Body

BOSTON - A combination of two drugs - one of them an immunotherapy agent - could become a new standard, first-line treatment for patients with metastatic kidney cancer, says an investigator from Dana-Farber Cancer Institute, reporting results from a phase 3 clinical trial.

Patients who received the immunotherapy drug avelumab plus axitinib, a targeted agent, had a significant advantage in progression-free survival compared with those who received sunitinib (Sutent), a targeted drug that has been a standard treatment for advanced clear cell renal cell carcinoma - the most common form of kidney cancer.

"Patients receiving the drug combination also had a higher response rate - meaning their tumors shrank - than the sunitinib-only group," said Toni K. Choueiri, MD, senior and co-corresponding author of the report on the JAVELIN Renal 101 trial in the New England Journal of Medicine and Director of the Lank Center for Genitourinary Oncology at Dana-Farber.

"This is certainly better than sunitinib -- hopefully this will lead to Food and Drug Administration approval soon," said Choueiri, The Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School

While progression-free survival was improved with the combination treatment, additional follow-up is needed to show whether the two-drug therapy extends overall survival compared to the standard regimen.

The trial is the first pivotal study to combine avelumab with a drug that targets the vascular endothelial growth factor receptor (VEGFR). VEGFR blockers like sunitinib and axitinib are designed to starve tumors by disrupting their blood supply. Immunotherapy drugs such as avelumab - which blocks an immune checkpoint called PD-L1 - work by activating "exhausted" immune T cells so they can more effectively attack cancer cells.

The clinical trial involved 886 patients with previously untreated, advanced renal cell carcinoma who were randomized to receive the drug combination or sunitinib alone.

The results from this study showed that the median progression-free survival (PFS) - the length of time before the cancer began to worsen - was 13.8 months in the combination group and 7.2 months in patients receiving only sunitinib. These results specifically applied to patients whose cancer cells tested positive for the PD-L1 checkpoint that is blocked by avelumab. The PFS for the overall population (PD-L1 positive or negative) was similar - 13.8 months versus 8.4 months.

The proportion of patients whose tumors shrank was 55.2 percent with avelumab plus axitinib and 25.5 percent with sunitinib in the patients who were positive for PD-L1.

"Interestingly, the analysis showed that all subgroups - good, intermediate, and poor-risk patient - benefited from the combination treatment," said Choueiri. This was the topic of an oral presentation Choueiri has just given at the 2019 Genitourinary Cancers Symposium in San Francisco. The results were simultaneously published in the New England Journal of Medicine.

Nearly all patients in both treatment groups experienced some side effects. In the combination treatment group, 38.2 percent of patients experienced immune-related adverse events, the most frequent being thyroid disorders, observed in 107 patients.

Choueiri said that for patients with advanced disease, "this is an important option. What we're doing in advanced kidney cancers is pushing the envelope - these treatments may not be curative, but patients are living longer, and the disease is becoming more chronic."

The promises of quantum computing are abundant: for years we've heard how it will break cryptography, make drug discovery a cinch and speed up database search. Researchers around the world have successfully made quantum computers with dozens of quantum bits, but in order to deliver on the promises, they'll need many more.

Debbie Leung, a fellow in CIFAR's Quantum Information Science program and a faculty member at the University of Waterloo's Institute for Quantum Computing, will discuss the challenges of scaling quantum computing at the AAAS meeting on 16 February. She will focus on the ingredients required for accurate quantum computing operations and discuss recent progress with error-correcting codes. According to Leung, there are significant challenges ahead, but there are also many good reasons to be optimistic.

Feb. 15, 2019--Adults with obstructive sleep apnea (OSA) who experience excessive sleepiness while awake appear to be at far greater risk for cardiovascular diseases than those without excessive daytime sleepiness, according to new research published online in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

In "Symptom Subtypes of Obstructive Sleep Apnea Predict Incidence of Cardiovascular Outcomes," Diego R. Mazzotti, PhD, and co-authors report on a study of adults with moderate to severe OSA who were categorized into four subtypes according to the symptoms they report: disturbed sleep, minimally symptomatic, moderately sleepy and excessively sleepy.

Previous studies have linked OSA and cardiovascular disease. To understand this association better, researchers have begun to categorize patients with OSA based on their symptoms.

"Multiple studies from our group have shown that patients with moderate to severe OSA throughout the world can be categorized into specific subtypes based on their reported symptoms," said Dr. Mazzotti, lead study author and a sleep researcher at the University of Pennsylvania. "However, until now, it was unclear whether these subtypes had different clinical consequences, especially in regard to future cardiovascular risk."

The current study analyzed data from 1,207 adults participating in the Sleep Heart Health Study, available from the National Sleep Research Resource. Patients were 40 years old or older at enrollment and were followed for nearly 12 years. The patients had moderate to severe OSA, which was defined as having at least 15 episodes per hour while sleeping when they stopped breathing (apnea) or had reduced breathing (hypopnea). The metric is known as the apnea-hypopnea index, or AHI.

Participant-reported symptoms, such as difficulty falling and staying asleep, snoring, fatigue, drowsy driving and daytime sleepiness, and responses to a widely used questionnaire called the Epworth Sleepiness Scale were used to determine the patient's subtype.

The study found participants exhibiting the excessively sleepy subtype were:

More than three times as likely to have been diagnosed with heart failure at enrollment than the other three subtypes.

About twice as likely to experience a cardiovascular event (heart attack, heart failure, stroke or cardiovascular death) during the follow-up period than the other three subtypes.

The only group that had higher rates of cardiovascular disease at enrollment when compared to individuals without OSA.

More likely to experience a new or recurrent cardiovascular event during the follow-up period.

The authors said that their study indicates the increased risk of cardiovascular disease associated with OSA appears to be driven by patients in the excessively sleepy subtype.

Given the observational study design, they could not prove that excessively sleepy subtype was a causal factor for cardiovascular disease. Ultimately, excessive sleepiness could be a "surrogate marker of underlying cardiovascular risk pathways," they wrote.

However, the authors demonstrate that the association is independent of a number of demographic and health factors that might have biased results, including age, body mass index , smoking, diabetes, hypertension, cholesterol and medications.

The authors suggest their findings should guide future research studies. For instance, the researchers believe that studies of the cardiovascular benefits of continuous positive airway pressure, or CPAP, treatment for OSA should focus on the excessively sleepy subtype, who are likely to benefit the most from what is considered the gold standard OSA treatment.

"Even without further research, clinicians should recognize that patients with OSA who complain of feeling tired when they wake up and sleepy during the day and have a high score on the Epworth Sleepiness Scale are at greater risk for cardiovascular disease," Dr. Mazzotti said.

He added that the research team is developing a simple tool to facilitate the accurate classification of patients into symptom subtypes, which should improve the clinical utility of their findings.

LOUISVILLE, Ky. - A research team at the University of Louisville has discovered that an immune checkpoint molecule they developed for cancer immunotherapy, also protects against future development of multiple types of cancer when administered by itself.

The recombinant protein molecule SA-4-1BBL has been used to enhance the therapeutic efficacy of cancer vaccines with success in pre-clinical animal models. It accomplishes this by boosting the effectiveness of CD8+ T cells, adaptive immune cells trained to target the tumor for destruction. Surprisingly, when the researchers treated normal healthy mice with SA-4-1BBL alone, the mice were protected when the researchers later exposed them to different types of tumor cells.

"The novelty we are reporting is the ability of this molecule to generate an immune response that patrols the body for the presence of rare tumor cells and to eliminate cancer before it takes hold in the body," said Haval Shirwan, Ph.D., professor in the UofL Department of Microbiology and Immunology and the UofL Institute for Cellular Therapeutics. "Generally, the immune system will need to be exposed to the tumor, recognize the tumor as dangerous, and then generate an adaptive and tumor-specific response to eliminate the tumor that it recognizes. Thus, our new finding is very surprising because the immune system has not seen a tumor, so the response is not to the presence of a tumor."

The researchers have determined that the molecule generates a tumor immune surveillance system through activation of what are known as CD4+ T cells and innate NK cells, thereby protecting the mice against various cancer types they have never had. This function is an indication of the molecule's effectiveness in cancer immunoprevention.

In the research, published today in Cancer Research, mice that had never had cancer were treated with SA-4-1BBL alone, then challenged with cervical and lung cancer tumor cells at various time intervals. The mice showed significant protection against tumor development, with the greatest protection when challenged two weeks after treatment with SA-4-1BBL. The cancer immunoprevention effect generated by SA-4-1BBL lasted more than eight weeks.

"Just giving SA-4-1BBL alone prevents the formation of tumors in animal models," Shirwan said. "To our knowledge, this is the first study to demonstrate that an immune checkpoint stimulator, known for its function for adaptive immunity, as a single agent can activate an immune system surveillance mechanism for protection against various tumor types."

Additional testing showed that CD8+ T cells were not required for the protection, but when CD4+ T and NK cells were eliminated in the mice, protection failed, indicating these two cell types were necessary to achieve the effect. The lack of necessity for CD8+ T cells indicates the process is not one of conventional acquired immunity.

Although the research, which was conducted in collaboration with FasCure Therapeutics, LLC, tested the mice for cervical and lung cancers, the protective function of SA-4-1BBL works without context of specific tumor antigens, giving it the potential to be effective in preventing any number of tumor types.

"We are very excited about the cancer immunoprevention possibilities of this molecule. Its effectiveness is not tumor specific, and as a natural ligand, it does not cause toxicity, as is found with 4-1BB agonist antibodies. Plus, the fear of autoimmunity is highly minimized, as evident from our data, because it is activating the innate immune cells," said Esma Yolcu, Ph.D., associate professor at UofL and co-author of the study.

Immune checkpoint stimulators and inhibitors are major regulators of the immune system and work in a similar fashion to the "brake" and "gas" pedals in a vehicle. Cancer evades the immune system by various means, including immune checkpoint inhibitors, which apply the brake on the immune response against a tumor. Stimulators, on the other hand, serve the accelerator function, improving immune responses against cancer.

Drugs to block the action of immune checkpoint inhibitors already have shown therapeutic efficacy for several cancer types in the clinic and are approved by the Food and Drug Administration (FDA). According to Shirwan, the focus now is on immune checkpoint stimulators.

"Several antibody molecules are in clinical testing for cancer immunotherapy as immune checkpoint stimulators. However, nothing so far is approved by the FDA that gives a positive signal to the T cells," Shirwan said. "The immune checkpoint inhibitors take the foot off the brake, so to speak. This ligand, as an immune checkpoint stimulator, puts the gas on the immune system to destroy the tumor.

"Another big surprise is that an antibody to the same receptor targeted by SA-4-1BBL did not protect against tumors, demonstrating unique and desired features of SA-4-1BBL for caner immunoprevention."

Shirwan and Yolcu plan to conduct further tests for SA-4-1BBL in cancer immunoprevention.

"Although the notion of cancer immunoprevention is an attractive one, the design of clinical trials presents a challenge with respect to the target population," Shirwan said. "However, with advances in cancer screening technologies and genetic tools to identify high-risk individuals, we ultimately are hoping to have the opportunity to test the SA-4-1BBL molecule for immunoprevention in individuals who are predisposed to certain cancers, as well as in the presence of precancerous lesions."

PHILADELPHIA - Offering compensation can be an important tactic to attract potential participants for enrollment in research studies, but it might come at a cost. A new study conducted by researchers in the Perelman School of Medicine at the University of Pennsylvania found that up to 23 percent of respondents lied about their eligibility to participate in a survey when offered payment, even small amounts.

Anecdotal evidence and common sense suggest that offering money may encourage participants to lie about their eligibility or other aspects of study participation in order to secure payment, the authors said. But few studies have investigated whether and to what extent people will deceive, leaving a major gap in the literature. The new findings, published in JAMA Network Open, suggest the practice may be pervasive.

A total of 2,275 respondents participated in a nationally representative, randomized survey on flu vaccination status. One study group lacked motivation to lie about whether they had recently had a flu shot because their eligibility didn't depend on it. Their reported rates of flu vaccination were therefore used to determine the true rate of vaccination in the study population. Other groups were offered $5, $10, or $20 for participation and were told they were eligible only if they had (or in some groups, had not) received a recent flu shot. If no one was lying, all study groups would have reported about the same rates of flu vaccination.

"Instead, we found evidence of significant deception by participants who were not eligible, but claimed they were in order to be able to join the study," said first author Holly Fernandez Lynch, JD, MBE, an assistant professor of Medical Ethics and Health Policy. "This type of behavior not only undermines a study's integrity and its results, but in a study with eligibility criteria that are intended to protect participants, it also has the potential to put participants at risk."

In the control group, 52.2 percent of respondents reported a recent flu shot. But when told that eligibility depended on recent flu vaccination and financial compensation of $5, $10, or $20 was offered, reports of vaccination jumped to 63.1 percent, 62.8 percent, and 62.1 percent, respectively. When told that eligibility depended on having not received a recent flu vaccination, reports of vaccination dropped to 46.5 percent at $5, 41.8 percent at $10, and 46.7 percent at $20. Because the only differences between these groups were their eligibility criteria and payment amounts, the differences in their reported vaccination rates can be attributed to deception. The researchers calculated that between 10.5 and 22.8 percent of participants engaged in deception about their eligibility to participate.

The authors say one of the study's most interesting findings is that more money wasn't associated with higher rates of deception. "This suggests that keeping payments low will not necessarily prevent deception," said study co-author Steven Joffe, MD, MPH, chief of the division of Medical Ethics, "It also suggests that higher payments may encourage recruitment without posing a greater risk to the study's integrity."

The study's senior author Emily A. Largent, PhD, JD, RN, an assistant professor of Medical Ethics and Health Policy, emphasized the importance of finding ways to minimize deception by study participants. "Rather than relying on self-reporting by participants, investigators should use objective metrics whenever possible," Largent said. "The best response to our findings is not necessarily to reduce or eliminate payment offers for participation. Payment can help boost legitimate enrollment; in addition, investigators may owe payment as compensation for the time, effort, and burden that participants assume by joining the study."

Although this study was conducted in the context of survey research, its findings support the need for further studies in clinical trials, where payment amounts and other benefits, like access to investigational drugs, as well as study risks, are often more substantial.

Researchers say they are closer to solving the mystery of how a good night's sleep protects against heart disease. In studies using mice, they discovered a previously unknown mechanism between the brain, bone marrow, and blood vessels that appears to protect against the development of atherosclerosis, or hardening of the arteries--but only when sleep is healthy and sound. The study, funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, will appear in the journal Nature.

The discovery of this pathway underscores the importance of getting enough, quality sleep to maintain cardiovascular health and could provide new targets for fighting heart disease, the leading cause of death among women and men in the United States, the researchers said.

"We've identified a mechanism by which a brain hormone controls production of inflammatory cells in the bone marrow in a way that helps protect the blood vessels from damage," explained Filip Swirski, Ph.D., the study's lead author who also is an associate professor at Harvard Medical School and Massachusetts General Hospital, Boston. "This anti-inflammatory mechanism is regulated by sleep, and it breaks down when you frequently disrupt sleep or experience poor sleep quality. It's a small piece of to a larger puzzle."

Swirski noted that while other similar mechanisms may exist, the findings are nonetheless exciting. Recent research has linked sleep deficiency and certain sleep disorders, such as sleep apnea, to an increased risk of obesity, diabetes, cancer, as well as heart disease. But scientists have known little about the cellular and molecular underpinnings that could help explain the link between sleep and cardiovascular health.

Poor or insufficient sleep is a major public health problem affecting millions of people of all ages. Studies show that getting enough quality sleep at the right times is vital for health, but fewer than half of adults in the United States get the recommended seven to eight hours per day.

To learn more about the impact of this deficiency on cardiovascular disease, the researchers focused on a group of mice that were genetically engineered to develop atherosclerosis. They disrupted the sleep patterns of half the mice and allowed the other half to sleep normally.

Over time, the mice with disrupted sleep developed progressively larger arterial lesions compared to the other mice. Specifically, the sleep-disrupted mice developed arterial plaques, or fatty deposits, that were up to one-third larger than the mice with normal sleep patterns. The sleep-disrupted mice also produced twice the level of certain inflammatory cells in their circulatory system than the control mice--and also lower amounts of a hypocretin, a hormone made by the brain that is thought to play a key role in regulating sleep and wake states.

The researchers also showed that sleep-deficient, atherosclerotic mice that received hypocretin supplementation tended to produce fewer inflammatory cells and develop smaller atherosclerotic lesions when compared to mice that did not get the supplementation. These results, they said, demonstrate that hypocretin loss during disrupted sleep contributes to inflammation and atherosclerosis. But they cautioned that more studies are needed, particularly in humans, to validate these findings and especially before experimenting with hypocretin therapeutically.

Still, health experts say, targeting the newly discovered biological mechanism--a so-called neuro-immune axis--could be a breakthrough that one day leads to new treatments for heart disease, sleep, and other disorders.

"This appears to be the most direct demonstration yet of the molecular connections linking blood and cardiovascular risk factors to sleep health," said Michael Twery, Ph.D., director of the National Center on Sleep Disorders Research at NHLBI. Circadian biology refers to the 24-hour internal body clock that governs the expression of many genes in most every tissue and the regulation of sleep and wake cycles.

"Understanding the potential impact of poor sleep and circadian health on blood cell formation and vascular disease opens new avenues for developing improved treatments," Twery added.

Sales of prescription psychiatric drugs such as Xanax and diazepam via darknet online drug markets have increased in the UK at an alarming rate, according to new research by the University of Kent and King's College London.

The findings validate concerns that non-medical prescription drug use (NMPDU) is becoming increasingly common in the UK and that policy makers need to act to address this issue.

Researchers from the universities set out to examine the scale of NMPDU via sales made on the darknet of three key drug types: sedatives, stimulants and opioid dependency products. They did this by analysing these types of drugs sold on 31 cryptomarkets in the USA, UK, Australia and European nations such as Germany and Sweden between September 2013 and July 2016.

In the UK the proportion of sales of sedatives such as alprazolam (popularly known by its trade name Xanax) and diazepam had increased by just under a percentage point (0.9%) each year over the study period to around 12% of the total of all drugs sold via the darknet in the UK by 2016, behind drug groups such as cannabis, MDMA-type products and cocaine. The researchers said this should alarm policy makers and demonstrates an increasing interest in these products.

Furthermore, this meant the UK accounted for close to a third (31.1%) of all sedatives sold on the darknet in the data analysed, not far behind the US that had the largest share at 41.4%. The report also notes that sales of Xanax are catching up with the more traditionally used UK sedative diazepam - growing from 10% to a quarter of sedative sales monitored over the study period.

The USA had the largest share of other prescription psychiatric drug sales monitored. In total it accounted for 59.2% of all stimulant sales monitored and 64.4% of opioid dependency products such as suboxone and methadone. Sales of sedatives and stimulants increased by half a percentage point, pointing to an increased popularity, though more muted than the increase for sedatives in the UK.

The researchers say the findings have a number of policy implications, not least by confirming that non-prescribed sedative demand is an increasing issue in the UK relative to other drugs, as has been previously noted by Public Health England, particularly with regards to the use of Xanax.

Dr Jack Cunliffe from the School of Social Policy, Sociology and Social Research at Kent said: 'The data shows that there is significant increase in the demand for nonmedical use of prescription drugs in the UK compared to other drugs in many advanced Western nations via the darknet. Governments must recognise this and look to create policies that react to these trends, especially if they wish to avoid a prescription drugs crisis similar to that which is occurring in the USA.'

On the rise of alprazolam, Dr Cunliffe added: 'Given that Xanax is not available in the UK on the NHS, the rising sales might have something to do with its notoriety in the USA, where its use is frequently glamorised in popular culture.'

The findings, co-authored with Dr Thomas Pollak from the Institute of Psychiatry, Psychology & Neuroscience, King's College London and Dr David Décary-Hétu from the University of Montreal, have been published in the International Journal of Drug Policy in a paper entitled Nonmedical prescription psychiatric drug use and the darknet: a cryptomarket analysis.

Survival after a diagnosis of heart failure in the United Kingdom has shown only modest improvement in the 21st century and lags behind other serious conditions, such as cancer, finds a large study published by The BMJ today.

The findings also show that survival is worse for people requiring admission to hospital around the time of diagnosis, and for those in the most deprived groups.

The researchers point out that, unlike cancer, heart failure has not been a priority for government policy or funding - and say their results "should alert policy makers to the need for further investment in heart failure services."

Heart failure is an increasingly common condition that affects over 920,000 people in the UK, and globally is estimated to cost US$108bn (£82.4bn; €94.5bn) each year.

Reliable survival estimates are important for any long term condition, yet studies exploring survival trends for heart failure over time are inconsistent.

So a research team led by Dr Clare Taylor and Professor Richard Hobbs at the Nuffield Department of Primary Care Health Sciences in Oxford, set out to report short and long term survival rates of people with heart failure, and to examine trends over time by year of diagnosis, hospital admission around the time of diagnosis, and socioeconomic group.

Using UK primary care data from 2000 to 2017 linked to hospital and mortality records, they compared survival rates for 55,959 patients aged 45 and over with a new diagnosis of heart failure with 278,679 matched controls.

They defined heart failure as people with a new diagnosis of heart failure in their medical record during the study period. Hospital data revealed whether a patient was admitted to hospital within three months of diagnosis.

Overall, one, five, and 10 year survival rates increased by 6.6% (from 74.2% in 2000 to 80.8% in 2016), 7.2% (from 41.0% in 2000 to 48.2% in 2012), and 6.4% (from 19.8% in 2000 to 26.2% in 2007), respectively.

Of 30,906 deaths in the heart failure group over the study period, heart failure was listed on the death certificate in 13,093 (42.4%) of these patients, and in 2,237 (7.2%) it was the primary cause of death.

Improvement in survival was on average 2.4 years greater for patients not requiring admission to hospital around the time of diagnosis (5.3 v 2.9 years), which the researchers say probably relates to a more advanced stage of disease.

They also found an average 2.4 year difference in survival (11.1 v 8.7 years) for people who were least deprived compared with the most deprived group.

This is an observational study, and as such, can't establish cause, and the researchers point to some limitations, such as being unable to identify type of heart failure, and the possibility that some data may have been incomplete or misclassified.

Nevertheless, they say survival after a diagnosis of heart failure "has shown only modest improvement in the 21st century and lags behind other serious conditions, such as cancer."

The lack of substantial progress in improving heart failure survival rates "should alert policy makers to the need for further investment in heart failure services," they write.

And they say new strategies "to achieve timely diagnosis and treatment initiation in primary care for all socioeconomic groups should be a priority for future research and policy."

The social stigmas and myths surrounding the human papilloma virus (HPV) could make women anxious, including raising fears about their partners' fidelity and putting them off going for cervical screening, according to research presented at Cancer Research UK's Early Diagnosis Conference in Birmingham today (Wednesday).

A survey of more than 2,000 women by Jo's Cervical Cancer Trust showed that the wide range of stigmas associated with HPV included shame, fear and promiscuity. Almost 40% said they would be worried about what people thought of them if told they had HPV and more than 40% would worry their partner had been unfaithful.

Seven in 10 women would be scared to hear they had HPV and two thirds would worry it meant they had cancer.

Many women who responded did not understand the link between HPV and cancer. One in three did not know it can cause cervical cancer and almost all of them did not know it can cause throat or mouth cancer.

Researchers found that only 15 per cent of those questioned realised HPV was commonplace. Eight in 10 women will have some form of HPV infection in their lifetime but only very few who have specific high-risk types of the virus will go on to develop cancer.

Sara Hiom, Cancer Research UK's director of early diagnosis, said: "It's really concerning that there's so much misunderstanding about HPV. It's a very common virus and most of the time, it will sit dormant and not cause a problem.

"Testing for the virus is a better way to identify people who may have changes in their cervix, which, if left untreated, could develop into cervical cancer. So HPV screening is an excellent way to prevent cervical cancer from developing in the first place.

"Every woman has the choice whether to go for screening but busting the myths and removing the stigmas surrounding HPV is vital to ensure people feel more confident to book and turn up for their cervical screening appointment."

This research comes as England prepares to replace the existing cervical cancer screening test, which looks for abnormal cells, with HPV screening later this year.*

People taking part in cervical screening won't notice anything different, but the new test can more accurately identify women who may be more at risk of developing abnormal cervical cells or cervical cancer.

Right now, samples taken during screening are sent to be analysed under a microscope, to look for abnormal cell changes that could lead to cancer.

When HPV screening is introduced, samples will first be tested for the presence of HPV. If the test is positive, the sample will then be analysed by specialists under the microscope to look for cell changes. This has been shown to be much more effective at preventing cancer.

Presenting at Cancer Research UK's Early Diagnosis conference, Robert Music, Chief Executive of Jo's Cervical Cancer Trust, said: "We must address the level of misunderstanding that exists around HPV. Most people will get the virus in their lifetime so it is worrying to see such high levels of fear or shame associated with it. With the screening programme moving to testing for HPV first, which is to be celebrated, we must normalise the virus to ensure people fully understand what it means to have it."

Cancer Research UK helped prove the value of cervical screening, which now prevents thousands of deaths from cervical cancer each year.

Philadelphia, PA, February 12, 2019 - Label-free digital pathology using infrared (IR) imaging with subsequent proteomic analysis for bladder cancer (BC) has revealed the first protein biomarker (AHNAK2) for BC. AHNAK2 differentiates between chronic cystitis (inflammation of the bladder) and a non-muscle invasive-type BC (carcinoma in situ) which is challenging to diagnose. A report in the American Journal of Pathology describes this new diagnostic procedure, which is label-free, automated, observer-independent, and as sensitive and specific as established histopathological methods.

Distinguishing benign inflammatory conditions in the bladder from low-grade and advanced cancers can be difficult, especially since some BC treatments induce inflammation.

"We developed this label-free digital pathology annotation system by IR imaging to support the pathologist, similar to driver assistance in cars. This technique in combination with a proteomics approach allowed us to identify AHNAK2 as an important new biomarker for BC, and the results encourage us to transfer this label-free digital technique to other pathologies," explained Klaus Gerwert, PhD, Chairman of the Department of Biophysics and the PURE (Protein Research Unit Ruhr within Europe) consortium at Ruhr University Bochum, Germany.

Using label-free Fourier transform IR (FTIR) imaging, investigators were able to classify unaltered tissue thin sections by color to identify regions of interest. "The resulting index color images automates tissue classification, including cancer type, subtype, tissue type, inflammation status, and even tumor grading," noted Prof. Dr. Gerwert.

In an analysis of 103 freshly-frozen samples that included confirmed diagnoses for 41 cystitis, 19 low-grade carcinoma, and 43 high-grade carcinoma, FTIR imaging showed a specificity of 95 percent, sensitivity of 95 percent, and an accuracy of 95 percent compared to stained images reviewed by a trained pathologist. The technique also differentiated cancerous from healthy tissue as well as low- from high-grade carcinoma.

Laser capture microdissection was then used to obtain homogenous tissue samples for protein analysis by proteomics. By comparing tissue from patients with inflammatory bladder (cystitis) to samples from patients with invasive, high-grade urothelial carcinoma, the investigators identified three potential biomarkers, with the protein AHNAK2 found to be the best performing candidate biomarker.

In a large cohort that included 310 freshly-frozen, paraffin-embedded tissue samples (51 high-grade cancers, 67 carcinoma in situ [CIS], 84 low-grade cancers, and 108 patients with severe cystitis), AHNAK2 measurement achieved 97 percent sensitivity and 69 percent specificity in differentiating between severe cystitis with reactive urothelial atypia (RUA) vs CIS. It also displayed high sensitivity in distinguishing low versus invasive high grades and low grades vs CIS.

"In our study, AHNAK2 was identified and verified in two steps as a candidate biomarker for BC," said Barbara Sitek, PhD, Deputy Director, Medizinisches Proteom-Center (MPC), Ruhr University, Bochum, Germany. "AHNAK2 has already been proposed as a potential prognostic biomarker for clear renal cell and pancreatic cancers and is part of a urinary mRNA panel for the diagnosis of BC and prediction of tumor aggressiveness."

The investigators believe AHNAK2 could be a very helpful tool for detecting CIS recurrence or persistence, particularly because misdiagnosis of CIS can delay treatment of an aggressive malignancy or could lead to unnecessary treatment or bladder removal.

BC is the second most common urogenital malignancy, with about 430,000 new cases diagnosed worldwide in 2012. About 75 percent of newly diagnosed patients have non-muscle invasive, mostly low-grade BC, and about 25 percent have high-grade BC at the stage of infiltration of smooth muscle. The presence of acute or chronic inflammation (urocystitis) with RUA can complicate diagnosis, especially when patients with BC have been purposely treated with pro-inflammatory agents. The current gold standard for tumor grading and staging of BC is the visual inspection of stained tissue thin sections by a pathologist; immunohistochemistry is also used but can be difficult to interpret.

Deaths from heart disease have decreased in recent decades, but these decreases have not occurred in women younger than 50. A new review in CMAJ (Canadian Medical Association Journal) provides guidance for physicians to identify and manage premenopausal women at high risk of heart disease.

"Addressing cardiovascular health in women younger than 50 years of age requires thinking 'outside the box' of traditional risk factors in primary prevention," says cardiologist Dr. Beth Abramson, St. Michael's Hospital, and the University of Toronto, Toronto, Ontario, with coauthors.

The review is based on the latest, high-quality evidence published from 2008 to 2018.

Some highlights:

Diabetes, metabolic syndrome and smoking are stronger risk factors in younger women.

Younger women with ovarian dysfunction may be at higher risk of cardiovascular disease.

Early menopause because of surgical or chemical interventions may be a risk factor.

Pregnancy complications, such as gestational hypertension and preeclampsia, are linked to higher risk of cardiovascular disease.

There are limited and conflicting data on whether infertility treatments are a risk factor; further research is needed.

"A challenge in risk assessment is addressing the subpopulation at elevated risk within a lower-risk group," write the authors. "Current risk assessment tools are largely based on age and traditional risk factors and tend to underestimate risk in certain groups of younger women who are at higher risk."

The authors suggest that premenopausal women with these risk factors should be screened early for cardiovascular disease with close follow up and advice on lifestyle modifications where appropriate. Physicians should place more emphasis on sex-specific risk factors in younger women such as preeclampsia and other pregnancy complications, infertility and reproductive technologies.

Identifying higher risk premenopausal women, who have traditionally been considered low risk for future events, is an important step in improving the cardiovascular health of young women. Starting the conversation with these women at risk is the first step in prevention.

Southern courts favor physicians in malpractice lawsuits over facial trauma treatment, while courts in the Midwest favor patients, according to a Rutgers study.

The study, which was published in the Journal of Oral and Maxillofacial Surgery, is the first to explore facial trauma litigation. It also found that outcomes in facial trauma lawsuits generally favor physicians, with nearly three-fourths of cases being dismissed before trial.

In 2016, nearly 43,000 cases totaling $3.8 billion in payouts were awarded for allegations surrounding diagnosis, treatment and surgery, with the top five defendant specialties being surgical. About 15 percent of plastic surgeons face at least one malpractice lawsuit annually.

The researchers studied defendant data from facial trauma malpractice cases in the Westlaw federal litigations database. They reviewed 69 cases from 1913 to 2016. Most decisions occurred between 1965 to 2013, with half processed through legal systems in the South, 29 percent in the Midwest, 11 percent in the West and less than 9 percent in the Northeast.

About 75 percent of the plaintiffs were males with injuries to the jaw or with multiple facial fractures. A complaint of delay or failure to diagnose accounted for 50 percent of the lawsuits, which were significantly more likely to be brought against an emergency physician who failed to diagnose a fracture.

The researchers found that patients who had an initial X-ray that was followed by imaging with a computed tomography (CT) scan or other, more sensitive scan were more likely to be diagnosed with a fracture. "This tells us that emergency medicine physicians may be able to reduce their risk of malpractice by using sensitive radiography, like CT scans, while evaluating potential facial fractures," said corresponding author Boris Paskhover, assistant professor, department of otolaryngology, facial plastic and reconstructive surgery at Rutgers New Jersey Medical School.

Of the cases that went to court, 58 percent were tried by a judge and 38 percent by a jury. Three-quarters of the examined cases were decided on behalf of the defendants, 19 percent on behalf of the plaintiff, 3 percent were settled and 3 percent had an unknown outcome. Awards ranged from $14,437 to more than $1.8 million.

"An overwhelming majority of cases decided in the favor of the plaintiff were jury trials," said Paskhover. "This finding is understandable given the overall litigation structure of the United States court system, where it is a constitutional right for persons to be initially tried by a jury of their peers and not experts within the field."

The Midwest upheld 40 percent of the malpractice suits, while the South dismissed more than 90 percent. The researchers considered four possible scenarios that could account for this finding: a tendency for juries of Midwesterners to side with the plaintiff, an increased rate of legitimate malpractice cases occurring in the Midwest, a preponderance for frivolous suits in the South or a proclivity for Southern judges to dismiss claims.

"It may behoove Midwestern physicians to consider settlements over a trial, while Southern healthcare professionals may be more comfortable allowing malpractice decisions to be decided through litigation," Paskhover said.

More than 70% of patients receiving surgery for hip fracture are women, yet they are less likely than men to receive geriatric care during hospitalization, or an anesthesiology consultation before surgery, found a study published in CMAJ (Canadian Medical Association Journal) http://www.cmaj.ca/lookup/doi/10.1503/cmaj.180564.

Previous studies have shown that older patients who receive geriatric care when hospitalized for hip fracture surgery are less likely to die after surgery and spend less time in hospital, and that anesthesiology consultations can help to avoid cancelled surgeries and may decrease length of stay. For these reasons, both practices are recommended by Health Quality Ontario and the Ontario Ministry of Health and Long-Term Care.

In this study of 22 661 patients aged 66 and older who had emergency hip fracture surgery between 2014 and 2016, 71.3% (16 162) were women. The researchers found that 8% of women received geriatric care compared to 10% of men.

"Overall, we found that geriatric care for these vulnerable hip fracture patients was not routinely provided. However, given that 70% of hip fractures occur in women, and what we know about the positive effect of providing geriatric care to older hip fracture patients, increasing access to this care should be a top priority," says senior author Dr. Daniel McIsaac, associate scientist and anesthesiologist at The Ottawa Hospital, Ottawa and ICES, Toronto, Ontario. "A person's sex or gender should not play a role in whether evidence-based care is provided."

Women from low-income neighbourhoods were also less likely to receive geriatric care than men from similar neighbourhoods. Women with dementia were less likely than men with dementia to receive an anesthesiology consultation before surgery.

The researchers suggest that sociocultural biases may be at play. Another possibility is that men have a higher risk of death after hip fracture surgery than women, which may influence how physicians decide to apply the resources available.

"Understanding that there are issues with sex- and gender-based equality is a first and important step toward improving outcomes," says Dr. McIsaac.

However, his group suggests that to make sure that women and men have equal, and ultimately increased, access to geriatric care in the future, more research is needed to understand factors driving this inequality and how to address them.

The first prospective, longitudinal study investigating treatment of chronic hepatitis C with direct-acting antivirals finds that the treatment is associated with reduced risk of mortality and liver cancer, according to a study published in The Lancet. The research is the first to demonstrate the clinical effectiveness of direct-acting antivirals on the disease and suggests that they should be considered for all patients with chronic hepatitis C infection.

For ethical reasons a trial with a control arm is not possible and researchers approached this by setting up an observational study of around 10,000 patients. At follow up, about three-quarters had been treated with direct-action antivirals and a quarter were untreated. The incidence of death and hepatocellular carcinoma - the most common form of liver cancer - were significantly decreased in patients who were treated. Their risk of decompensated cirrhosis was not reduced by the treatment.

Around the world, an estimated 71 million people are chronically infected with the hepatitis C virus (HCV). The infection causes complications such as cirrhosis, liver disease, hepatocellular carcinoma, and many people die as a result. Over the last 15 years, these complications have tripled and models predict they will peak between 2030 and 2035. The World Health Organization (WHO) has set targets for the elimination of hepatitis C, and a reduction of related complications. Recently, a modelling study published in The Lancet found that major progress towards these targets by 2030 is possible, but will require vast improvements in screening, prevention, and treatment [1].

Previous work has shown there is a reduction of risk for complications and mortality in patients who are treated with interferon or direct-acting antivirals, but few studies have compared treated and untreated patients. The aim of direct-acting antiviral drugs is to achieve a sustained virological response, meaning that the virus is undetectable in the blood of the patients. A recent Cochrane Review [2] found no evidence for or against the treatment having a long-term effect on death and disease, so this large study is timely, and may help doctors and patients with treatment plans.

In this study, 10,166 patients were recruited from 32 centres in France. At a median of 33 months, 9,895 patients had available follow up information and were included in the analysis, with 7,344 treated with direct-acting antivirals and 2,551 untreated. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated).

Overall, the study finds that direct-acting antiviral treatment is associated with reduced risk for global mortality and hepatocellular cancer, but not decompensation of cirrhosis. The researchers initially found an increase in risk associated with treatment with direct-acting antiviral treatment, but once they had adjusted for variables such as age, sex, body-mass index, severity of liver disease, geographical origin, infection route and other factors, they found a reduced risk.

Patients who were treated were 52% less likely to die prematurely than people who were not treated (the estimated adjusted risk of death at one year in untreated patients in the cohort is 84 deaths per 10,000 patients, and in those who were treated was 40 per 10,000), and 33% less likely to present with hepatocellular carcinoma (the estimated adjusted risk of developing hepatocellular carcinoma within a year in untreated patients in the cohort was 129 cases per 10,000 patients, and 86 per 10,000 in people who were treated). [3]

In a subgroup of 3,045 patients with cirrhosis at baseline, the same association was found for mortality and hepatocellular cancer, provided the patients achieved an undetectable level of HCV in their blood. The researchers believe this is because the treatment induces a sustained virological response, allowing the liver to regenerate which decreases risk.

Professor Fabrice Carrat of the Sorbonne Université, France, said: "Taking a large cohort like this provides the opportunity to evaluate the effect of direct-acting antiviral therapy on the long-term outcomes of patients with hepatitis C. We saw a reduction of risk for complications related to the disease, and to mortality, and believe this treatment should be considered for all patients with chronic hepatitis C infection." [4]

In the study, only a few patients underwent liver biopsy to confirm cirrhosis, with platelet levels or prothrombin time - a blood test - used to classify whether a patient had cirrhosis or not. A validation study using other non-invasive markers of fibrosis suggested that their methods correctly classified cirrhosis in the patients.

Patients who received more than one course of direct-acting antivirals were considered to have had continuous exposure, even where there may have been a lag time or if the first course may not have been associated with sustained virological response. This should have underestimated the response to the drugs rather than overestimated them so does not affect the result.

The study excluded patients with a history of decompensated cirrhosis and liver transplantation and these are the patients who would be at highest risk for complications. The potential benefits of treatment in this group could be underestimated because of their exclusion, as trial data shows improvements in liver function in patients with decompensated cirrhosis who achieved a sustained virological response.

Writing in a linked Comment, Dr Raymond T Chung, Director of the Liver Center at Massachusetts General Hospital, USA, says: "The study by Carrat and colleagues offers substantive evidence that cure of HCV delivered by all-oral direct-acting antiviral regimens is associated with clinical benefits. These findings firmly counter those of a Cochrane review of direct-acting antiviral treatment trials that could neither confirm nor reject if direct-acting antivirals had an effect on long-term HCV-related morbidity and mortality. They also provide the best evidence to date to support guidance documents that recommend direct-acting antiviral treatment for all patients with chronic HCV infection. Finally, they provide credence to the achievability of the goals set out by WHO, not only to eliminate HCV but also to substantially reduce its complications."

Physicians may soon have a new way to measure the efficacy or failure of hormone therapy for breast cancer patients, according to new research published in the February issue of The Journal of Nuclear Medicine. Researchers report that positron emission tomography (PET) imaging with 18F-fluorofuranylnorprogesterone (18F-FFNP) has been found to successfully measure changes in progesterone receptor (PR) levels resulting from a short-course estrogen treatment, also known as an estradiol challenge.

Estrogen-receptor (ER)-positive breast cancer is the most common class of breast cancer, affecting nearly 70 percent of patients. By participating in an estradiol challenge, physicians can determine the likelihood of potential benefit of hormonal therapies targeting ER for individual patients. Many hormone therapies interfere with the ability of estrogen to regulate the expression of PR protein, which is more pronounced in the presence of estrogen. As such, several PET tracers have been developed to monitor and analyze changes in the PR level during therapy. "Typically, anatomic size and proliferation biomarkers are analyzed to determine endocrine sensitivity," said Amy M. Fowler, MD, PhD, assistant professor, Section of Breast Imaging, Department of Radiology, University of Wisconsin-Madison. "However, non-invasive detection of changes in PR expression with 18F-FFNP during an estradiol challenge may be an earlier indicator of the effectiveness of a specific hormone therapy."

In this study, T47D human breast cancer cells (cells with estrogen and progesterone receptors, but without human epidermal growth factor receptor-2) and mice bearing T47D tumor xenografts were treated with estrogen to increase PR expression. The cells and mice were imaged with 18F-FFNP, and assays were conducted for cell uptake and tissue biodistribution. To investigate the separate role of PR-A and PR-B isoforms on overall 18F-FFNP binding, triple-negative MDA-MB-231 breast cancer cells were engineered to express either PR-A or PR-B. In vitro 18F-FFNP binding was measured by saturation and competitive binding assays, while in vivo uptake was measured with PET imaging.

In T47D cells treated with estrogen, an increase in 18F-FFNP uptake was measured at 48 hours after treatment; in mice with T47D tumor xenografts, increased uptake was seen at 48 and 72 hours after treatment. This increase in 18F-FFNP uptake also correlated with an increase in PR protein expression and proliferation. Results showed that there was no significant preferential 18F-FFNP binding or uptake by PR-A versus PR-B in PR isoform cell lines or tumor xenografts. "This is an important finding given the variability of PR isoform expression observed in breast cancer patients," stated Fowler.

She continued, "Validation of PR imaging as a biomarker of endocrine sensitivity in patients before and after estradiol challenge could provide new opportunities in the field of molecular imaging and nuclear medicine for breast cancer imaging. Improved methods for testing endocrine sensitivity in patients could better inform decisions for optimal individualized ER-positive breast cancer therapy, potentially reducing morbidity and mortality."