both amount and intensity of physical activity.

The researchers found that the intensity of physical activity, as well as the way that physical activity is spread throughout the day, should be matched to each individual's physical health to minimize their likelihood for developing major mobility disability.

First, they recommend that frail individuals focus on building strength and balance as a key step in preventing mobility disability. Next, as strength and balance develop, older adults should focus on increasing the amount of moderate to vigorous intensity physical activity they do each day through activities like working around the home, walking for transport, or purposeful exercise.

Once individuals develop strength and balance, and engage in at least a small amount of moderate to vigorous activity, they can further reduce their risk for mobility disability by increasing the amount of light activity they do each day, and by spreading this activity across the full day, for instance through hobbies like cooking, woodworking, or light gardening.

The researchers concluded by echoing the current United States Physical Activity Guidelines, suggesting that a "move more, more often" recommendation is a good starting place for older adults who want to maintain physical functioning and an independent lifestyle.

DALLAS - June 11, 2020 - Shelter-in-place orders to reduce the spread of COVID-19 put unusual strains on people with obesity, making it more difficult for them to eat properly and manage their weight, according to a UT Southwestern study.

The study, published in the journal Clinical Obesity, surveyed 123 weight management patients at the UT Southwestern Weight Wellness Program and a community bariatric surgery practice. In addition to less exercise and more stress eating, most patients also reported increased anxiety and depression.

"You don't have to contract the virus to be adversely affected by it. The major strength of this study is that it is one of the first data-driven snapshots into how the COVID-19 pandemic has influenced health behaviors for patients with obesity," says Jaime Almandoz, M.D., MBA, an endocrinologist and assistant professor of internal medicine at UT Southwestern who authored the study. Almandoz is also medical director for the UT Southwestern Weight Wellness Program, a multidisciplinary weight management and post-bariatric care clinic.

Beyond challenges with diet and exercise, the researchers are also concerned that patients may be missing medical appointments, surgeries, and medications due to the pandemic. People with obesity are at higher risk for complications and death from the virus due to many factors, including comorbidities such as diabetes and hypertension.

According to the Centers for Disease Control and Prevention, more than 42 percent of American adults are obese. Obesity-related health conditions include heart disease, stroke, Type 2 diabetes,

Almandoz points out that many patients with obesity struggle with access to appropriate fresh, healthy foods. Some reside in food deserts lacking grocery stores, where the only options are fast food and processed foods from convenience stores.

"Unchecked diabetes, hypertension, and other obesity-related comorbidities will create a huge backlog of needs that will come back to haunt us. When you throw in disruptions like social isolation, coupled with losing your job and insurance coverage, a potential disaster is waiting to unfold," Almandoz notes.

Although just 1.7 percent of the study group who were tested for COVID-19 were positive, the pandemic is having a significant impact on the group's physical and mental health.

Nearly 70 percent said their weight loss goals were more difficult to achieve during the shelter-in-place period. More than 47 percent exercised less, 49 percent stockpiled food, and 61 percent confessed to stress eating. Mental health issues also rose significantly, with 72 percent reporting anxiety and 83 percent noting depression.

"Those with obesity and severe obesity are already at the highest risk of death from COVID-19. We're concerned that they can be severely affected if a second wave hits in the fall," says senior author Sarah Messiah, Ph.D., M.P.H., an adjunct professor in the UTSW department of population and data sciences and also a professor in the department of epidemiology, human genetics and environmental sciences at the UTHealth School of Public Health.

Chronic stress, coupled with working from home and in some cases home schooling children, makes it difficult to follow recommendations for a healthy diet and exercise regimen. Job losses due to the pandemic present additional difficulties. In this study, 10 percent reported losing their jobs and health insurance coverage, which put them at further risk of health complications due to lack of access to care.

"We don't yet know how many additional lives will be lost to heart disease and diabetes simply because people did not receive care during COVID-19," says Messiah. "Unfortunately, many of these are ethnic minorities who are already hit hard with disease burdens."

The researchers believe their work can inform clinicians and other health professionals on effective strategies to minimize the physical and psychosocial health impacts from COVID-19 among adults with obesity both during and after the pandemic.

The study data came from an online questionnaire conducted April 15 through May 31. The study population was racially and ethnically diverse, had a mean age of 51, and 87 percent were women. The mean body mass index (BMI) for these patients was 40.

A scalable "lab-on-a-chip" technology based on inkjet printing methods detected breast cancer in plasma samples from patients with more than 90% accuracy, according to a new study. The new chips, which sniffed out both early-stage and metastatic tumors when tested using plasma from 100 individuals, could one day allow clinicians to detect new cancers and monitor existing tumors less invasively compared with current diagnostic methods. Catching cancers during their early stages is key to achieve the best clinical outcomes, as advanced tumors that have metastasized are far more difficult to eradicate. But current cancer detection techniques suffer from a plethora of drawbacks: standard tissue biopsies are invasive and cannot be repeated, and imaging techniques such as radiography fail to capture important changes in the growth of tumors. A liquid biopsy - a test that detects cancers with a simple blood or plasma draw - would overcome many of these issues, but despite years of research there is still not a liquid biopsy test that has entered widespread clinical practice. Peng Zhang and colleagues have now taken a step toward liquid biopsies with their EV-CLUE chip, a device that they manufactured using colloidal inkjet printing methods. The chip works by capturing extracellular vesicles - tiny structures that ferry molecules between cells - and scanning for the presence and activity of MMP14, an enzyme that has been linked to the progression and metastasis of tumors. EV-CLUE successfully differentiated between controls and patients with early-stage or metastatic breast cancer with an accuracy of 96.7% in an initial group of 30 individuals and an accuracy of 92.9% in a second group of 70 people. Zhang et al. add that their printing technique's robustness and scalability will allow for clinical studies with larger numbers of patients in the future.

A good vitamin D status is beneficial both in cancer prevention and in the prognosis of several cancers, according to a new research review. The anti-cancer effects of vitamin D are especially pronounced in the prevention and treatment of colon cancer and blood cancers. In addition, high vitamin D responsiveness can be linked to a smaller cancer risk. Vitamin D responsiveness varies between individuals, affecting their need for vitamin D supplementation.

The review article, published in Seminars in Cancer Biology and written by Professor Carsten Carlberg from the University of Eastern Finland and Professor Alberto Muñoz from the Autonomous University of Madrid, provides an update on the molecular basis of vitamin D signaling and its role in cancer prevention and therapy.

Vitamin D is commonly known for its crucial role in bone health, but the authors point out it also regulates the immune system, and its anti-cancer effects are mediated mainly by immune cells, such as monocytes and T cells. Vitamin D exerts its effects via the vitamin D receptor (VDR), which is a transcription factor involved in the expression and epigenetic regulation of numerous genes.

According to the review, studies focusing on the effect of vitamin D on different types of cancers provide the strongest evidence of its benefits in colorectal cancer and in blood cancers, such as leukemias and lymphomas. Vitamin D is important both for the differentiation of blood cells during hematopoiesis as well as adult stem cells in rapidly regenerating tissues, such as colon or skin. A too low vitamin D status leads to a suboptimal function of the VDR and in an increased risk that these cells are not fully differentiating and start to turn into uncontrolled growing cancer cells.

Even in other types of cancer, such as breast and prostate cancer, a low vitamin D status, measured as the level of 25-hydroxyvitamin D in the blood, has been associated with a higher cancer incidence and a poorer prognosis. However, vitamin D supplementation has not been consistently shown to reduce cancer mortality in randomized controlled trials. According to the authors of the review, the impact of vitamin D could be shown more clearly if the participants were stratified according to their individual vitamin D responsiveness and the health outcomes analyzed in relation to changes in individual vitamin D status.

Professor Carlberg's research group has earlier shown that individuals differ in their molecular response or sensitivity to vitamin D supplementation. For example, 25% of the Finnish population seem to be low responders, needing a higher dose of vitamin D supplementation to reach the full clinical benefit. In terms of cancer risk, being a high responder can be expected to have a protective effect.

According to the review, a good vitamin D status is beneficial in general cancer prevention. There is less evidence of its usefulness in the treatment of cancer.

ARLINGTON, Va., June 10, 2020 -- A new clinical guideline from the American Society for Radiation Oncology (ASTRO) provides recommendations for radiation therapy to treat patients with nonmetastatic cervical cancer. The guideline--ASTRO's first for cervical cancer--outlines indications and best practices for external beam radiation therapy and brachytherapy in the postoperative and definitive settings. Recommendations also address other treatments including chemotherapy and surgery when used in combination with radiation. The guideline is published online in Practical Radiation Oncology.

"Cervical cancer treatment has advanced dramatically over the last 20 years. Increased use of intensity-modulated radiation therapy (IMRT) and image-guided brachytherapy, in particular, have resulted in better patient outcomes and fewer treatment complications. Our intention in developing this guideline is to encourage physicians to make these approaches part of their daily practice," said Akila N. Viswanathan, MD, MPH, chair of the guideline task force and professor and interim director of radiation oncology and molecular radiation sciences at the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore.

An estimated 13,800 American women will be diagnosed with invasive cervical cancer this year and nearly 4,300 women are expected to die from the disease. Cervical cancer can be highly treatable if detected early, however; the estimated five-year survival rate is 92% for early-stage disease and 56% for locally advanced disease. "Cervical cancer can be highly treatable if detected early; the estimated five-year survival rate is 92% for early-stage disease." The estimated five-year survival rate is 56% for locally advanced disease, however, underscoring the importance of early detection.

Radiation is an integral part of cervical cancer treatment, either following surgery for patients at risk of recurrence or as a primary definitive treatment. The regimen involves pelvic external beam radiation therapy (EBRT), often combined with chemotherapy and a brachytherapy boost.

"We've moved from 2-D and 3-D treatments for the pelvis into IMRT, a highly focused form of radiation that reduces a patient's risk of treatment complications. We also have seen significant improvements in outcomes with image guidance for brachytherapy. Treatment teams use the most advanced imaging modalities available, and that allows us to treat exactly what we need to treat and avoid normal tissues," said Junzo Chino, MD, vice chair of the guideline task force and an associate professor of radiation oncology at Duke University Cancer Center in Durham, N.C.

The guideline's recommendations address the indications for postoperative and definitive radiation therapy, the use of chemotherapy in combination with radiation, the use of IMRT, and the indications and techniques of brachytherapy. Key recommendations are as follows:

Recommendations: Radiation Therapy for Locally Advanced Cervical Cancer

In the postoperative setting following radical hysterectomy, radiation with concurrent platinum-based chemotherapy (chemoradiation) is recommended for patients with high risk factors such as positive margins. Postoperative radiation therapy is recommended for patients with intermediate risk factors such as larger tumors. Risk criteria are defined in the guideline.

In the definitive setting, chemoradiation therapy is recommended for patients with FIGO stage IB3-IVA Definitive radiation or chemoradiation is conditionally recommended for patients with stage IA1-IB2 disease who are medically inoperable.

Intensity-modulated radiation therapy (IMRT) is recommended for postoperative EBRT and conditionally recommended for definitive EBRT, to reduce short-term and long-term toxicity.

Brachytherapy is strongly recommended for patients receiving definitive radiation or chemoradiation. Neither SBRT nor IMRT is a suitable substitute for brachytherapy. In the postoperative setting, brachytherapy is conditionally recommended with the presence of positive margin(s).

The guideline also addresses optimal dosing, fractionation and technique for EBRT and brachytherapy, including recommendations for image guidance, volume-based treatment planning and strategies to limit radiation spread to organs at risk.

COVID-19 and Cervical Cancer

The guideline was completed before the pandemic and therefore does not address COVID-19. Dr. Viswanathan and Dr. Chino also expressed concern about the effects of the coronavirus pandemic on patients with cervical cancer.

"Cervical cancer is one of those cancers where you just can't wait. You need to treat it right away in order to have the greatest chance of cure," said Dr. Viswanathan.

"I worry about women not coming in at a time when earlier treatment could be exceedingly beneficial to them," agreed Dr. Chino. "I hope that women who have symptoms will continue to be identified early and come in for treatment. We are also preparing for a potential surge of cases where, for understandable reasons, they did not seek screening or treatment as early as they may have before the pandemic. I fear that we will see more patients with more advanced disease."

Both doctors noted that their clinics implemented a series of safety enhancements and process upgrades that have allowed them to continue cervical cancer treatments safely during the pandemic. A recent ASTRO survey similarly found widespread adoption of screening, social distancing and other infection control measures at radiation oncology practices across the country.

Treatment-Related Side Effects

Treatment for cervical cancer can be a challenging experience for patients, given the proximity of the cervix to other critical organs in the pelvis and the combination of multiple therapies.

"Irrespective of the techniques used, radiation therapy for cervical cancer causes side effects for many patients, most commonly fatigue and complications in the bowel and bladder. Newer radiation technologies can significantly reduce these complications, however. The hallmark of MR-guided brachytherapy, for example, is fewer bowel or bladder side effects than with traditional brachytherapy techniques. Medications to manage side effects have also improved considerably," said Dr. Viswanathan.

"The issues facing women with cervical cancer are unique," said Dr. Chino. "Doing everything we can to eliminate the tumor is only part of our job. The other part is to make sure that patients are doing well throughout the treatment process."

PHILADELPHIA (June 10, 2020)- Older adults with COVID-19 who survive hospitalizations and return to their homes confront substantial health challenges and an unpredictable future. Early evidence suggests that complex and long-term physical, functional, cognitive, and emotional negative health consequences will be the norm for them. However, the trajectories of health care needs of older adults with COVID-19 in the weeks and months following hospital discharge have yet to be identified.

In an article in the Journal of Aging and Social Policy, three researchers from the University of Pennsylvania School of Nursing (Penn Nursing) explain how the core components of the Transitional Care Model, along with early findings regarding the unique concerns of those with COVID-19, suggest a path for immediate practice and policy responses to caring for this population as they transition from the hospital back to the community.

The Transitional Care Model is a care management strategy proven in multiple National Institutes of Health clinical trials to enhance health and quality of life and reduce health-care costs for diverse subgroups of hospitalized older adults to home. It encompasses comprehensive discharge planning and home follow-up.

"Informed by this evidence-based framework, immediate implementation of targeted federal and state policy solutions would position health and community-based care systems to respond more effectively to the enormous challenges encountered by older adults with COVID-19 throughout transitions from hospital to home," wrote the three authors: Mary D. Naylor, PhD, RN, FAAN, the Marian S. Ware Professor in Gerontology and the Director of the NewCourtland Center for Transitions and Health; Karen B. Hirschman, PhD, MSW, research associate professor; and Kathleen McCauley, PhD, RN, FAAN, FAHA, Professor Emerita of Cardiovascular Nursing.

Toxoplasma gondii infection is one of the most frequent parasitic infections of humans. This parasite is present in the brain of an estimated two billion people--about 40 percent of all humans on earth. It is endemic throughout the world, causing water and food-borne epidemics that result in toxoplasmosis.

This neglected, often mistreated or untreated infection, is transmitted to humans when a person eats infected undercooked meat, drinks contaminated water or is exposed to parasites in soil, usually from cat feces. Few victims recognize the exposure immediately, but the parasite causes life-long infection. It cannot presently be cured.

This disease can begin before or after birth. It can permanently damage the eyes and the brain during the initial active infection. Dormant infections can re-activate, causing severe illness or death, especially in immuno-compromised patients with cancer, autoimmune disease, AIDS or transplantation. There is no preventive vaccine.

The related tropical parasitic disease, malaria, caused by plasmodia, kills one child every 11 seconds, or about 500,000 children each year. Malaria remains an ongoing threat for travelers who visit endemic areas. Drug resistance is a significant clinical problem.

"New and improved medicines are urgently needed to prevent and cure both toxoplasmosis and malaria," said the study's senior author, Rima McLeod, MD, professor of pediatrics (infectious diseases) and ophthalmology/visual sciences at the University of Chicago Medicine and an authority on the parasite and the care of patients with toxoplasmosis.

"Many people suffer and quite a few die from these infections," she said. "Until now, no medicine has been able to eliminate the chronic, encysted form of Toxoplasma. But we may soon have medicines that can make a real difference in preventing and treating active and dormant infections."

This remarkable study, "Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites," to be published June 9, 2020, in the journal Frontiers in Cellular and Infection Microbiology, focused on the discovery and development of new, highly effective compounds against both T. gondii and P. falciparum. The researchers discovered a lead compound that can significantly reduce or eliminate toxoplasmosis as well as malaria. These compounds are highly effective against multiple drug-resistant strains of plasmodia in vitro.

The researchers were able to dramatically improve outcomes for both diseases in mouse models. There is a relatively close phylogenetic relationship. The parasites share similarities in a molecule, known as cytochrome bc1, important for energy production.

In developing this new series of compounds, "we aimed to identify a mature lead compound with both anti-plasmodium and anti-T. gondii activity," said organic chemist Martin McPhillie, PhD, at the University of Leeds (UK). His team focused on molecules with an increased percentage of 'sp3 character.' These tend to be more three-dimensional than the more rigid 'sp2-rich' counterparts. Those with greater sp3 tend to be more specific for their protein targets. They have better physicochemical properties and can accommodate bulkier substituents (atoms taking the place of another atom or group) to minimize the effects on the human enzyme.

The scientists used enzymatic, crystallographic, cryoelectron microscopy and other in vitro and in vivo conclusive empiric studies with parasites, as well as a simple but novel nano-formulation method to find compounds that reduce or eliminate toxoplasmosis and malaria. They created and tested their lead anti-apicomplexan compound, which showed promise for treatment of these infections. This led to characterization of this compound, which revealed drug-like chemical lproperties. If utility and safety are retained and no toxicity appears in next-stage studies, this lead compound, known as JAG21 (named for James A. Gordon who synthesized it as a graduate student), "may be able to treat both T. gondii and P. falciparum human infections," said McLeod.

Colin Fishwick, PhD, dean of the Leeds School of Chemistry, and McPhillie led the team of medicinal chemists who created JAG21. Fishwick found it "absolutely stunning," that following a single, oral, low dose of JAG21, there were no surviving malarial parasites and no death of mice with otherwise lethal plasmodia infections. Mark Hickman, PhD, at Walter Reed Army Institute of Research, noted that JAG21 "has the potential to prevent and cure all three life-cycle stages of malaria."

Teams from The University of Strathclyde and UChicago found that their compound eliminated 100 percent of the active form and more than 95 percent of the previously untreatable encysted Toxoplasma parasites in mice. They also found another compound that improves efficacy of JAG21.

A few residual organisms remained after JAG21 treatment of long-established infections. UChicago scientists, working with Hernan Lorenzi at the J. Craig Venter Institute, probed for mechanisms that could eliminate potential remaining organisms. They found that different "persister stasis-like organisms" of T. gondii, grown in human brain stem cells, use a distinct genetic pathway to survive. This pathway has similarities to one recently identified in hypnozoites, a form of dormant plasmodia.

Such critical differences in gene expression sustain these novel life-cycle stages of Toxoplasma, which JAG21 can only partially inhibit in an immune-compromised mouse model. These studies point to genes that are molecular targets for new methods to eliminate the few remaining dormant organisms. Targeting these can form the basis of a companion medicine for JAG21. "The impact of these findings will be felt," said the U.Kentucky's Anthony Sinai.

Robert Prud'homme and graduate student Kurt Ristroph at Princeton University developed a method to make an oral formulation of JAG21 that is stable for months. Ying Zhou, in the McLeod group, found that this formulation of JAG21 given orally to mice--once daily for 3 days--is highly effective, even against large amounts of extremely virulent Toxoplasma.

"JAG21," the authors agree, "has the potential to become an orally administered medicine, or part of a combination, that is curative for toxoplasmosis and is a single-dose prevention and cure for malaria." If utility and safety are retained and no toxicity appears in the next series of studies, this compound may become suitable for treatment of T. gondii and P. falciparum infections. "JAG21," the team added, "has real promise."

into the factors affecting recurrence, particularly tumor molecular genetics such as EGFR mutations, is needed.

These authors conducted a single-center retrospective study of 282 patients with early or locally advanced lung adenocarcinoma, with or without EGFR mutations, who underwent definitive therapy.

Then they assessed recurrence, stage at recurrence, time to recurrence, and progression-free survival.

However, among those who recurred, EGFR-mutated lung cancer had increased rates of metastatic recurrence compared to EGFR-wildtype disease.

Dr. Victoria Villaflor from The Division of Hematology-Oncology, as well as The Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois, said, "According to the World Health Organization (WHO), lung cancer is the most common cause of cancer and cancer-related mortality in both men and women worldwide."

Lung cancer can be divided into small cell lung cancer, which accounts for ~15% of cases, and non-small cell lung cancer, which accounts for ~85% of cases.

Despite definitive therapy, 30 55% of patients with early NSCLC will eventually experience disease recurrence and die of their disease.

With tumor molecular genetics at the forefront of precision medicine, subclassification of NSCLC based on EGFR mutation status has been paramount for predicting response to EGFR targeted therapies in unresectable advanced and metastatic disease.

Despite advances in those with unresectable disease, little is known about the prognostic implications of EGFR mutation status in early and locally advanced NSCLC amenable to definitive therapy.

This single-institution retrospective study aims to better understand the implications of EGFR mutation status on localized or locally advanced NSCLC amenable to definitive therapy.

"This single-institution retrospective study aims to better understand the implications of EGFR mutation status on localized or locally advanced NSCLC amenable to definitive therapy"

The Villaflor Research Team concluded in their Oncotarget Research Paper, "this study suggests EGFR mutation as an important marker for predicting metastatic disease recurrence and highlights the growing need for precision medicine in early and locally advanced NSCLC. Early identification of these recurrences is paramount given the improved post-relapse survival observed in this population. A better understanding of the factors leading to relapse rates using prospective, multi-center investigations could help guide future surveillance practices, identify those patients at higher risk, and ultimately extend patient survival."

Journal

Oncotarget

DOI

10.18632/oncotarget.27602

Volume 11, Issue 22 of @Oncotarget reported that there are rationale and evidence supporting immune therapy in Ovarian Cancers. The authors investigated the potential for adoptive cell therapy from in vitro expanded tumor-infiltrating lymphocytes in combination with checkpoint inhibitors and conducted immunological testing of ex vivo expanded TILs.

Six patients with late-stage metastatic high-grade serous Ovarian Cancer were treated with immune therapy consisting of ipilimumab followed by surgery to obtain TILs and infusion of REP-TILs, low-dose IL-2, and nivolumab.

Analysis of the REP-TILs with the flow- and mass-cytometry show primarily activated and differentiated effector memory T cells.

Furthermore, the authors' data indicate that the addition of ipilimumab therapy improves the T cell fold expansion during production, increases the level of CD8 T cell tumor reactivity, and favorably affects the T cell phenotype.

Dr. Inge Marie Svane from The National Center for Cancer Immune Therapy, Department of Oncology at Copenhagen University Hospital in Denmark said, "Ovarian cancers are frequently infiltrated with immune cells. T cell infiltration and, especially the number of CD8 T cells, is correlated to longer survival in ovarian cancer patients."

"T cell infiltration and, especially the number of CD8 T cells, is correlated to longer survival in ovarian cancer patients"

While ovarian cancer is characterized by a low to an intermediate mutational burden, a feature generally considered as an indication of low immunogenicity and responsiveness to immune therapy, the authors and others have demonstrated tumor reactivity amongst TILs and peripheral blood lymphocytes in ovarian cancer patients suggesting a potential for immune therapy.

Several clinical trials have tested ICI in ovarian cancer patients but so far with very modest results.

A study in 20 ovarian cancer patients showed an overall response rate of 15% with the anti-PD-1 antibody nivolumab, but in a recently published, and much larger trial of 294 patients, the ORR was only 8% with the anti-PD-1 antibody pembrolizumab.

The same authors here, recently published results from a small ACT pilot trial in ovarian cancer demonstrating feasibility but with no patients achieving objective responses.

The Marie Svane Research Team concluded in their Oncotarget Research Paper that ACT for ovarian cancer is still in its cradle compared to malignant melanoma that is presently in phase III clinical testing.

However, accumulative evidence points towards a potential role of immunotherapy in ovarian cancer but with a modest efficacy of established ICIs. Thus, combination immunotherapy might be a way forward supporting the continuous development and refinement of ACT therapy for this purpose.

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DOI - https://doi.org/10.18632/oncotarget.27604

Full text - https://www.oncotarget.com/article/27604/text/

Correspondence to - Inge Marie Svane - inge.marie.svane@regionh.dk

Keywords -
adoptive cell therapy,
tumor-infiltrating lymphocytes,
ovarian cancer,
combinational immune therapy,
checkpoint inihibors

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

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Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27604

Volume 11, Issue 22 of @Oncotarget reported that more and more patients receive first-line treatment with immunotherapy combinations and not all patients respond in metastatic renal cell carcinoma.

After IO-IO progression, the authors stated “we do not have a standard of treatment because it is not available for prospective data on this setting.”

Therefore the authors present the case of a patient with metastatic renal cell carcinoma who suffered hyperprogression with IO-IO combination in the first line.

The molecular mechanism to explain patients' response, its the probably crosstalk between MET and NOTCH pathway.

Nowadays, there is not clear the subsequent treatment in those patients who progress to IO-IO first line.

More efforts in biomarker development should be made to better selection of patients' treatment along with the disease.

Dr. Javier Molina-Cerrillo from The Medical Oncology Department, Ramón y Cajal University Hospital in Madrid Spain said "We present the case of a 50-year-old male who came to the emergency room in March 2019 due to the recent appearance of a mass in the lower region of the left thigh."

Body CT scan revealed the presence of myocardial implants with extension towards the left ventricular lumen measuring up to 50 mm and pericardial implants, micronodules in both lungs, several lesions in the right gluteus, up to 21 mm and a mass in the upper pole of the left kidney of 6.8 5.5 cm.

The radiological assessment confirmed the clinical suspicion of disease progression with an increase in the renal tumor mass of 7.7 5.9 cm, new intraabdominal implants in the right perirenal space of 4 cm, and left of 3 cm, right hypochondrium of 5.5 cm and left iliac fossa of 4 cm.

The patient began this treatment in early June 2019 with close monitoring of adverse events and tumor assessment.

After 2 weeks of treatment, the patient began to experience significant clinical improvement, recovering to a KI of 90% and with an objective tumor reduction of the visible implants in the left dorsolumbar region, right gluteus muscle, and disappearance in the vast intermediate lesion.

"After 2 weeks of treatment, the patient began to experience significant clinical improvement, recovering to a KI of 90% and with an objective tumor reduction of the visible implants in the left dorsolumbar region, right gluteus muscle, and disappearance in the vast intermediate lesion"

Those data show some activity from TKIs in this setting, but in patients not responding to the IO-IO combination, response durations are below 5 months, representing a subgroup of patients with a particularly poor prognosis.

The Molina-Cerrillo Research Team concluded in their Oncotarget Case Report that there may be hyperprogressions with the new combinations in RCC, the NOTCH pathway may be activated in some patients, and MET inhibition may be key to its control.

In this case, it is demonstrated that a TKI such cabozantinib can control hyperprogression phenomena in 2L of m cc RCC. Clinical trials are currently ongoing in this setting trying to elucidate, prospectively, which is the best strategy.

In this sense, biomarker research is essential to identify those tumor profiles that provide information about the best approach in the first-line setting and beyond.

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DOI - https://doi.org/10.18632/oncotarget.27598

Full text - https://www.oncotarget.com/article/27598/text/

Correspondence to - Javier Molina-Cerrillo - javier.molinace@gmail.com

Keywords -
immunotherapy,
renal cell carninoma,
cabozantinib,
NOTCH

About Oncotarget

Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with:

SoundCloud - https://soundcloud.com/oncotarget
Facebook - https://www.facebook.com/Oncotarget/
Twitter - https://twitter.com/oncotarget
LinkedIn - https://www.linkedin.com/company/oncotarget
Pinterest - https://www.pinterest.com/oncotarget/
Reddit - https://www.reddit.com/user/Oncotarget/

Oncotarget is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls

Journal

Oncotarget

DOI

10.18632/oncotarget.27598

(TORONTO, June 9, 2020) - A new clinical research study by Dr. Marjan Rafiee and Dr. Taufik Valiante of the Krembil Brain Institute at Toronto Western Hospital, part of University Health Network, has found that a Mozart composition may reduce seizure frequency in patients with epilepsy.

The results of the research study, "The Rhyme and Rhythm of Music in Epilepsy," was recently published in the international journal Epilepsia Open. It looks at the effects of the Mozart melody, "Sonata for Two Pianos in D Major, K. 448" on reducing seizures, as compared to another auditory stimulus - a scrambled version of the original Mozart composition, with similar mathematical features, but shuffled randomly and lacking any rhythmicity.

"In the past 15 to 20 years, we have learned a lot about how listening to one of Mozart's compositions in individuals with epilepsy appears to demonstrate a reduction in seizure frequency," says Dr. Marjan Rafiee, lead author on the study. "But, one of the questions that still needed to be answered was whether individuals would show a similar reduction in seizure frequency by listening to another auditory stimulus - a control piece - as compared to Mozart."

The researchers recruited 13 patients to participate in the novel, year-long study. After three months of a baseline period, half of the patients listened to Mozart's Sonata once daily for three months, then switched to the scrambled version for three months. The others started the intervention by listening to the scrambled version for three months, then switched to daily listening of Mozart.

Patients kept "seizure diaries" to document their seizure frequency during the intervention. Their medications were kept unchanged during the course of the study.

"Our results showed daily listening to the first movement of Mozart K.448 was associated with reducing seizure frequency in adult individuals with epilepsy," says Dr. Rafiee. "This suggests that daily Mozart listening may be considered as a supplemental therapeutic option to reduce seizures in individuals with epilepsy."

Epilepsy is the most common serious neurological disorder in the world, affecting approximately 300,000 Canadians and 50 million people worldwide.

Many experience debilitating seizures. The treatment is often one or more anti-seizure medications. But for 30 per cent of patients, the medications are not effective in controlling their seizures.

"As a surgeon, I have the pleasure of seeing individuals benefit from surgery, however I also know well those individuals for whom surgery is not an option, or those who have not benefitted from surgery, so, we are always looking for ways to improve symptom control, and improve quality of life for those with epilepsy," says Dr. Taufik Valiante, senior author of the study and the Director of the Surgical Epilepsy Program at Krembil Brain Institute at UHN and co-Director of CRANIA.

"Like all research, ours raises a lot of questions that we are excited to continue to answer with further research and support from the epilepsy community."

While these results are promising, the next step is to conduct larger studies with more patients, over a longer period of time.

Early-View article: Why Challenge Trials of SARS-CoV-2 Vaccines Could be Ethical Despite Risk of Severe Adverse Events\

Nir Eyal

Human challenge trials to test the efficacy of vaccine candidates against SARS?CoV?2, the novel coronavirus behind Covid?19, could save considerable time and many lives. But they may initially seem unethical because they expose healthy volunteers to a live virus that is killing many people and for which no cure exists. This article argues that this is not the correct test of their ethics. The correct test is comparative. And in the special circumstances of the Covid?19 pandemic, human challenge trials meet the correct test better than standard efficacy testing would. Eyal directs the Center or Population-Level Bioethics at Rutgers University and is a professor at the university.

Early-view article: Equitably Sharing the Benefits and Burdens of Research: Covid-19 Raises the Stakes

Carl H. Coleman

One of the central principles of research ethics is that the benefits and burdens of research with human participants should be equitably distributed. This principle has important implications for questions about where research will be conducted, how participants will be recruited, what questions will be investigated, and who will control the distribution of any innovations that result. In the rush to initiate clinical trials of treatments and vaccines for Covid?19, careful attention to these questions is particularly important. If clinical trials are not designed with equity considerations in mind, the response to the pandemic may exacerbate disparities in health status between population groups. This article calls for an international governance system to oversee access to Covid-19 vaccines and treatments. Coleman is a professor of law at Seton Hall University School of Law

May-June 2020 issue:

Justice and Domestic Health Research

The Importance of Engaging Children in Research Decision-Making: A Preliminary Mixed-Methods Study

Data Safety Monitoring during Covid-19: Keep on Keeping On

Adolescent and Parent Perceptions about Participation in Biomedical Sexual Health Trials

Genomics and Infectious Diseases: Expert Perspectives on Public Health Considerations regarding Actionability and Privacy

IRB Policies for Obtaining Informed Consent from Non-English-Speaking People

INDIANAPOLIS - Researchers from Regenstrief Institute and Indiana University report that nearly half of the time medical treatments and orders received for incapacitated patients were not compatible with goals of care requested by their surrogate decision makers. The most common disagreement involved a "full-code" medical order prepared for patients whose surrogates had indicated preference for less aggressive care options.

"The significant lack of agreement that we found between the surrogate's wishes on behalf of an incapacitated patient and the care that is actually being provided is concerning and that concern is heightened during the pandemic, as many COVID-19 patients cannot make decisions for themselves because they are on ventilators and sedated," said Regenstrief Institute Research Scientist Alexia Torke, M.D., associate professor of medicine at IU School of Medicine and the senior author of the new study which is published on JAMA Network Open. "Family members and other surrogate decision makers can't visit patients during the pandemic, which also means they can't gather information and feedback from the nurses, doctors and other clinicians, making two-way communication with the care team more difficult than ever."

In the study, which was carried out at three hospitals, surrogates of patients age 65 and older were asked to classify treatment they wished the patient to have into one of three categories - comfort care (focused primarily on relief of pain and suffering), intermediate care (routine hospital care such as oxygen and intravenous medications) or aggressive care ("full code" including cardio-pulmonary resuscitation, ventilator and other therapies available in an ICU). The surrogate's preferred goal of care was compared with electronic medical record (EMR) data outlining treatment received and medical orders written during the patient's hospitalization. The surrogate's preferred goal of care did not agree with the EMR data 47 percent of the time.

"How can we decrease discordance between what the surrogate wants and what actually happens in the hospital? We need to start at the beginning, before the patient loses capacity to engage in advance care planning, thus ensuring the patient and surrogate are on the same page," said Dr. Torke, who has conducted several previous studies on surrogate decision making. "Then good communication - preferably face to face - between the surrogate and clinicians during hospitalization is important to ensure the patient receives the care they and the surrogate desire.

"This is not TV or the movies - only one in eight critically ill patients will survive CPR. Difficult decisions have to be made and they can best be made when the surrogate knows the patient's wishes and has successful two-way communication with the care team," she observed.

The researchers found that patients who resided in a nursing home were more likely to receive medical care that agreed with the surrogate's stated goals of care than individuals who were admitted to the hospital directly from their own home. Individuals who lived with their surrogates or saw them at least weekly were more likely to receive the care that the surrogate requested than patients who had less contact with the surrogate.

"No matter how well you think you know someone, there is no substitute for having a conversation about his or her end-of-life wishes," said study co-author Amber R. Comer, PhD, J.D., of IU School of Health and Human Sciences at IUPUI, the study's corresponding author. "These conversations are crucial for ensuring that loved one receives medical treatments that he or she would have wanted. These conversations help alleviate some of the stress that surrogates experience when trying to make these difficult life and death decisions." Dr. Comer is a Regenstrief Institute affiliated scientist.