Body

MORGANTOWN, W.Va.--In a study funded by the National Institutes of Health, West Virginia University neuroscientists linked white light at night--the kind that typically illuminates hospital rooms--to inflammation, brain-cell death and higher mortality risk in cardiac patients.

Randy Nelson, who chairs the Department of Neuroscience in the WVU School of Medicine, and Courtney DeVries, the John T. and June R. Chambers Chair of Oncology Research at WVU, re-created cardiac arrest in animal models. Doing so temporarily interrupted the brain's oxygen supply. Then the researchers and their colleagues divided the models into three groups that would spend their nights in--respectively--dim red light, dim white light and the dark.

After seven nights of this regimen, the researchers evaluated the health of the models' brain cells. Exposure to white light at night caused multiple poor outcomes. The researchers' findings are published in Experimental Neurology.

Cardiac arrest was more likely to be lethal for models in the white-light-at-night group, whereas the mortality rate in the red-light-at-night group did not differ from the group that stayed in darkness.

Exposure to white light at night also correlated to greater cell death in the hippocampus--a part of the brain that's key to memory formation--and more aggressive inflammation overall. In fact, just one dimly illuminated night was enough to cause pro-inflammatory cytokines--tiny proteins critical to immune responses--to surge. This was only the case, however, if the light was white. Red light had no effect.

"When you see long-wavelength, blue light first thing in the morning, those long wavelengths set your circadian clock to precisely 24 hours. The problem is, if you see blue light at night--from your phones, TVs, computers and compact fluorescent lights--they're disrupting your circadian system all night long. Those lights look white to us, but frankly, they're mostly blue," explained Nelson, who--along with DeVries--receives support from the West Virginia Clinical and Translational Science Institute. His previous research has associated nocturnal blue light with higher rates of obesity, metabolic disorders and depression.

"Clearly light at night is required in patients' rooms acutely after cardiac arrest and other major health events," said Laura Fonken, lead author on the study and an assistant professor at the University of Texas at Austin. "Our data suggest that a relatively simple shift--changing the light color from broad-spectrum white to a red hue--benefits outcomes in an animal model of cardiac arrest. If this also occurs in clinical populations, then it would be important because it would not require complicated clinical trials to implement for patients and could improve recovery from various other health events that require hospital stays."

To that end, the researchers are exploring whether white light at night provokes a similar physiological response in people. For four nights in a row, they outfit one group of hospitalized cardiac patients in special "gaming glasses" with orange lenses that filter out the troublesome blue light. Wearing the glasses seems to bathe everything in warm, sunset tones. Another group of patients wears identically shaped glasses that have clear lenses, allowing the full spectrum of white light--including blue tones--to pass through.

"The cool thing from our perspective is, we believe these longer-wavelength lights won't have that detrimental effect, and people will recover faster," Nelson said. If studies bear out the researchers' hunch, gaming glasses may be an affordable, practical option for preserving brain function, reducing inflammation and lowering the risk of death in cardiac patients.

LA JOLLA--(April 2, 2019) Metastatic ovarian, prostate and breast cancers are notoriously difficult to treat and often deadly. Now, Salk Institute researchers have revealed a new role for the CDK12 protein. The findings were published in the print version of Genes & Development on April 1, 2019.

"Approximately 3-5 percent of prostate, ovarian, and breast cancers contain mutations in the CDK12 gene, and recent studies have shown that this subset is uniquely responsive to immunotherapy drugs, whereas the majority of these cancers do not respond," says Salk Professor Katherine Jones, senior author of the paper. "This suggests, for the majority of these cancers that lack a CDK12 mutation, chemical inhibitors of CDK12 could be used to make the cancer more easily killed by chemotherapy drugs, and potentially more sensitive to immunotherapy treatments as well." The results suggest it could be a drug target for many cancers that have spread throughout the body.

By analyzing the role of CDK12 in protecting the cells from chemotherapy, the team discovered a new group of genes that are controlled by CDK12, including many genes that are regulated by another protein called mTORC1, which controls cancer cell metabolism. And although CDK12 is predominantly located in the nucleus of the cell, it works with mTORC1 to control the process of translation--an important step in creating a new protein within the cell.

"CDK12 is a recently identified gene that controls the expression of genes required for DNA repair, but its detailed mechanism and function are just beginning to be explored," says first author Seung Choi, a former staff scientist and a current Salk research collaborator. "Therefore, if CDK12 is inhibited, the cell cannot repair DNA efficiently, and the cells are more prone to dying in response to chemotherapy. We wanted to understand how CDK12 might be involved in cancer in order to advance cancer treatment options."

In a collaboration with the lab of Salk Professor Alan Saghatelian, the team was able to identify specific genes that were regulated by CDK12 at the level of translation. Several hundred genes were found to be controlled by CDK12 in this new way, many of which are tied to cancer cell growth.

To the surprise of the researchers, many of the other newly identified CDK12-regulated genes were critical for cell division (mitosis). Microscopy imaging studies by Seunjae Kim, a postdoctoral fellow at Salk, revealed that CDK12 helped the chromosomes condense and then separate to become two distinct cells. This role for CDK12 in the expression of a whole network of genes necessary for mitosis was entirely unknown.

"We've discovered a new translation pathway that nobody knew existed, which is used by a lot of the factors that are involved in cell division--specifically, separating the chromosomes," says Jones, who holds the Edwin K. Hunter Chair in the Regulatory Biology Laboratory. "This new information about the role of CDK12 helps us understand how cancer cells are disorganized, and also how chemical inhibitors of CDK12 could help kill cancer cells. The findings suggest that targeted inhibitors to CDK12 might also block parts of the mTOR pathway, and synergize with mTOR inhibitors or mitotic inhibitors that are important components of current therapies."

The scientists are now studying how CDK12 is inhibited in normal cells, which could suggest new approaches to blocking CDK12 activity in metastatic cancer cell therapy.

ARLINGTON HEIGHTS, IL - (APRIL 2, 2019) - Allergy shots (subcutaneous immunotherapy or SCIT) have been available for more than 100 years. Allergy tablets (sublingual immunotherapy or SLIT) have been approved by the Food and Drug Administration (FDA) for use in the United States for four years. A new study in Annals of Allergy, Asthma and Immunology, the scientific journal of the American College of Allergy, Asthma and Immunology (ACAAI) shows that most American allergists now prescribe the tablets for some patients to treat certain allergies. The study was developed by the ACAAI Immunotherapy and Diagnostics Committee.

"Five years ago, allergy tablets hadn't been approved by the FDA and weren't being prescribed for people with allergies in the U.S.," said allergist Anita Sivam, DO, ACAAI member and lead author. "Allergists were prescribing allergy shots because they were, and continue to be, a proven effective treatment. Once allergy tablets were approved in 2014, allergists began prescribing them for their patients. Of the 268 US allergists who responded to our survey in 2018, 197 (73 percent) reported prescribing allergy tablets."

Allergy tablets are available to treat northern grass pollens, Timothy grass pollen, ragweed and house dust mite. The northern grass pollens and the Timothy grass pollen tablets are both approved down to age 5 years and the other two for those 18 years and older. The tablets differ from allergy shots because after the first dose is given in an allergist's office, they can be taken at home. The tablets are placed under the tongue and dissolve.

In immunotherapy, the regular administration of the allergen doses causes your immune system to become less sensitive to the allergen. Reducing your sensitivity reduces your allergy symptoms.

"One of the big differences between shots and tablets is that shots are formulated by your allergist to treat your specific allergy or allergies," says allergist Mike Tankersley, MD, MBA, vice-chair of the ACAAI Immunotherapy and Diagnostics Committee and co-author of the study. "Tablets target a single allergy, and our study found that was the main barrier for allergists in prescribing tablets. If a patient has more than one allergy and is able to travel regularly to receive allergy shots, an allergist may recommend shots over tablets."

Both shots and tablets - the only FDA-approved immunotherapy treatments for allergies - are successful because they work by changing your immune system. They decrease some cells, chemicals and antibodies in your system that cause allergy symptoms and increase others that improve health. Allergy shots and tablets allow you to encounter your allergens without having a reaction. Immunotherapy also reduces the inflammation that characterizes hay fever and asthma, so many sufferers find their symptoms improve.

If your attention gets diverted in different directions by smartphones and other digital devices, take note: Media multitasking has now been linked to obesity.

New research from Rice University indicates that mindless switching between digital devices is associated with increased susceptibility to food temptations and lack of self-control, which may result in weight gain.

"Increased exposure to phones, tablets and other portable devices has been one of the most significant changes to our environments in the past few decades, and this occurred during a period in which obesity rates also climbed in many places," said Richard Lopez, a postdoctoral research fellow at Rice and the study's lead author. "So, we wanted to conduct this research to determine whether links exists between obesity and abuse of digital devices -- as captured by people's tendency to engage in media multitasking."

An upcoming print edition of Brain Imaging and Behavior will report on the study, entitled "Media multitasking is associated with higher risk for obesity and increased responsiveness to rewarding food stimuli."

The research was conducted in two parts. In the first study, 132 participants between the ages of 18 and 23 completed a questionnaire assessing their levels of media multitasking and distractibility. This was done using a newly developed, 18-item Media Multitasking-Revised (MMT-R) scale. The MMT-R scale measures proactive behaviors of compulsive or inappropriate phone use (like feeling the urge to check your phone for messages while you're talking to someone else) as well as more passive behaviors (like media-related distractions that interfere with your work).

The researchers found that higher MMT-R scores were associated with higher body mass index (BMI) and greater percentage of body fat, suggesting a possible link.

In follow-up research, 72 participants from the prior study underwent an fMRI scan, during which the researchers measured brain activity while people were shown a series of images. Mixed in with a variety of unrelated photos were pictures of appetizing but fattening foods.

When media multitaskers saw pictures of food, researchers observed increased activity in the part of the brain dealing with food temptation. These same study participants, who also had higher BMIs and more body fat, were also more likely to spend time around campus cafeterias.

Overall, Lopez said these findings, although preliminary, suggest there are indeed links between media multitasking, risk for obesity, brain-based measures for self-control and exposure to real-world food cues.

"Such links are important to establish, given rising obesity rates and the prevalence of multimedia use in much of the modern world," he said of the findings.

Lopez and his fellow researchers hope the study will raise awareness of the issue and promote future work on the topic.

A new study published today in The Lancet, has found that a simple blood test can help make the diagnosis for a common and potentially fatal pregnancy complication.

The team of scientists from King's College London found that by measuring the concentration of placental growth factor (PlGF) in a woman's blood, doctors were able to diagnose pre-eclampsia on average two days sooner. This was associated with significant improvements in outcomes for women without causing health problems for babies.

Lead author Professor Lucy Chappell, NIHR Research Professor in Obstetrics at King's College London said: "For the last hundred years, we have diagnosed pre-eclampsia through measuring blood pressure and checking for protein in a woman's urine. These are relatively imprecise and often quite subjective.

"We knew that monitoring PlGF was an accurate way to help detect the condition but were unsure whether making this tool available to clinicians would lead to better care for women. Now we know that it does."

Between June 2016, and October 2017, the team from King's enrolled 1,035 women with suspected pre-eclampsia to the study from 11 maternity units across the UK. Women were randomly assigned to two groups. One had their PlGF test results made available to their clinical team, the other did not.

PlGF testing was shown to reduce the average time to pre-eclampsia diagnosis from 4·1 days to 1·9 days and serious complications before birth (such as eclampsia, stroke, and maternal death) from 5% to 4%.

There was no change in the likelihood of complications for the baby, the age at which babies were delivered prematurely or whether they were admitted to a neonatal unit. It was important that this test did not cause more unnecessary cases of preterm birth for babies.

In response to the trial, NHS England has announced that they would be making the test more widely available across the NHS.

Professor Tony Young, national clinical lead for innovation at NHS England, said: "This innovative blood test, as set out in this new study, helps determine the risks of pre-eclampsia in pregnancy, enabling women to be directed to appropriate care or reduce unnecessary worry more quickly.

"The NHS, with partners in government, will be making this test more widely available across the NHS as part of our plans to ensure as many patients as possible can benefit from world-class health innovations."

Professor Chappell added: "The evidence shows that widespread PlGF testing could saves lives and it is fantastic news that NHS England agree. Many tests have come into practice without robust assessment. This time, we have evaluated this new test and shown that it improves care and outcomes for pregnant women and their babies."

Pre-eclampsia is suspected in around ten per cent of UK pregnancies, affecting approximately 80,000 women annually. If untreated, it can progress to cause complications in the woman, including damage to vital organs, fits and can be fatal for the woman and baby. Globally, 100 women die as a result of the condition every day.

As political leaders debate the future of the U.S. health care system, a pair of health financing experts discovered that all of the current proposals -- from Medicare for All to "repeal and replace" -- have been circulating in various forms since the 1940s.

In an article published today in the Annals of Internal Medicine, "Medicare for All and its rivals: new offshoots of old health policy roots," longtime health care researchers Steffie Woolhandler, M.D., M.P.H., and David U. Himmelstein, M.D., reveal the historical foundations of today's health care debate.

For example, the Medicare for All Act of 2019 (H.R. 1384), recently filed by Reps. Pramila Jayapal and Debbie Dingell, traces its roots back to the 1948 Wagner-Murray-Dingell national health insurance bill and the 1971 single-payer plan proposed by Sen. Ted Kennedy and Rep. Martha Griffiths. Today's "public option" plans that would offer individuals the option to buy-in to Medicare or Medicaid were first proposed by two Republicans, Sen. Jacob Javits and Rep. John Lindsay in the early 1960s. Even President Trump's recent budget proposal -- which seeks to shrink the government's role in health care by cutting trillions in Medicare and Medicaid funding, further privatizing Medicare and the VA, stripping the basic protections of the Affordable Care Act, and saddling patients with higher deductibles - echoes policies favored by President Richard Nixon and others in 1971.

Drs. Himmelstein and Woolhandler inherited the archives of Dr. Sidney S. Lee, who was a professor of health policy at Harvard Medical School and former general director of Beth Israel Hospital in Boston and chief executive of Michael Reese Hospital in Chicago. While recently exploring Dr. Lee's archives, the researchers came upon news clips, transcripts of Congressional hearings, and other descriptions of proposals that closely mirrored those still being proposed today.

"When Sen. Kennedy introduced a comprehensive single-payer bill in 1971, Republicans countered with a public option alternative that was friendlier to private insurers, and some conservative Democrats proposed settling for coverage with sky-high deductibles," said Dr. Woolhandler, an internist in the South Bronx, Distinguished Professor at CUNY/Hunter College and Lecturer in Medicine at Harvard. "In response, Sen. Kennedy complained that anything short of single-payer Medicare-for-All '...calms down the flame, but it really doesn't meet the need,' an observation that still holds true today."

Dr. Himmelstein, a Distinguished Professor at the City University of New York's (CUNY) Hunter College and Lecturer at Harvard Medical School, urged current political leaders not to repeat the mistakes of earlier generations that tinkered around the edges of the U.S. health system while ignoring its fundamental flaws.

"The leading option for U.S. health reform would leave 36 million people uninsured in 2027, while costs would balloon to nearly $6 trillion. And the disgraceful trends of decreasing life expectancy, rising drug prices, medical bankruptcy, and physician burnout would persist" said Dr. Himmelstein. "That option is called the status quo."

New Rochelle, NY, April 1, 2019--Modern medicines have positively contributed to public health and changed the ways human diseases are prevented and treated. Yet, most drugs are not without side effects. Adverse drug reactions (ADRs) rank among the leading causes of morbidity and mortality worldwide. The current paradigm of drug development can detect only the most common ADRs in clinical trials.

A new strategy to enhance pharmacovigilance signal detection for ADRs, drug safety and efficacy was described in a technology horizon scanning article, "Toward Panvigilance for Medicinal Product Regulation: Clinical Trial Design Using Extremely Discordant Biomarkers", published in the March issue of OMICS: A Journal of Integrative Biology, the peer-reviewed interdisciplinary journal by Mary Ann Liebert, Inc., publishers.

The article introduces the concept "panvigilance" as a systems approach to pharmacovigilance. Panvigilance is based on forecasting of signals on unknown drug effects, be they adverse, toxic, or therapeutic, by prioritizing pharmacokinetic and pharmacodynamic analyses in population edges as defined by biomarkers. Subsequently, it becomes easier to extrapolate drug safety and effectiveness performance to the general population.

An expert review article on panvigilance was also published in the same issue of OMICS, "Panvigilance: Integrating Biomarkers in Clinical Trials for Systems Pharmacovigilance", coauthored by Semra ?arda? and Asl?gül Kendirci at ?stinye University in ?stanbul, Turkey. The corresponding author for the expert review, Professor Semra ?arda?, PhD has noted "Panvigilance offers a new opportunity for integration of biomarkers in clinical trials beyond traditional contexts such as personalized medicine. Moreover, panvigilance and pharmacovigilance are complementary. Panvigilance approach can be applied not only to pharmaceuticals but also vaccines, nutrition research, cosmetics and medical devices as well."

Vural Özdemir, MD, PhD, DABCP, Editor-in-Chief of OMICS, has commented, "As with aircrafts or automobiles tested in wind tunnel experiments, new medicines, too, warrant stress testing to identify, early on, their safety performance under conditions that mimic the population extremes (edges) in regards to drug pharmacokinetics and molecular targets. Panvigilance clinical trial design, as described in the March issue of OMICS, offers innovation to reduce drug development risks and design medicines with greater safety performance and predictability in the clinic."

These articles are available free on the OMICS website until May 1, 2019.

Share of Medicare Advantage plans with broad networks increased from 80.1 percent in 2011 to 82.5 percent in 2015, and enrollment in broad-network plans grew from 54.1 percent to 64.9 percent.

A new study led by Boston University School of Public Health (BUSPH) researchers finds that networks in Medicare Advantage--a private plan alternative to traditional Medicare--are relatively broad and may be getting broader. The study, published in the April issue of Health Affairs, found that the share of Medicare Advantage plans with broad networks increased from 80.1 percent in 2011 to 82.5 percent in 2015, and enrollment in broad-network plans grew from 54.1 percent to 64.9 percent over the same period. Narrow networks were associated with urban areas, higher average income, and having more physicians nearby, as well as more competition between plans.

"This should be good news for folks concerned about insurers excessively restricting access to providers," says lead study author Yevgeniy Feyman, a doctoral student at BUSPH.

Previous studies have suggested that over a third of Medicare Advantage beneficiaries were in narrow networks, but these studies relied on physician directories, which are prone to error. For this study, supported by the Commonwealth Fund, the researchers instead used Medicare prescription claims data from 2011 through 2015 to infer networks of primary care physicians based on prescription patterns. Using this approach, they were able to look at about half of all Medicare Advantage local Coordinated Care Plan enrollment in the country.

The researchers found that narrow network plans dropped from 2.7 percent of all Medicare Advantage plans in 2011 to 1.8 percent in 2015. When the researchers controlled for demographic factors, they found that the proportion of broad-network plans in rural areas held at around 85 percent, and in urban areas grew from 76 percent to 79 percent. Among plans that were on the market for all five years of the analysis, the researchers found that 64 percent of the plans with narrow networks in 2011 were no longer narrow in 2015, while 99.5 percent of plans with medium or broad networks in 2011 still did in 2015. The researchers also found that health maintenance organizations (HMOs) had narrower networks than point-of-service (POS) plans and preferred provider organizations (PPOs).

ATLANTA --Excess weight before age 50 may be more strongly associated with pancreatic cancer mortality risk than excess weight at older ages, according to results of a study presented at the AACR Annual Meeting 2019, March 29-April 3.

Pancreatic cancer is relatively uncommon, accounting for just over 3 percent of all new cancer cases. However, it is an extremely deadly type of cancer, with a five-year survival rate of just 8.5 percent, according to the National Cancer Institute's Surveillance, Epidemiology, and End Results database. In the United States, pancreatic cancer is the third leading cause of cancer death, after lung and colorectal cancer, and is expected to cause about 46,000 deaths in 2019.

"Pancreatic cancer rates have been steadily increasing since the early 2000s," said the study's lead author, Eric J. Jacobs, PhD, senior scientific director of Epidemiology Research at the American Cancer Society in Atlanta. "We've been puzzled by that increase because smoking--a major risk factor for pancreatic cancer--is declining.

"Increased weight in the U.S. population is a likely suspect, but previous studies have indicated that excess weight is linked with only a relatively small increase in risk, which doesn't look large enough to fully explain recent increases in pancreatic cancer rates," Jacobs continued.

Jacobs said, however, that most previous studies on the link between weight and pancreatic cancer were based on weight measured in older adulthood, which may be less informative because it could reflect body fat gained too late in life to influence risk of pancreatic cancer during a typical lifespan. In this study, researchers sought to find out if excess weight measured earlier in adulthood might be more strongly linked to pancreatic cancer risk than excess weight measured at older ages.

Researchers examined data from 963,317 U.S. adults with no history of cancer who enrolled in the American Cancer Society's Cancer Prevention Study II, a nationwide study of cancer mortality that began in 1982 and followed participants through 2014. All participants reported their weight and height just once, at the start of the study, when some were as young as 30 while others were in their 70s or 80s. The researchers used this information to calculate body mass index (BMI), a measure of weight relative to height, as an indicator of excess weight.

During the follow-up period, 8,354 participants died of pancreatic cancer. As expected, higher BMI was linked with increased risk of dying of pancreatic cancer, but this increase in risk was largest for BMI assessed at earlier ages. An increase of five units of BMI, about 32 pounds for a 5-foot, 7-inch adult, was associated with 25 percent increased risk in those who had their BMI assessed between ages 30 and 49; 19 percent increased risk in those assessed between 50 and 59; 14 percent increased risk in those assessed between ages 60 and 69; and 13 percent increased risk in those assessed between ages 70 and 89. Jacobs noted that while the study only had information on deaths from pancreatic cancer, the disease is nearly always fatal, so results are expected to be similar to those for new diagnoses of pancreatic cancer.

Jacobs said the study results indicate that excess weight could increase risk of death from pancreatic cancer more than previously believed. Furthermore, Jacobs noted that recent generations are reaching early middle age with more excess weight than earlier generations did.

Therefore, he anticipates that excess weight will explain a larger proportion of pancreatic cancer risk in the future as newer and heavier generations reach the older ages when pancreatic cancer typically occurs. For example, he estimates that 28 percent of pancreatic cancer deaths in Americans born between 1970 and 1974 will be attributable to excess weight, compared to only 15 percent of pancreatic cancer deaths among Americans born in the 1930s, a group that was much less likely to be obese in early middle age.

"Our results strongly suggest that to stop and eventually reverse recent increases in pancreatic cancer rates, we will need to do better in preventing excess weight gain in children and younger adults, an achievement which would help prevent many other diseases as well," Jacobs said.

ATLANTA -- A combination of the anti-CTLA-4 immunotherapeutic ipilimumab (Yervoy) and the anti-PD-1 immunotherapeutic nivolumab (Opdivo) showed clinical benefit among patients with rare, high-grade neuroendocrine carcinoma, according to results from the DART phase II clinical trial presented at the AACR Annual Meeting 2019, March 29-April 3.

"Rare tumor types, as an aggregate, represent nearly a quarter of all cancers," said Sandip Patel, MD, associate professor of medicine at the University of California San Diego School of Medicine in La Jolla. "Our study highlights the feasibility of performing clinical trials among patients with rare cancers, and hopefully will help dispel the belief that clinical trials are not feasible for this patient population.

"We were pleased to see that patients with high-grade neuroendocrine carcinoma derived benefit from a combination of the two immune checkpoint inhibitors in the DART trial," said Patel, who is also a medical oncologist with Moores Cancer Center at UC San Diego Health. "Given that current treatment options for patients with high-grade neuroendocrine carcinoma are generally limited to aggressive chemotherapy regimens, this is an exciting finding for this patient population."

The aim of the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) trial is to evaluate the combinatorial efficacy of ipilimumab (1mg/kg every six weeks) and nivolumab (240mg every two weeks) in patients with rare tumor types. This study summarizes the findings from 33 patients with neuroendocrine tumors, with patients with pancreatic neuroendocrine cancers currently being studied in a separate ongoing cohort of DART. The primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS).

The most common tumor sites were gastrointestinal (15 patients) and lung (six patients); 58 percent (19 patients) had high-grade disease. Patients had received a median of two lines of therapy prior to enrollment in the trial.

In this neuroendocrine cohort, the ORR was 24 percent, which included one complete response (CR) and seven partial responses (PR). All patients who had a CR or PR had high-grade disease.

"We only observed complete and partial responses among patients with high-grade carcinoma, and one preliminary hypothesis for this finding is that high-grade neuroendocrine carcinomas may have a higher tumor mutational burden, which is an indicator of better response to immunotherapy," said Patel. "We are planning to verify these results, specifically in patients with high-grade neuroendocrine carcinoma, later this year, as a separate cohort in the DART trial."

The six-month PFS was 30 percent, and the median OS was 11 months. The most common toxicities included fatigue (30 percent of patients) and nausea (27 percent of patients). The most common immune-related adverse event (irAE) was grade 3-4 abnormal liver function; no grade 5 irAEs were observed.

Patel noted that an advantage of the DART trial was that patients could be treated at local centers, which was convenient for participants and facilitated their accrual. However, due to this design, there was no central pathology review, which represents a key limitation of the study, he added.

The SWOG Cancer Research Network, part of the National Cancer Institute's National Clinical Trials Network, created DART and is managing the trial. The DART study is funded by the National Institutes of Health through National Cancer Institute grant awards and in part by Bristol-Myers Squibb.

(PHILADELPHIA) - Glioblastoma is the most aggressive type of primary brain cancer, one with a prognosis of 11-15 months with standard treatment. Results from a phase 1b clinical trial of a new experimental glioblastoma vaccine developed by Jefferson and Imvax, show the treatment was tolerated well by patients, slowed tumor recurrence, and prolonged patient survival.

The research was presented at an oral session of the American Association for Cancer Research (AACR) annual meeting on March 31st in Atlanta, Georgia.

Researchers treated 33 patients with newly diagnosed glioblastoma multiforme with the novel cancer vaccine (IGV-001) in a prospective phase 1b clinical study and compared outcomes to a historical comparator group of 35 patients treated with standard of care at the same institution. The results showed patients treated with the vaccine had improved progression-free survival and overall survival compared to the control group treated with standard of care alone.

"The response we see in some patients is very encouraging," says David Andrews, MD, Professor of Neurosurgery at the Vickie & Jack Farber Institute for Neuroscience -- Jefferson Health and co-founder, Chief Medical Officer and interim Chief Executive Officer of Imvax. "We look forward to initiating a phase II trial later this year to confirm these phase 1b results."

The vaccine is created from the patient's own tumor cells sampled during surgical removal of the primary brain tumor. Researchers first take the cancer cells, treat them with an antisense oligodeoxynucleotide (AS-ODN) against IGF-R1, a receptor shown to drive tumor growth and metastasis, and load them with additional AS-ODN into diffusion chambers. Then the dime-sized chambers and their contents are irradiated and implanted under the skin of the patient's abdomen.

"As a consequence of the combined effects of the IGF-1R antisense and irradiation, our evidence shows that the chambered tumor cells release antigens, which together with the immunomodulatory AS-ODN, diffuse out of the chamber into the patient's body and activate the immune system against brain tumor cells," says immunologist D. Craig Hooper, PhD, a Professor of Cancer Biology at the Sidney Kimmel Cancer Center - Jefferson Health and a co-founder and Chief Scientific Officer of Imvax.

As a nationally renowned neurosurgeon treating glioblastoma patients for decades, Dr. Andrews was frustrated with the poor options for treatment in glioblastoma. He was interested in using antisense molecules, ones that render glioblastoma cells more susceptible to conventional radiotherapy. However, preclinical experiments and an early clinical study of the effect of implantation of diffusion chambers containing glioblastoma cells showed there was radiographic evidence of delayed tumor shrinkage. This delay suggested that a systemic, possibly immune response may be at play. To better understand the observations, Dr. Andrews reached out to Dr. Hooper, who has an extensive background in studying immune regulation and particular expertise in neuroimmunity.

Over the course of fifteen years, translational research led by Dr. Hooper and clinical studies led by Dr. Andrews refined the diffusion chamber combination product used in the current phase 1b trial.

"This is an incredibly important advance emerging from leading investigators from the Sidney Kimmel Cancer Center. We are enthusiastic about the potential for this intervention, and as is befitting for an NCI designated Cancer Center, were proud to have provided the initial seed funds to develop the bold new idea," says Karen E Knudsen, PhD, EVP of Oncology Services and Enterprise Director of the Sidney Kimmel Cancer Center.

The phase 1b clinical trial builds on earlier work showing that standard-of-care treatment for glioblastoma damages the immune system and suggesting that the vaccine would be more effective in patients whose immune systems had not been compromised by prior therapy. The phase 1b trial only enrolled patients who were scheduled to have surgery, prior to the start of standard-of-care adjuvant therapy.

The study enrolled 33 patients between September 2015 and March 2018. The study participants were divided into four groups treated at various doses of vaccine, ranging from 10 chambers for 24 hours at the minimum dose, to a maximum of 20 chambers for 48 hours. Patients were followed for a median of 13 months (ranging from four to 39 months).

The results showed that patients who received the Imvax glioblastoma vaccine had longer progression-free survival and overall survival - two common measures of cancer treatment success - than the control group. The researchers saw no vaccine-related adverse events. The median prognosis, or overall survival, for patients treated with the highest dose of the vaccine was 21.9 months, compared to 14.6 months for standard of care. Median progression-free survival was 10.4 months for the highest dose vaccine, significantly higher than the 6.9 and 5.4 months in published standard of care studies.

"This is creative collaboration at its best. We have physicians challenged with the limitations of medicine who therefore reach out to basic researchers in order to brainstorm potential solutions," says Robert Rosenwasser, MD,MBA, President and CEO of the Vickie & Jack Farber Institute for Neuroscience. "This is the reason academic medical centers like Jefferson excel with innovations that improve lives. The depth of cellular and molecular knowledge in bench science generates the design of treatments that are most likely to succeed. When basic laboratory science and clinical research come together with a passionate need to improve the lives of our patients and families, we develop incredible advances in treatment paradigms."

ATLANTA -- A chimeric antigen receptor (CAR) T-cell therapy that targets the protein mesothelin showed no evidence of major toxicity and had antitumor activity in patients with malignant pleural disease from mesothelioma, according to results from a phase I clinical trial presented at the AACR Annual Meeting 2019, March 29-April 3.

"Patients with advanced-stage solid tumors, such as mesothelioma, and lung and breast cancers, that are metastatic to the chest cavity have poor outcomes despite treatment," said Prasad S. Adusumilli, MD, deputy chief of thoracic surgery at Memorial Sloan Kettering Cancer Center (MSK). "Treatment with CAR T cells results in dramatic successes in blood cancers; however, results have been disappointing to date for solid tumors."

Adusumilli, senior author of the study Michel Sadelain, MD, PhD, and colleagues engineered the mesothelin-targeted CAR T cells called IcasM28z using completely human components, which includes the Icaspase-9 safety "suicide" switch that can be activated to kill all CAR T cells in a patient's body in case of an unexpected toxicity.

"The novelty of our study is that the CAR T cells target the cancer cell-surface protein, mesothelin, which is expressed on the majority of cancer cells, and they are delivered directly to the tumor site using regional delivery techniques," Adusumilli said. "If this approach is successful, 2 million patients with mesothelin-expressing solid tumors per year in the United States will be eligible for this treatment."

The investigators recruited 21 patients with malignant pleural disease (19 with malignant pleural mesothelioma, one with metastatic lung cancer, and one with metastatic breast cancer); 40 percent of them had received three or more lines of prior therapy. After cyclophosphamide preconditioning, IcasM28z CAR T cells were injected directly into the pleural cavity using an interventional radiology procedure.

The investigators evaluated multiple clinical, radiological, and laboratory parameters in the patients who received the CAR T cells and found no evidence of toxicity at the doses tested. CAR T cells were found to be persistent in the peripheral blood of 13 patients during the 38-week evaluation, and their presence was associated with more than 50 percent decrease in the levels of a mesothelin-related peptide in the blood and evidence of tumor regression on imaging studies.

One patient with mesothelioma underwent curative-intent surgery followed by radiation therapy to the chest. "Twenty months from diagnosis, the patient is doing well, with no further treatment," Adusumilli noted.

Fourteen patients went on to receive anti-PD1 checkpoint blockade agents. In preclinical studies, the researchers found that in large tumors, the CAR T cells became functionally exhausted even while residing in the tumor. Treatment with anti-PD-1 agents could reactivate the exhausted CAR T cells and eradicate the tumors in a proportion of mice. "On the basis of these published observations, in some patients who received CAR T cells, we administered anti-PD-1 agents off-protocol as next line of therapy," Adusumilli said.

After up to 21 cycles of treatment with an anti-PD1 agent, two patients had complete metabolic response on PET scans at 60 and 32 weeks, respectively, and these responses are ongoing at the time of this reporting; five patients had partial response; and four had stable disease.

"Combining rationally developed strategies--such as interventional radiology, T-cell genetic engineering, and newer immunotherapy agents--has produced encouraging results and provides rationale to further investigate this approach in aggressive, therapy-resistant cancers such as mesothelioma, for which the currently available treatment options are not optimal," Adusumilli noted.

A limitation to the study is that this is a phase I trial, and the long-term efficacy of this approach has not yet been established, Adusumilli noted.

TORONTO, March 29, 2019 -- Researchers at the University of Toronto and The Hospital for Sick Children (SickKids) have teamed up with educators, public health practitioners and grade seven students in Ontario to develop and implement a new approach to delivering school-based vaccines that improves student experience.

The CARD System (Comfort, Ask, Relax, Distract) is an evidence-based approach that can be implemented as an in-class game to help students better prepare for vaccination clinics, thereby improving their experiences. Findings were published as a collection of studies in a special open source edition of Paediatrics & Child Health, the official journal of the Canadian Paediatric Society.

"Vaccine hesitancy has been identified as a major threat to global health," says Anna Taddio, lead author and researcher the University of Toronto's Leslie Dan Faculty of Pharmacy and a senior associate scientist at SickKids.

"While school-based programs are an efficient way to deliver vaccines that help protect youth and prevent the spread of illness, many youth have negative experiences due to fear of injection-related pain."

"Fear of pain and needles, compounded by negative experiences, can lead to vaccine refusal and even a longer term reluctance to fully engage health care services throughout life," says Taddio, who is an internationally recognized expert in children's experience of pain.

The CARD System allows students to select coping strategies they want to use during their vaccination by selecting a letter of the CARD system.

On vaccination day, nurses explicitly ask students about their level of fear and what 'CARDs they want to play' to help them cope and support them in their choices. For example, a student may wish to play from category "A" and ask to be vaccinated in a private place, or "D" and bring an electronic device to serve as a distraction.

This approach was implemented in a controlled clinical trial involving 10 Niagara Region schools. The results showed improved student symptoms and increased use of the CARD tools. Students, educators and public health nurses involved were pleased with the approach and expressed support for continuing to use CARD beyond the study. Now the Niagara Region has implemented the CARD system across all schools in their area.

"CARD is the first knowledge translation tool to integrate all that is known about pain, fear and fainting mitigation into a simple, low-cost, appealing training approach for youth," says Taddio.

Involving youth in the design and development of CARD was crucial because it allowed the tools to be developed based on students' needs and preferences.

"The CARD system is a very intuitive and intentional approach to immunization that enhances the student immunization experience," says Leslie Alderman, Vaccine Preventable Diseases Supervisor with Niagara Public Health and member of the Pain Pain Go Away Project Team that oversaw the pilot implementation project.

Video: School Vaccinations - The CARD System: Play your power CARD

Earlier this year the World Health Organization (WHO) identified vaccine hesitancy as one of ten threats to global health, alongside climate change, antimicrobial resistance and Ebola. Taddio believes that acknowledging barriers to vaccination, like fear and pain, and then designing approaches to address these barriers, should help improve vaccine hesitancy over time. Talking to students about needles and their fears did not make them more scared or not want to get immunized.

The pilot implementation project demonstrated a reduction in fear and dizziness, and also resulted in fewer children coming back to the clinic after their vaccination with associated symptoms. However, the pilot did not show an uptake in vaccinations by students.

"This is not entirely surprising," says Taddio. "CARD represents a major change in how we deliver school-based vaccines and it will take some time before we can start to measure the impact of CARD on vaccination rates. But it's also important to point out that we didn't see a decline in vaccination rates, either."

As increasing numbers of patients gain online access to their radiology reports, a new study published in the April 2019 issue of the American Journal of Roentgenology (AJR) assesses how thoroughly patients understand these complex documents.

Traditionally intended to communicate findings and diagnoses to clinicians, radiology reports have become much more accessible to patients through the advent of online portals and an increasing focus among radiologists on patient-centered care. But what are these patients learning from this unprecedented access to their health records?

The study, "Readability of Lumbar Spine MRI Reports: Will Patients Understand?," reviewed 110 lumbar spine MRI reports dictated by 11 fellowship-trained radiologists at a single academic medical center. Reports were evaluated using five quantitative readability tests: the Flesch-Kincaid Grade Level, Flesch Reading Ease, Gunning Fog Index, Coleman-Liau Index, and the Simple Measure of Gobbledygook.

Unfortunately for patients looking for easily understandable health information, the authors found that all the lumbar spine MRI reports were written at a readability level significantly above the average reading ability of U.S. adults. Only one report studied was written at or below eight-grade level (the average reading ability of U.S. adults) and the mean readability grade level of all the reports was greater than a 12th-grade reading level. The authors note that in prior studies patients cited complex language, specialized terminology, and report length, as contributing factors in their difficulty understanding radiology reports.

The National Institutes of Health and the American Medical Association recommend a reading level at or below sixth-grade for patient education materials, which begs the question of how much increasing patient access to electronic health information should determine the character of the information itself. The evolving role of patient reports -- from documents written exclusively for referring clinical providers to "educational" materials routinely accessed by patients -- raises new considerations for how these documents might be written and presented in the future, and the role radiologists may play in helping patients to better understand them.

Paul Yi, MD, one of the authors of the study said, "It is our hope that we bring awareness to the potential difficulties patients' may have in interpreting their healthcare information, so that potential solutions can start to be developed."

An essential part of breast intervention is the process of assessing concordance between imaging findings and core biopsy results. When pathology results are considered benign discordant, current standard of care is surgical excision, even though many of these lesions will ultimately be found benign.

A new study published in the April 2019 issue of the American Journal of Roentgenology (AJR) investigates whether including contrast-enhanced MRI in the assessment process might significantly benefit patient care.

The authors hypothesized that contrast-enhanced MRI -- used in high-risk screening and widely considered the most sensitive detection method of invasive breast cancer -- could provide useful findings to successfully triage patients with discordant benign biopsy results to surgical or nonsurgical management.

The study, "Use of Contrast-Enhanced MRI in Management of Discordant Core Biopsy Results," identified 45 patients (46 lesions) who received discordant ultrasound or stereotactic biopsy results and subsequently underwent contrast-enhanced MRI between 2012 and mid-2018. Findings at diagnostic imaging prior to MRI were classified BI-RADS category 4 -- suspicious abnormality (between 2-95% likelihood of malignancy).

31 patients had negative or benign MRI findings (32 lesions), confirmed stable at follow-up imaging of at least 6 months in four patients and at least 1 year in 27 patients. Fourteen patients had suspicious MRI findings and proceeded to surgery. All malignancies and borderline lesions necessitating surgery (atypia, papilloma) were defined as disease-positive. Eight of the 14 lesions were ultimately malignant, 4 lesions were borderline. There were two false positive MRIs.

Excluding the four patients with only 6 month follow up confirming stability, sensitivity, specificity, positive predictive value, and negative predictive value of MRI were calculated as 100%, 93.3%, 85.7%, and 100%. The false-positive rate of MRI was 2 of 30 (6.7%); the false-negative rate was 0%.

In conclusion, the authors found that contrast-enhanced MRI in the management of discordant benign core biopsy results did allow a significant number of patients -- 31 of the original 45 patients (68.9%) -- to avoid unnecessary surgery.

"MRI is the most sensitive test for diagnosis of breast malignancy," Linda Sanders, MD--one of the authors of the study--said. "Further investigation is recommended to evaluate the use of MRI in specific diagnostic situations, particularly those nine scenarios that the American Society of Breast Surgeons considers indications for surgical excision, including anatomic inaccessibility of lesion, or interval change in a lesion previously diagnosed as benign by core biopsy. An achievable goal is to reduce the frequency of surgery performed on patients with benign disease. A more ambitious goal is to reduce the frequency of benign core biopsies by incorporating MRI into the management algorithm of BI-RADS 4 lesions."