Body

CINCINNATI - Scientists used an experimental targeted molecular therapy to block a matrix-forming protein in heart cells damaged by heart attack, reducing levels of scarred muscle tissue and saving mouse models from heart failure.

Researchers at the Cincinnati Children's Heart Institute report in the journal Circulation testing a manufactured peptide called pUR4 to block the fibronectin protein in human heart cells donated by heart failure patients. The treatment prevented the human heart cells from failing and restored their function. The treatment also reduced fibrosis and improved heart function after a simulated heart attack in mice.

Fibronectin is normally a good actor in the body. It helps form a cell-supporting matrix for the body's connective tissues, aiding tissue repair after injury.

But after a heart attack, fibronectin overreacts, it polymerizes and helps produce too much connective matrix. It also causes hyperactive production of clogged and dysfunctional cardio myofibroblast cells that damage the heart. The pUR4 compound is designed so it will attach to surface points on fibronectin, effectively inhibiting its effects in injured heart cells.

"Our data are a strong proof of principle and the first to show that inhibiting fibronectin polymerization preserves heart function, reduces left ventricle remodeling and limits formation of fibrotic connective tissue," said the study's lead investigator Burns Blaxall, PhD, director of translational research in the Heart Institute and the Center for Translational Fibrosis Research.

Testing a Tiny Solution for a Big Problem

Although heart disease is the leading cause of death in the world, few effective treatment options are available for patients--many having had a previous heart attack or congenital heart disease. The pUR4 molecular treatment used in the current study is one of several compounds Blaxall and his colleagues are testing that show promise in preliminary preclinical research data.

Heart fibrosis and cardiac remodeling are medical challenges that are also faced by children with congenital heart disorders, and ongoing medical challenges requiring specialized care often follow these children into adulthood.

A key question in the current Circulation study was verifying the results of pUR4 targeted molecular therapy in both the mouse models and human heart failure cells. In mice with simulated heart attack that as a control experiment received a placebo therapy, the animals developed significant fibrosis and heart failure. When researchers treated mice with pUR4 for just the first seven days after heart attack, or genetically deleted fibronectin activity from the heart cells of mice, these reduced fibrosis and improved cardiac function. Treatment of human failing heart cells with pUR4 also reduced their fibrotic behavior.

Next Steps

The researchers emphasize it's too early to know whether the experimental therapy in this study can one day be used to treat human heart patients clinically. Extensive additional research is needed first, including proving pUR4's safety in larger animal models and then moving on to establish proof-of-principal effectiveness treating heart failure in those models, according to Blaxall.

Researchers also are working to refine the pUR4 peptide to enhance its capabilities for localized administration to the heart and for extended-release in patients.

Even the briefest increase in airborne fine particulate matter PM2.5, pollution-causing particles that are about 3 percent of the diameter of human hair, is associated with the development of acute lower respiratory infection (ALRI) in young children, according to newly published research.

Increases in PM2.5 levels also led to increased doctor visits for these lung infections.

The groundbreaking study, "Short-Term Elevation of Fine Particulate Matter Air Pollution and Acute Lower Respiratory Infection," is the largest to date on this health concern, involving more than 100,000 patients.

The research was undertaken by a team from Intermountain Healthcare, Brigham Young University, and the University of Utah, and is published online in the American Journal of Respiratory and Critical Care Medicine, an American Thoracic Society journal.

"The most important finding of this study is that infectious processes of respiratory disease may be influenced by particulate matter pollution at various levels," said lead author Benjamin Horne, PhD, director of cardiovascular and genetic epidemiology at the Intermountain Medical Center Heart Institute in Salt Lake City, Utah. "The exact biological implications of the study's findings require further investigation."

Dr. Horne and colleagues studied 146,397 individuals who were treated for ALRI between 1999 and 2016 at Intermountain Healthcare facilities throughout Utah's Wasatch Front region.

The Wasatch Front is approximately 80 miles long and 10-20 miles wide, bordered on both sides by mountains. It consists primarily of suburbs, but also includes the cities of Salt Lake City, Ogden and Provo/Orem.

PM2.5 levels were estimated based on data from air quality monitoring stations along the Wasatch Front, where approximately 80% of Utah's population resides. Measurements were also made at secondary locations. Short-term periods of PM2.5 elevation were matched with the timing of increases in healthcare visits for ALRI.

The primary aim of the study was to determine if there was an association between these fine particulates and ALRI in very young children, with a secondary objective of finding the same associations for older children, adolescents and adults.

The research team found ALRI associated with elevated levels of PM2.5 in both children and adults - even in newborns and toddlers up to age two, who represented 77% (112,467) of those who had an ALRI diagnosis.

Nearly 60% of U.S. children live in counties with PM2.5 concentrations above air quality standards.

This study was performed in a location where the average daily PM2.5 level is lower than places like Los Angeles and New York. Due to the topography of the region, though, air pollution may become trapped in the high mountain valleys of the Wasatch Front--especially during temperature inversions, which typically occur in the winter months.

When PM2.5 becomes trapped in the valleys, this often leads to sharp increases in PM2.5 to levels considered to be unhealthy (>35 micrograms per cubic meter, and at times approaching 100 ug/m3).

"In many places that have higher average PM2.5, the PM2.5 level does not vary as much as it does on the Wasatch Front, so it is not clear how this study's findings may transfer to those locales where the air pollution exposure is higher over the long term, but short term spikes do not occur," said Dr. Horne. "It may be, though, that long-term exposure to air pollution makes people more susceptible to ALRI on a routine basis, although additional studies will be required to test this hypothesis."

Bronchiolitis, a condition in which small breathing tubes in the lungs called bronchioles become infected and clogged with mucus, is the most common acute lower respiratory infection in children.

Fifty to 90 percent of bronchiolitis cases are caused by respiratory syncytial virus (RSV), which is the most common cause of hospitalization in the first two years of life. Sixty-four percent of individuals studied had a diagnosis of bronchiolitis.

"Overall, it took about 2-3 weeks for the ALRI hospitalizations or clinic visits to occur in this study after the rapid rise in PM2.5 had been observed," said Dr. Horne.

In an analysis of death rates among the study population, 17 children ages 0-2, nine children ages 3-17 and 81 adults (18+) died within 30 days of diagnosis with ALRI.

In theorizing about the connection between PM2.5 and ALRI, Dr. Horne said: "The air pollution itself may make the human body more susceptible to infection or may impair the body's ability to fight off the infectious agents. It may be that PM2.5 causes damage to the airway so that a virus can successfully cause an infection or that PM2.5 impairs the immune response so that the body mounts a less effective response in fighting off the infection. This could lead to longer periods of ALRI symptoms or more severe symptoms requiring a higher intensity of medical care for the infected individual. It may also be that periods of acute increases in PM2.5 lead people to stay indoors more where they are in closer contact with others who carry infectious agents and can transmit the infection to them."

Motor vehicles contribute about 48% of emissions that lead to the formation of fine particulates. Small industry and businesses such as gas stations and dry cleaners, as well as home heating, emit about 39% of all fine particulates. Large manufacturing accounts for 13% of fine particulates.

"The practical implications for prevention of ALRI and amelioration of symptoms include that when an acute increase in the level of PM2.5 occurs, people may be able to prevent infections or decrease ALRI symptom severity or duration by reducing their exposure to the air pollution," said Dr. Horne. "Furthermore, a substantial elevation in PM2.5 may also serve as a nudge that reminds or alerts people to avoid areas and activities where other people may share an infection with them, to not touch their face with dirty hands, to be vigilant about washing their hands when reasonably possible or prudent, and to engage in other preventive behaviors that are known to reduce infection risk."

Regularly drinking more than the recommended UK guidelines for alcohol could take years off your life, according to new research published today in the Lancet. Part-funded by the British Heart Foundation, the study shows that drinking more alcohol is associated with a higher risk of stroke, fatal aneurysm, heart failure and death.

The authors say their findings challenge the widely held belief that moderate drinking is beneficial to cardiovascular health, and support the UK's recently lowered guidelines.

The study compared the health and drinking habits of around 600,000 current drinkers in 19 countries worldwide and controlled for age, smoking, history of diabetes, level of education and occupation.

The upper safe limit of drinking was about 5 drinks per week (100g of pure alcohol, 12.5 units or just over five pints of 4% ABV2 beer or five 175ml glasses of 13% ABV wine).

However, drinking above this limit was linked with lower life expectancy. For example, having 10 or more drinks per week was linked with 1-2 years shorter life expectancy1. Having 18 drinks or more per week was linked with 4-5 years shorter life expectancy.

The research supports the UK's recently lowered guidelines, which since 2016 recommend both men and women should not drink more than 14 units of alcohol each week. This equates to around 6 pints of beer or 6 glasses of wine a week.

However, the worldwide study carries implications for countries across the world, where alcohol guidelines vary substantially.

The researchers also looked at the association between alcohol consumption and different types of cardiovascular disease. Alcohol consumption was associated with a higher risk of stroke, heart failure, fatal aortic aneurysms, fatal hypertensive disease and heart failure and there were no clear thresholds where drinking less did not have a benefit.

By contrast, alcohol consumption was associated with a slightly lower risk of non-fatal heart attacks.

The authors note that the different relationships between alcohol intake and various types of cardiovascular disease may relate to alcohol's elevating effects on blood pressure and on factors related to elevated high-density lipoprotein cholesterol (HDL-C) (also known as good cholesterol). They stress that the lower risk of non-fatal heart attack must be considered in the context of the increased risk of several other serious and often fatal cardiovascular diseases.

The study focused on current drinkers to reduce the risk of bias caused by those who abstain from alcohol due to poor health. However, the study used self-reported alcohol consumption and relied on observational data, so no firm conclusions can me made about cause and effect. The study did not look at the effect of alcohol consumption over the life-course or account for people who may have reduced their consumption due to health complications.

Dr Angela Wood, from the University of Cambridge, lead author of the study said:

"The key message of this research is that, if you already drink alcohol, drinking less may help you live longer and lower your risk of several cardiovascular conditions."

"Alcohol consumption is associated with a slightly lower risk of non-fatal heart attacks but this must be balanced against the higher risk associated with other serious - and potentially fatal - cardiovascular diseases,"

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which part funded the study, said:

"This is a serious wakeup call for many countries."

Victoria Taylor, Senior dietician at the British Heart Foundation said:

"This powerful study may make sobering reading for countries that have set their recommendations at higher levels than the UK, but this does seem to broadly reinforce government guidelines for the UK.

"This doesn't mean we should rest on our laurels, many people in the UK regularly drink over what's recommended.

"We should always remember that alcohol guidelines should act as a limit, not a target, and try to drink well below this threshold."

PARIS, 12 April 2018 - An affordable hepatitis C combination treatment including the new drug candidate ravidasvir has been shown to be safe and effective, with extremely high cure rates for patients, including hard-to-treat cases, according to interim results from the Phase II/III STORM-C-1 trial presented by the non-profit research and development organisation Drugs for Neglected Diseases initiative (DNDi) at the International Liver Conference in Paris.

"The results indicate that the sofosbuvir/ravidasvir combination is comparable to the very best hepatitis C therapies available today but it is priced affordably and could allow an alternative option in countries excluded from pharmaceutical company access programs," said Bernard Pécoul Executive Director, DNDi.

The trial using medicines produced by Egyptian drug manufacturer Pharco Pharmaceuticals was run by DNDi and co-sponsored by the Malaysian Ministry of Health, in ten sites in Malaysia and Thailand. Agreements signed in 2016 and 2017 enabling the trials and patient scale-up in Malaysia set out a target price of US$300 for a 12-week treatment, an almost 100% drop from existing treatment prices in Malaysia.

"As hepatitis C has become a major public health concern in Malaysia, it is crucial to increase access to treatment for the benefit of the nation," said Datuk Dr Noor Hisham Abdullah Director General of Health, Ministry of Health, Malaysia. In September 2017, the government of Malaysia issued a "government-use" license on sofosbuvir patents to allow 400,000 people living with hepatitis C in Malaysia to access generic HCV regimens in public hospitals.

DNDi conducted the STORM-C-1 open label trial to assess the efficacy, safety, tolerance and pharmacokinetics of the drug candidate ravidasvir combined with sofosbuvir. 301 chronically infected adults were treated with the ravidasvir/sofosbuvir combination for 12 weeks for patients without cirrhosis of the liver, and for 24 weeks for those with compensated cirrhosis. In accordance with international standards defining cure for HCV treatments, 12 weeks after treatment completion, 97% of those enrolled were cured (95% CI: 94.4-98.6). Cure rates were very high even for the hardest-to-treat patients: people with liver cirrhosis (96% cured), people living with HIV using their usual treatment (97%), people infected with genotype 3 (97%) including those with cirrhosis (96%), and people who had been exposed to previous HCV treatments (96%). Importantly, patients combining several of these risk factors were cured, and no unexpected safety signals were detected.

"From a treatment provider perspective, this is very exciting as we have been waiting for a simple, affordable, robust treatment tolerated by all patients groups, including those whose treatment outcomes are currently poorer, like patients under antiretroviral therapy," said Pierre Mendiharat, Deputy Operations Director for Médecins Sans Frontières / Doctors Without Borders (MSF). "This will be crucial to expand treatment to the most vulnerable categories of patients in developing countries."MSF and DNDi are working together to increase access to care and treatment for HCV patients in key low- and middle-income countries, through the STORM-C project financed by MSF's Transformational Investment Capacity (TIC) initiative.

Over 71 million people live with hepatitis C worldwide, a disease which causes 400,000 deaths a year. Although highly effective treatments have existed for a number of years, less than three million people are on treatment, with more people infected every year than are put on treatment. The World Health Organization aims for 80% of people diagnosed with HCV to be put on treatment by 2030.

Ravidasvir is an oral NS5A inhibitor licensed to DNDi by Presidio Pharmaceuticals. Most people enrolled in the DNDi trial in Malaysia and Thailand had genotype 1 (42% of participants) or genotype 3 (53%), thereby confirming the combination's effectiveness for those two additional genotypes. Further trials are planned to document the efficacy and safety of the combination in patients infected with the other HCV genotypes and in particularly vulnerable groups, to enable a public health approach to the treatment of hepatitis C.

"Pharco is proud to enable a public health approach to hepatitis C treatment by providing affordable treatments. We look forward to future collaboration in additional clinical trials to confirm the safety and efficacy of ravidasvir," said Dr. Sherine Helmy, CEO, Pharco.

PHILADELPHIA - (April 12, 2018) - Wistar researchers have identified a novel therapeutic vulnerability in NRAS mutant melanoma and an effective strategy to address it, using a combination of two clinically relevant inhibitors, according to study results published online in EMBO Molecular Medicine.

NRAS mutant melanoma represents about 25 percent of melanoma cases. The prognosis for patients is generally poor because NRAS mutant melanoma is aggressive and resistant to most therapies. In addition, development of secondary NRAS mutations represents a mechanism of acquired resistance to targeted therapies.

"NRAS is a very attractive therapeutic target but also an extremely challenging one," said lead researcher Jessie Villanueva, Ph.D., assistant professor in the Molecular & Cellular Oncogenesis Program at Wistar. "Despite years of efforts, we don't yet have effective ways to block the activity of mutant NRAS, and the picture is further complicated by the heterogeneity of resistance mechanisms."

"We have identified a novel vulnerability in NRAS-dependent melanoma and developed a combination therapy that may offer a valuable strategy to target therapy resistant melanoma," she added.

Because NRAS and the other members of the RAS family have proven to be difficult to target directly, the most effective approach is to discover other areas of vulnerability. In such an effort, Villanueva and her team found that elevated expression of BRD4, a member of the BET family of transcriptional regulators, correlates with poor survival in NRAS mutant melanoma patients and that BRD4 is required for cell proliferation.

Small molecule inhibitors of BET proteins decreased viability of NRAS mutant melanoma cells, and this sensitivity correlated with BRD4 expression levels. To potentiate the effects of this treatment, the researchers evaluated it in combination with other RAS-related inhibitors that are currently in clinical trials. The combination of BET inhibitors with MEK inhibitors, which block a fundamental signaling pathway for melanoma, had a potent effect on melanoma both in vitro and, more importantly, in vivo, slowing down tumor growth and increasing survival in a mouse model of NRAS mutant melanoma.

The mechanism of this combined effect was analyzed, and in-depth studies showed the combination treatment caused a much more robust perturbation in the expression of genes that regulate cell division and survival compared to the either treatment alone. The effect included a strong inhibition of the TCF19 transcriptional regulator.

To further establish the therapeutic and clinical significance of these data, the Villanueva Lab tested the combination therapy in different models of melanoma with intrinsic and acquired therapy resistance. The combination of BET and MEK inhibitors significantly affected tumor growth and prolonged survival of mice bearing melanoma resistant to several targeted therapies and immunotherapies, confirming that co-targeting BET and MEK elicits potent anti-tumor effects and may be a valuable salvage strategy for patients that have failed all currently available therapies.

"We are confident that clinical studies of BET and MEK combination therapy could be rapidly implemented, since BET inhibitors are in advanced clinical trials and MEK inhibitors are FDA-approved for BRAF mutant melanoma patients," added Villanueva.

Geneva, Switzerland, 12 April 2018 - Alectinib provides longer symptom improvement than crizotinib in ALK-positive non-small-cell lung cancer (NSCLC), according to results from the ALEX trial (1) presented at the ELCC 2018 (European Lung Cancer Congress) in Geneva, Switzerland. (2)

The phase III ALEX trial was a head-to-head comparison of the next-generation tyrosine kinase inhibitor (TKI) alectinib versus the standard of care TKI crizotinib in patients with anaplastic lymphoma kinase (ALK)-positive NSCLC, dependent on a rearrangement of the ALK gene. Approximately 4% of NSCLC patients are ALK-positive and are at high risk of central nervous system (CNS) metastases. Alectinib improved progression-free survival and prolonged the time to CNS progression compared to crizotinib. Alectinib had a better toxicity profile than crizotinib despite a longer duration of treatment. (3)

Patient-reported outcomes in terms of health-related quality of life and lung cancer-related symptoms with alectinib and crizotinib are reported for the first time at ELCC. The EORTC QLQ-C30 questionnaire was used to evaluate health-related quality of life and the EORTC QLQ-LC13 questionnaire was used to assess lung cancer-related symptoms. Patients completed the questionnaires at baseline, every four weeks during treatment, within the four weeks after study withdrawal, and after disease progression. The reasons for withdrawal have been previously reported (3); very few were due to symptom deterioration in either group.

Around two-thirds of patients in both treatment groups completed the questionnaires (66% and 64% in the alectinib and crizotinib groups, respectively). Patients in both the alectinib and crizotinib treatment groups had clinically meaningful improvements in health-related quality of life. However, there was a longer duration of improvement in health-related quality of life for patients treated with alectinib (88 weeks) compared to crizotinib (68 weeks).

For the patients with CNS metastases at baseline, a lower proportion of patients in the alectinib arm had worsening in health-related quality of life compared with crizotinib starting at week four (10.8% vs. 20.6%) and persisting for most assessments through week 84 (0% vs. 16.7 %). In addition, a lower proportion of these patients reported worsening in cognitive function with alectinib compared to crizotinib (17.9% vs. 34.6% at week 32, respectively).

Regarding lung cancer symptoms, there was a clinically meaningful improvement in both treatment arms. But the duration of improvement was longer with alectinib compared to crizotinib (cough: 96 versus 84 weeks; chest pain: 96 versus 80 weeks; fatigue: 96 versus 68 weeks; pain in other parts: 96 versus 68 weeks, respectively).

Fewer patients in the alectinib group reported a clinically meaningful worsening in treatment-related symptoms such as diarrhoea, peripheral neuropathy, constipation, dysphagia, appetite loss, and nausea/vomiting.

Lead author Dr Maurice Pérol, medical oncologist, Centre Léon Bérard, Lyon, France, co-chair of ELCC 2018, said: "The patient-reported outcome data is consistent with the main results of the study. The primary analysis showed a similar response rate for crizotinib and alectinib, but a longer duration of response with alectinib. This is consistent with the improvements in health-related quality of life and lung cancer symptoms, which were of similar magnitude in both groups but lasted longer with alectinib."

"The high level of CNS activity shown with alectinib in the primary analysis is consistent with the fact that fewer patients treated with alectinib reported clinically meaningful worsening in health-related quality of life or cognitive function compared to crizotinib," he continued. "Finally, the superior tolerability profile of alectinib compared to crizotinib shown in this analysis is consistent with the adverse events profile recorded during the study."

Pérol said: "The patient-reported outcome data supports the use of alectinib as a new standard of care in the frontline treatment of patients with ALK-positive lung cancer."

Commenting on the study, Dr Fiona Blackhall, Honorary Consultant in Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK, said: "The ALEX trial was a practice-changing study that firmly placed alectinib as a first-line palliative treatment for ALK-positive non-small-cell lung cancer patients. This secondary analysis strengthens the rationale for alectinib as the standard of care in first-line treatment."

Blackhall said that increasingly, because of the cost of conducting clinical trials, patient-reported outcomes are not measured. But she said: "In this context of palliating advanced lung cancer, living better is as important, if arguably not more important, than living longer. And for this reason, patient-reported outcomes and health-related quality of life are crucial to assess and analyse."

She continued: "In patients with advanced lung cancer the symptom burden is high, particularly cough, breathlessness and chest pain. And so to have meaningful palliation and improvement in symptoms is of paramount importance. So alongside wishing to identify drugs that improve progression-free survival and overall survival ultimately, we need to ensure that those drugs also allow patients to live better. Goals of care are important in the everyday management of patients with lung cancer and alleviating the symptoms it causes is a key goal."

Regarding the impact of alectinib on symptoms in the ALEX trial, Blackhall said: "The time to deterioration in common and difficult to palliate lung cancer symptoms including cough, dyspnoea, and chest pain was comparable between alectinib and crizotinib. However, alectinib prolonged the improvement in those symptoms. That fits in with the previously reported improvement in progression-free survival and favourable tolerability with alectinib."

Cloud computing, "exhausted" T cells, breast cancer risk in childhood cancer survivors and clinical trial design for CAR-T therapy in solid tumors are among the topics St. Jude Children's Research Hospital investigators will discuss at the five-day American Association for Cancer Research annual meeting that begins Saturday, April 14, in Chicago.

Secure sharing and collaborative analysis of huge datasets are essential in the quest to discover cures for pediatric cancer. Scott Newman, Ph.D., group lead for bioinformatics analysis in the St. Jude Department of Computational Biology, will present St. Jude Cloud, a new publicly available data-sharing and collaboration platform. His talk is set for 3:05 p.m., Sunday, April 15, in Room N228, Level 2 of McCormick Place North. Abstract: 922

St. Jude Cloud is the world's largest public repository of pediatric cancer genomics data and also provides unique analysis tools and visualizations. The platform was developed by scientists at St. Jude in collaboration with Microsoft and DNAnexus. St. Jude Cloud allows scientists to explore more than 5,000 whole-genome (WGS), 5,000 whole-exome (WES) and 1,200 RNA-Seq datasets from more than 5,000 pediatric cancer patients and survivors. By 2019, 10,000 whole-genome sequences will be available on St. Jude Cloud.

Along with the presentations detailed below, St. Jude faculty and staff will also chair major symposiums, give educational talks and participate in forums and sessions on hereditary cancer surveillance and the regulatory horizon for development of CAR-T therapy for solid tumors.

April 14 Education Sessions

Paul Northcott, Ph.D., of the St. Jude Department of Developmental Neurobiology, will give a 1:30 p.m. talk about subgroup-specific enhancer hijacking in the brain tumor medulloblastoma. The talk is part of the "Hijacking the Epigenome in Cancer: Challenges and Opportunities" session set for Room N427, Level 4, McCormick Place North.

Suzanne Baker, Ph.D., of the St. Jude Department of Developmental Neurobiology, will give a 2 p.m. talk about cell context and consequence of oncogenic histone mutations in pediatric gliomas. The talk is part of a session titled "Genetic, Epigenetic and Cellular Context Driving Pediatric Brain Tumor Development," which will be held in Room S402, Level 4, McCormick Place South.

Zoran Rankovic, Ph.D., of the St. Jude Department of Chemical Biology and Therapeutics, will give a 3:15 pm. talk about the challenges and principles of drug design in neuro-oncology. He will speak at a session titled "From Chemistry to the Clinic: Part 3 - Approaches to Drug Design for Neuro-oncology," which will be held in Room S103, Level 1, McCormick Place South.

Other Sessions

CAR-T therapy for solid tumors

Scientific and regulatory challenges for developing CAR-T therapy for treatment of solid tumors will feature Stephen Gottschalk, M.D., chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. The session will include an update on CAR-T therapy for sarcoma, brain and other solid tumors. The event is set for 10:30 a.m., Monday, April 16, Room S401bcd, Level 4, McCormick Place South.

Surveillance in hereditary cancer

The National Cancer Institute estimates inherited mutations play a role in 5 to 10 percent of cancers, and more than 50 cancer predisposition syndromes have been identified. The debate continues about how best to monitor individuals with the syndromes, which can affect multiple organs. This session will include Kim Nichols, M.D., a member of the St. Jude Department of Oncology and director of the Cancer Predisposition Division. The forum is set for 5 p.m., Monday, April 16, Room N227, Level 2, McCormick Place North.

Researcher tracks his discovery from the bench to the bedside

More than 25 years ago, research led by Charles Sherr, M.D., Ph.D., yielded a discovery that today is helping cancer patients live longer. Sherr chairs the St. Jude Department of Tumor Cell Biology and is a Howard Hughes Medical Institute investigator. In 1991, Sherr and his colleagues discovered the cyclin D proteins and, one year later, identified cyclin D-dependent kinase 4 (CDK4), a key enzyme that regulates cell proliferation. Cyclin D-dependent CDK6 was discovered in 1994.

Today three FDA-approved CDK4/6 inhibitors are prolonging survival of patients with advanced breast cancer and are also in clinical trials for treatment of many other cancers. At the AACR meeting, Sherr will chair a major symposium on CDK inhibitors and will present an overview of how CDK4/6 inhibitors work in cancer therapy. "Combination targeted therapies with CDK4/6 inhibitors and certain other precision medicines durably arrest the proliferation of tumor cells, triggering the immune response that can kill tumor cells," Sherr said. "These combination targeted therapies can significantly prolong progression-free survival for cancer patients."

DATE: Monday, April 16
TIME: 10:30 a.m.
LOCATION: Room N227, Level 2, McCormick Place North
TITLE: CDK4/6 inhibitors: A paradigm shift in cancer treatment
ABSTRACT: None

Lethal brain tumor depends on common mutation for continued growth

Suzanne Baker, PhD, a member of the St. Jude Department of Developmental Neurobiology, will present evidence that a mutation carried in about 80 percent of patients with a lethal brain tumor is important for tumor growth. "The mutation causes massive deregulation of the epigenome, but how that contributes to cancer had been unclear," Baker said. "Our models suggest the mutation is very important for ongoing tumor growth." Baker and others had previously identified the point mutation in a family of DNA packaging proteins called histone H3 in most patients with the brain tumor diffuse intrinsic pontine glioma. The tumor has a dismal prognosis. The mutation affects the epigenome, which helps to regulate gene expression. The research reflects an ongoing effort to develop effective chemotherapy and targeted agents. The laboratory models researchers used included patient-derived xenografts, which makes it possible for researchers to study patient tumors growing in the same organ in mice. Baker is chairing the major symposium, where she is presenting the research.

DATE: Monday, April 16
TIME: 2:05 p.m.
LOCATION: Room S102 (Grand Ballroom), Level 1, McCormick Place South
TITLE: Transforming chromatin: Oncogenic histone H3 in diffuse intrinsic pontine gliomas
ABSTRACT: None

Research reveals the surprising origins of rhabdomyosarcoma

Researchers led by Mark Hatley, M.D., Ph.D., an assistant member of the St. Jude Department of Oncology, have written a new origin story for rhabdomyosarcoma, the most common soft tissue cancer in children. Under the microscope, rhabdomyosarcoma resembles muscle cells. Scientists have long believed the tumor originates in immature muscle cells, even though the tumor can occur in tissue without skeletal muscle. Using genetic fate mapping in genetically engineered mice, Hatley and his colleagues have determined that rhabdomyosarcoma originates not in immature muscle cells, but in immature cells meant to line the inner surface of blood vessels. Evidence suggests that problems arise when genetic programs meant to drive muscle development are mistakenly activated in non-muscle cells. "Despite aggressive treatment, clinical outcomes have not improved in three decades," Hatley said. "Revealing the molecular underpinnings of this tumor is an important step for developing more effective treatments." Catherine Drummond, Ph.D., a St. Jude postdoctoral fellow, will present the findings.

DATE: Monday, April 16
TIME: 3:05 p.m.
LOCATION: Room S405, Level 4, McCormick Place South
TITLE: Location specificity in fusion-negative rhabdomyosarcoma driven by cell of origin
ABSTRACT: 3014

Researchers rank breast cancer risk for childhood cancer survivors

Researchers know female childhood cancer survivors are at increased risk for developing breast cancer, primarily due to their earlier cancer therapy. Now St. Jude scientists have combined whole-genome sequencing results with clinical risk factors such as prior treatment exposure to measure the breast cancer risk of individual survivors. The approach is an apparent first and calculates breast cancer susceptibility based on the presence of rare, high-risk genetic mutations in any of the well-established breast cancer predisposition genes as well as mutations in 172 genetic variants that individually confer more modest risk. Survivors with high-risk mutations had a 17-fold increased risk of developing breast cancer. The approach also helped to stratify risk among survivors without high-risk mutations. Among those survivors, those with the highest scores were three times more likely to develop breast cancer than survivors with the lowest scores. "Such individual risk profiles will help survivors and their health care providers better understand and manage survivors' risk, not only for breast cancer but possibly for other health risks with a genetic component," said Zhaoming Wang, Ph.D., of the St. Jude Department of Computational Biology. He is presenting the findings. The study involved 1,133 female St. Jude cancer survivors enrolled in the St. Jude Lifetime Cohort study (St. Jude LIFE).

DATE: Monday, April 16
TIME: 3:05 p.m.
LOCATION: Room S101, Level 1, McCormick Place South
TITLE: Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE)
ABSTRACT: 3007

Progress reported in quest to 'revive' T cells for treatment of solid tumors

Benjamin Youngblood, Ph.D., an assistant member of the St. Jude Department of Immunology, will detail research that suggests reversing DNA methylation may be essential for effective immunotherapy against solid tumors. Researchers discovered that T cell "exhaustion" in mice was epigenetically regulated by DNA methylation, which functions as an off-switch for gene expression. Researchers also identified a chemotherapy drug that reversed the epigenetic process. Investigators checked pediatric solid tumors and found tumor-associated T cells that were similarly exhausted. The exhausted T cells failed to mount an immune response against the tumor. Youngblood and his colleagues are now exploring an epigenetic contribution to T cell exhaustion in cancer patients. "That may lead to combination therapy to enhance the anti-tumor immune response," Youngblood said.

DATE: Wednesday, April 18
TIME: 10:50 a.m.
LOCATION: Room S100 (Grand Ballroom), Level 1, McCormick Place South
TITLE: Epigenetic regulation of T-cell exhaustion: Implications for cancer immunotherapy
ABSTRACT: SY07-02

Geneva, Switzerland, 12 April 2018 - Investing in the continuity of care for lung cancer patients can bring tremendous benefits in terms of patient satisfaction and quality of life. In Quebec, Canada, this investment has taken the form of a dedicated role on the medical team: The Pivot Nurse in Oncology (PNO). A study presented at ELCC 2018 (European Lung Cancer Congress) in Geneva (1) has produced new evidence of the different ways in which this service improves patients' lives during treatment. (2)

"Introduced to oncology clinics in 2001, the position of the pivot nurse was enshrined by the Ministry of Health and Social Services of Quebec in 2005 as part of its Fight Against Cancer campaign," said study author Elie Kassouf, haematologist and medical oncologist at Centre Hospitalier de Lanaudière (CHDL) in Saint-Charles-Borromée, Canada. "In over 15 years of existence, however, very little data has been collected about its impact on patients' lives. Our study's main goal was therefore to determine whether the continuity of nursing care has tangible benefits to patients treated for lung cancer, as compared to the usual standard of care without a coordinating nurse."

Lung cancer is the number one cause of cancer-related deaths in both men and women. (3) Although progress has been made with treatment, according to Kassouf, increased cure rates and survival have come at the cost of higher toxicity. The multidisciplinary teams required to administer combination therapy have also led to greater complexity in the care process. Quality of life during treatment has deteriorated as a result, and healthcare institutions are increasingly confronted with discontent about delays, service fragmentation or even misinformation - all of which are thought to lead to confusion, distress and compliance issues among patients.

"At the CHUM, patients who enjoy continuity of care have a treating pivot nurse in addition to their treating physician. Each pivot nurse cares for 50 to 60 patients, who all have his or her direct phone number," Kassouf explained. "The PNO has the patients' files and can take care of scheduling follow-up appointments with their physician as soon as they receive new test results. If a patient calls to report worrying symptoms, the nurse will also speak directly to their doctor, who may then see that person on short notice without the latter having to go through the regular emergency system."

To study the efficacy of this service, Kassouf recruited 65 patients with advanced lung cancer at Notre Dame University Hospital in Montreal three months after the start of their treatment. The patients were divided into two cohorts: 82% were assigned to the continuous care (CC) arm, and the 12 individuals who had not had access to a pivot nurse during their treatment constituted the usual care (UC) control group. Patients in both cohorts answered validated patient satisfaction and quality-of-life questionnaires, as well as questions to assess their understanding of their health status. The CC group additionally filled out a specific survey on the role of their pivot nurse.

"The size difference between the two cohorts is because the PNO program has been around for 15 years, and the vast majority of patients in Quebec today have access to a pivot nurse," Kassouf explained. "The reasons why the study participants in the control group had not used this service three months into their treatment were unrelated to the study." This made the data more difficult to compare, but, as Kassouf reported, the differences found between the two groups were so wide that the results are statistically significant nonetheless.

"The Princess Margaret Hospital Patient Satisfaction with Doctor Questionnaire (PMH / PSQ-D) that we used in the study covers four dimensions of a patient's relationship with his physician: interpersonal skills, empathy, information exchange and quality of time," said Kassouf. "The score difference we saw between the two cohorts was huge across the board: not because the usual care group scored poorly - their results were similar to those found in other studies based on the same questionnaire - but because the continuous care cohort produced exceptionally high scores."

In the so-called FACT-L scale, which is a validated questionnaire for evaluating lung cancer patients' quality of life in Canada, the results also favoured the CC cohort in all categories - including physical, emotional and functional wellbeing - although the difference between the two groups was less marked. "This can be attributed to the fact that, contrary to their level of satisfaction with care, patients' quality of life is heavily influenced by the disease itself," said Kassouf.

"A previous study of the PNO system (4) had shown no difference in patients' quality of life, but most of the nurses in its usual care arm had specialised oncology certifications and over 10 years of experience, which was not necessarily the case of the pivot nurses at the time," he added. "With the generalisation of the PNO program, this asymmetry had disappeared when we conducted our study, so the results are a useful addition to the literature on the subject."

In their assessment of the PNO service, a large majority of patients stated that they had a better understanding of the course of their disease and treatment side-effects, and that the presence of their pivot nurse gave them more strength in their fight against cancer. "The only concerns that many people felt were not sufficiently addressed by their PNO were those pertaining to intimacy," said Kassouf.

Due to its small sample size and confinement to a single hospital, it is difficult to generalise the results of this study. "Earlier data suggests, however, that lung cancer is the malignancy associated with the highest levels of psychological distress compared to other forms of cancer. (5) Presenting more unmet psychosocial needs, these patients could thus be particularly susceptible to the benefits of continuous follow-up and medical scrutiny," Kassouf remarked. "Our results certainly show that it is an avenue worth exploring."

Anja Kröner, a PhD-prepared nurse in oncology and member of the management team at the Comprehensive Cancer Centre in Zurich, Switzerland, commented: "Despite the small number of patients involved, which means we must be cautious with the results, this work shows a clear tendency of continuity of care improving when there is an established role similar to that of the pivot nurse on a patient's medical team," she said. "In Europe, too, we have seen promising signals: several clinics in Germany, for example, found it was beneficial to assign a case manager to cancer patients."

Kröner further underlined that the growing complexity of cancer treatment - from surgery to oral therapy and radiation -creates many breaks in the care process. "Parallel to this, we see patients with financial or social burdens who are at particular risk for low adherence to treatment," she said. "In oral therapy, for example, they have pills to take on their own at home that cause severe side-effects: The routine care process is not very good at detecting individuals who stop taking their medication without telling their doctor about it. That is where pivot nurses can make a real difference."

According to Kröner, however, cancer patients should not only be satisfied with their doctor, but rather with the entire care setting. "It would be interesting to take the research further by framing patient satisfaction more broadly, as well as considering other outcomes alongside quality of life, such as patients' ability to carry their own weight, or to work, throughout the process," she added. "In light of the financial pressure faced by many healthcare systems today, it would also be worth exploring whether pivot nurses can reduce the cost of cancer, as another study (6) has already suggested."

ANN ARBOR, Mich. - A vaccine may successfully turn off peanut allergy in mice, a new study shows.

Just three monthly doses of a nasal vaccine protected the mice from allergic reactions upon exposure to peanut, according to research from the Mary H. Weiser Food Allergy Center at the University of Michigan.

The study, funded by grants from Food Allergy Research and Education (FARE) and the Department of Defense, was published in the Journal of Allergy and Clinical Immunology.

U-M researchers have spent nearly two decades developing a vaccine agent and have recently translated this work to the development of a vaccine to treat food allergies. In the new study, immunizing peanut allergic mice can redirect how immune cells responded to peanuts in allergic mice. The new approach activates a different type of immune response that prevents allergic symptoms.

"We're changing the way the immune cells respond upon exposure to allergens," says lead author Jessica O'Konek, Ph.D. a research investigator at the food allergy center. "Importantly, we can do this after allergy is established, which provides for potential therapy of allergies in humans."

"By re-directing the immune responses, our vaccine not only suppresses the response but prevents the activation of cells that would initiate allergic reactions."

The mouse models studied responded to peanut allergies similarly as affected humans, with symptoms that included itchy skin and trouble breathing. The study assessed protection from allergic reactions two weeks after the final dose of vaccine was administered. Studies to determine duration of protection are ongoing, but researchers are encouraged that this approach will lead to long-lasting suppression of allergies.

The findings are another step toward a potential clinical trial down the road to test the method in humans.

"Right now, the only FDA approved way to address food allergy is to avoid the food or suppress allergic reactions after they have already started," O'Konek says. "Our goal is to use immunotherapy to change the immune system's response by developing a therapeutic vaccine for food allergies."

Next steps include further studies in mice to better understand the mechanisms responsible for the suppression of food allergies and learn whether protection from peanut allergies can be extended for an even longer period of time.

"Food allergy has exploded in prevalence and incidence but we still know so little about it because there hasn't been that much research in the field," says senior author James Baker, Jr., M.D., director of the U-M Mary H. Weiser Food Allergy Center and who is also the CEO of FARE.

"This research is also teaching us more about how food allergies develop and the science behind what needs to change in the immune system to treat them."

A new paper has called for an end to the term 'healthy obesity', due to it being misleading and flawed. The focus should instead be on conducting more in-depth research to understand causes and consequences of varying health among people with the same BMI.

The term 'healthy obesity' was first used in the 1980's to describe obese individuals who were apparently healthy -- for example they didn't suffer with hypertension or diabetes.

Dr William Johnson, from the School of Sport, Exercise and Health Sciences at Loughborough University, emphasizes in the journal Annals of Human Biology that the construct of 'healthy obesity' is limited. This is because categorizing a population using cut-offs (e.g., BMI > 30 kg/m2 and blood pressure

However, Dr Johnson does acknowledge that there are health differences between obese individuals with the same BMI and explains that there should be further investigation into contributing factors such as being obese for longer, adverse early life events, and smoking during adolescence. Such research would explain why one person has a disease or dies, while another with the same BMI (or waist circumference) is fine.
Dr Johnson explains, "It is undeniable that obesity is bad for health, but there are clearly differences between individuals in the extent to which it is bad."

"While the concept of healthy obesity is crude and problematic and may best be laid to rest, there is great opportunity for human biological investigation of the levels, causes, and consequences of heterogeneity in health among people with the same BMI."

"While epidemiology has revealed many of the life course processes and exposures that lead to a given disease, we know relatively little about the things that occur across someone's life that lead to them having a heart attack, for example, while their friend with the same BMI is fine. Existing birth cohort studies have the data necessary to improve knowledge on this topic." Johnson suggests.

With obesity at epidemic levels worldwide, such research could inform the development of more stratified disease prevention and intervention efforts targeted at individuals who have the highest risk.

APRIL 11, 2018, NEW YORK - Ludwig Cancer Research released today the full scope of findings to be presented by Ludwig researchers at this year's American Association for Cancer Research (AACR) Annual Meeting in Chicago, Ill., April 14-18, 2018. Research conducted by more than 100 Ludwig scientists will be presented in symposiums, plenaries, town meetings, education sessions and poster sessions.

"The AACR Annual Meeting is an invaluable opportunity for Ludwig scientists to build relationships and exchange ideas with the global community of cancer researchers," said Chi Van Dang, scientific director, Ludwig Institute for Cancer Research and Editor-in-Chief of AACR's Cancer Research journal. "The theme of this year's meeting, 'Driving Innovative Cancer Science to Patient Care,' is very much in line with Ludwig's mission. The gathering, which brings together researchers with expertise in a wide variety of scientific disciplines, will present Ludwig researchers with many opportunities to forge collaborations to advance our understanding of cancer and help improve its prevention, diagnosis and treatment."

Ludwig scientists at the meeting will present new data and insights from basic and translational research on cancers including colorectal, brain, breast and ovarian. Ludwig Lausanne Director George Coukos will deliver an Opening Plenary on mobilizing immunity against ovarian cancer.

Ludwig scientists and affiliated researchers will also present early results from innovative clinical trials, new approaches to developing minimally invasive cancer diagnostics, and research spanning the spectrum of cancer biology, from the tumor microenvironment to tumor immunology and cancer metabolism. They will also present novel approaches to personalizing cancer immunotherapy and report on progress made by Stand Up to Cancer Dream Teams focusing on pediatric and colorectal cancers. In addition, a raft of posters by Ludwig scientists will cover everything from new immunotherapeutic agents and treatment strategies to novel diagnostics and cancer genomics.

Click here for a comprehensive list of Ludwig scientists' activities at the Meeting.

The risk of dementia, including Alzheimer's, was significantly higher in people who had experienced a traumatic brain injury (TBI) than with people who had no history of TBI, according to one of the largest studies to date on that association.

Findings from a review of nearly 2.8 million patient cases in Denmark were published April 10 in The Lancet Psychiatry.

The overall risk of dementia in individuals with a history of TBI was 24 percent higher than those without a history of TBI, after accounting for other risk factors for the disease.

A single TBI characterized as "severe" increased the risk by 35 percent; a single "mild" TBI or concussion increased the risk by 17 percent, the research indicated.

"What surprised us was that even a single mild TBI was associated with a significantly higher risk of dementia," said lead author Jesse Fann, a professor of psychiatry and behavioral sciences at the University of Washington School of Medicine. "And the relationship between the number of traumatic brain injuries and risk of dementia was very clear....Similiarly, a single severe brain injury seems to have twice the risk associated with dementia as a single mild traumatic brain injury."

The study found that the risk of dementia increased 33 percent higher for two or three TBIs, 61 percent higher for four TBIs, and 183 percent higher for five or more TBIs.

Fann said another important finding is that if you have a brain injury in your 20s, the risk of developing dementia in your 50s is increased by 60 percent.

"Severe TBI is particularly frequent in young people, and it is concerning that the risk of dementia is particular high in relatively young persons who suffer TBI," said co-author Jakob Christensen, associate professor of neurology at Aarhus University Hospital in Denmark.

Dementia affects 47 million people worldwide, a number expected to double in the next 20 years. Every year, more than 50 million people worldwide experience a TBI, which occurs when an external force disrupts the brain's normal function. Leading causes include falls, motor vehicle accidents, and assaults.

Fann said it's important to recognize that most people who sustain a single concussion do not develop dementia. And he clarified that the findings do not suggest that every person who sustains a severe TBI will develop dementia later in life. But he said the findings might lead people with TBI histories to change their behaviors toward other potential risk factors for dementia, such as limiting alcohol and tobacco use, engaging in regular exercise, preventing obesity, and treating hypertension, diabetes, and depression.

He also suggested people who suffer a TBI get an evaluation and seek treatment for persisting problems.

"There are some cognitive rehabilitation strategies that may decrease the cognitive deficits associated with a brain injury," he said.

The potential link between TBI and dementia has become a pressing issue among military veterans and participants of contact sports such as boxing, football, soccer, and hockey. The researchers sought to resolve conflicting findings from previous studies on the link between TBI and dementia.

This research encompassed a large study population, 36 years of follow-up, and access to a uniform healthcare system that tracks the number and severity of TBIs.

Among the nearly 2.8 million people observed, 4.7 percent had at least one TBI diagnosis. Among first TBI diagnoses, 85 percent had been characterized as mild and 15 percent had been characterized as severe or skull fracture. From 1999 to 2013, 4.5 percent of the patients over age 50 years developed dementia. Of those, 5.3 percent had sustained at least one TBI during the observation period, which began in 1977. The mean age at first diagnosis of dementia was 80.7 years.

Among men and women with TBI histories, men had slightly higher rate of developing dementia (30 percent vs. 19 percent).

Fann said more research is needed to understand who is at greatest risk of dementia and what other factors contribute to that risk. He warns parents and children to be well-aware of risks of TBIs in contact sports.

"If someone has a traumatic brain injury or concussion, they need to strictly follow the protocols to leave the game and get the proper assessment and treatment that is necessary." he said. "If they have a history of traumatic brain injury, they should do their best to prevent further traumatic brain injuries."

The authors called for heightened efforts to prevent TBI, especially among younger people, and said strategies are needed to ameliorate the risk and impact of dementia associated with TBI.

Writing in a linked comment, Professor Carol Brayne from the Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK says, "Now we need to tease out what is happening in terms of traumatic brain injury, wider spectrum exposures and how these occur across different ages, by gender, and also by community within societies. The attributable risk of traumatic brain injury to different exposures and how these change across time needs policy attention, given it is likely that prevention of these need be considered at societal, community, and local levels."

"Most people with a mild head injury take off work for a week and then forget about it, but some end up with long-term ailments like headaches," says Lena Hoem Nordhaug, a PhD candidate in neuromedicine at the Norwegian University of Science and Technology (NTNU).

She recently published her findings in the The Journal of Headache and Pain.

Headaches became worse

The study shows that people who were hospitalized with a mild head injury had twice as high a risk of developing headaches, or exacerbating pre-existing headaches, than the rest of the population.

Nordhaug used numbers from the HUNT 2 and 3 Nord-Trøndelag Health Study, two large Norwegian epidemiological surveys, and linked them to hospitalizations due to head injuries. She included 294 individuals who had been hospitalized with head trauma in Trondheim, Levanger or Namsos in the eleven-year period between the HUNT 2 and 3 studies.

Falls are frequent cause of head injury

Most of the 211 individuals who had suffered a concussion - a mild head injury - reported a fall as the cause of their head trauma. Traffic accidents were the second most noted cause.

"Headaches are a major social problem. They lead to a reduced quality of life and labour loss, and are a very common complaint that especially affects women in the most active years of their lives, "says Nordhaug.

Previous research at NTNU shows that four out of ten Norwegian women and three out of ten Norwegian men are plagued by headaches.

"It's important to find out what distinguishes the head injury patients who suffer from long-term ailments from those who don't. Then the patients in the high-risk group could be followed more closely," says Nordhaug.

Head trauma in the US

Norway and several other countries are currently debating whether to implement a ban on heading in children's football.

The United States is one of the countries that have introduced a ban on heading the ball to minimize the risk of brain injury. Children under the age of 10 are not allowed to head the ball, and heading is restricted for children between the ages of 11 and 13.

"The U.S. is doing a lot of research on headaches after head injury," says Nordhaug.

She believes that may be due in part to the many veterans who have suffered head trauma in the United States.

"Many more people there experience repeated head injury from playing ice hockey and American football. You can't really compare someone who's been kicked in the head once by a cow on their farm with someone who's suffered a head injury in a chaotic war situation," says Nordhaug.

Different conditions in Norway

She also points out that the American health system is very different in terms of litigation and the possibility of compensation.

"All this means that numbers from the United States can't necessarily be directly compared with Norwegian statistics," says Nordhaug.

NTNU and St. Olavs Hospital in Trondheim have conducted a study based on everyone who comes to the hospital's urgent care with mild head injuries, in order to obtain more data about conditions in Norway. The results will soon be available.

PHILADELPHIA - The longer a patient with a positive screening result waits for diagnostic testing, the worse their cancer outcomes may become, according to a literature review of breast, cervical, colorectal, and lung studies in the journal CA led by researchers at the Perelman School of Medicine at the University of Pennsylvania.

After a patient receives a positive cancer screening result, the next recommended step is a follow-up evaluation with diagnostic testing, a CT scan for example, which is key to confirm the absence or presence of cancer(s) and the severity of any that may be present.

The authors, an interdisciplinary team of cancer experts from the Population-Based Research Optimizing Screening Through Personalized Regimens Consortium, urge patients who receive a positive screening to schedule a diagnostic test as soon as feasible. Articles considered were published between January 1998 and December 2017, conducted in an average-risk population, except in lung cancer, and used study designs that provided empirical evidence and evaluated the key question.

Although the findings of this research follow the longstanding conventional wisdom, this literature review backs up this message with patient outcome data. The authors make clear that each patient's cancer trajectory is different and there is no established timeframe that is OK to wait before a diagnostic test without risk of cancer progression.

"To ignore these findings is not patient-centered," said lead author Chyke Doubeni, MD, chair of Family Medicine and Community Health. "The longer a patient waits, the less likely they are to get the diagnostic testing done. There is also the risk that precancerous or early tumors will become more advanced cancers that are more difficult or impossible to cure."

The paper offers suggested targets for each of the four cancers within which diagnostic testing should be performed. The targets range from 60-90 days, but were not able to ascribe a certain number of risk points based on exactly how long a patient waits. For example, on average, cervical cancer takes longer to progress than lung cancer does, but the authors caution against ascribing a safe period to wait or saying it's safe to wait a little longer if you have cervical cancer vs another type based on the limited body of knowledge to date.

The National Academy of Medicine has identified improving the timeliness and patient-centeredness of care as an important unmet health priority. Screening is proven to reduce the risk of death from some cancers and is currently recommended at grade A or B by the US Preventive Services Task Force in eligible persons for breast, cervical, colorectal, and lung cancers, which enables full coverage of those services under the Affordable Care Act.

Future research will aim to identify the appropriate data to identify time intervals during which it is potentially safe to wait before undergoing diagnostic testing.

Doubeni and his colleagues note that prompt diagnostic testing may also reduce mortality risk, and may also reduce worries about uncertainty about the procedure. Additionally, sooner is better, as provider or system delays in follow-up may increase the likelihood that diagnostic testing may not occur at all, such as changes in patient contact information or insurance coverage changes.

Based on the few direct studies cited, overall, there is evidence that if you wait longer than 60-90 days, generally cancer will progress. This is not surprising biologically, but the paper provides guidance on how to set metrics to measure improvement. Next steps for the research will seek out the most effective interventions to reduce the time to diagnosis for vulnerable and minority populations, and any patients who have barriers to timely follow up.

Heart failure is a leading cause of maternal morbidity and death in the U.S. -- with the rate of pregnancy-related deaths more than doubling between 1987 and 2011. Even so, much about heart failure-related hospitalizations before, during and after delivery is unknown.

A study from the University of Illinois at Chicago has found that women are at the highest risk for heart failure within the six weeks after delivery, known as the postpartum period.

"This finding lends support to using delivery-related hospitalization as a window of opportunity to identify high-risk women and develop surveillance strategies before discharge," said the study's lead author, Mulubrhan Mogos, assistant professor of nursing at UIC.

The results of the study also suggest that heart failure is a significant clinical problem among relatively young reproductive-age women, especially among women with the presence of an additional disease or condition, such as hypertension, Mogos said.

The study found that although less than 2 percent of all pregnancy-related hospitalizations occurred during the postpartum period, nearly 60 percent of pregnancy-related heart failure hospitalizations took place during the same time.

The researchers published their findings in the journal Circulation: Heart Failure.

The study's findings highlight the need for close monitoring of high-risk women before they are discharged from the hospital after giving birth and through the postpartum period, according to Mogos and his colleagues. Typically, women are discharged from the hospital within two to three days after delivery and are not evaluated by their health care providers again until six weeks later.

The study analyzed more than 50 million pregnancy-related hospitalizations in the U.S. from 2001 to 2011. From 2001 to 2006, there was a 7.1 percent increase each year in heart failure diagnoses among postpartum hospitalizations, the rates then stabilized until 2011, the final year analyzed.

Heart failure rates during the antepartum period, or prior to delivery, increased by an average of 4.9 percent per year from 2001 to 2011, which may be attributable, at least in part, to the presence of high blood pressure, diabetes or other risk factors or conditions the women had before becoming pregnant, as well as improved testing to detect heart failure, researchers found.

The women who had a heart failure diagnosis -- before and after giving birth -- tended to be older and black, according to researchers. The women were from the southern United States and lived in low-income household areas and engaged in risky behaviors, including using tobacco, drugs and alcohol, according to the study.

Mogos and his co-authors concluded that at-risk mothers require close observation postpartum, ideally from a multidisciplinary team that includes heart failure specialists. This attention has been linked to better outcomes and fewer readmission rates.

"Health education about expectations and their risk status during delivery-related hospitalization may empower women to seek immediate support from their social network and healthcare provider," Mogos said.

In addition, "There is a need for increased awareness and public health measures to address risk factors and promote prevention strategies among historically disadvantaged groups," he said.