Body

Bottom Line: Administration of the EGLN inhibitor FG-4592 prior to ablative radiotherapy provided protection against fatal gastrointestinal bleeding and improved survival in a mouse model of unresectable pancreatic cancer.

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

Author: Cullen Taniguchi, MD, PhD, assistant professor of radiation oncology at The University of Texas MD Anderson Cancer Center

Background: Surgery is required for the curative treatment of pancreatic cancer, yet the majority of patients with this disease have unresectable tumors, said Taniguchi. While radiation therapy may be a future alternative to surgery in this patient population, the required dose of radiation to effectively treat the disease can damage the neighboring organs, which can lead to gastrointestinal bleeding and even death, he explained. "This study was conducted to understand if it was possible to protect the bowels from radiation damage in order to give enough radiation to effectively treat unresectable pancreatic cancer," he said.

Hypoxic cells induce a powerful regenerative response, resulting in the protection of tissue, Taniguchi said. "Inhibition of EGLN mimics hypoxia, allowing us to take advantage of the healing response of this phenomenon without actually depriving the cell of oxygen," he explained.

How the Study Was Conducted and Results: Tumor hypoxia is a feature of many cancerous cells that can lead to disease progression and metastasis and is especially prevalent in pancreatic cancer, Taniguchi noted. The researchers found that murine pancreatic tumors were already highly hypoxic and adding FG-4592 did not induce further hypoxia; however, in normal murine tissues, which are not hypoxic, adding the EGLN inhibitor effectively mimicked hypoxia and protected the tissue.

To determine if administration of FG-4592 could improve survival following ablative radiation therapy, the researchers assigned 70 mice bearing spontaneous, palpable pancreatic tumors one of four treatments: vehicle only, FG-4592 only, vehicle plus radiotherapy, and FG-4592 plus radiotherapy. FG-4592 and vehicle were administered orally, and radiotherapy treatments consisted of 15 fractions to a limited tumor field totaling 75 Gray.

Overall, mice treated with radiotherapy with prior radioprotection via FG-4592 had the highest median overall survival (43 days); no gastrointestinal bleeding was observed. Mice treated with radiotherapy without radioprotection had decreased median overall survival (36 days), and fatal gastrointestinal bleeding was observed in 56 percent of mice in this cohort. The difference in overall survival between these two groups was statistically significant.

Among mice that did not receive radiotherapy, treatment with FG-4592 increased the median overall survival compared to vehicle alone (29 days versus nine days, respectively).

Author's Comments: "The fact that treatment with FG-4592 alone increased survival in mice harboring pancreatic cancer was a surprising finding," said Taniguchi. "We are actively investigating this result, and one preliminary hypothesis is that EGLN inhibition may modulate the immune system and contribute to this therapeutic effect," he added.

"Our proof-of-concept study illustrates that higher doses of radiation therapy can improve outcomes in unresectable pancreatic cancer as long as treatment toxicity is reduced with a radiation protector," said Taniguchi. "As toxicity is a major limiting factor of cancer treatment, protecting normal tissues from radiation damage is an important concept in the field of oncology that warrants additional attention," he noted.

"While we utilized EGLN inhibitors in our study, we want to emphasize that radioprotection is not limited to this class of drugs," noted Taniguchi. "We hope that our results stimulate more research in this area."

Study Limitations: Taniguchi noted that a major limitation in this preclinical mouse study was that no chemotherapy was administered, which would be considered standard of care in humans before the initiation of radiotherapy. "In this preliminary study, we felt that the addition of chemotherapy might complicate the key question of whether we could give an ablative dose of radiation to pancreatic tumors without lethally damaging the small bowel," Taniguchi explained. "As such, future experiments with clinically relevant chemotherapy, such as FOLFIRINOX or gemcitabine, will need to be conducted in mice before initiating a clinical trial," he added.

Funding & Disclosures: This study was supported by funding from the Cancer Prevention & Research Institute of Texas, the V Foundation, the Sidney Kimmel Foundation, the Sabin Family Foundation Fellowship, the McNair Foundation, and the National Cancer Institute.

Taniguchi declares no conflict of interest.

ARLINGTON HEIGHTS, IL - (APRIL 30, 2019) - Many children with asthma think they are using their asthma inhaler medications correctly when they are not. This makes it very difficult to keep their asthma under control. A new study in Annals of Allergy, Asthma and Immunology, the scientific journal of the American College of Allergy, Asthma and Immunology (ACAAI) finds African American school children, along with their parents, had misplaced confidence in their asthma inhaler technique.

"We know from past studies that both parents and children overestimate the ability of children to properly use their inhaler," says Anna Volerman, MD, lead study author. "We examined whether parent and child confidence were the same and whether either was a good sign of the child's actual ability to use the inhaler correctly. We found most parents and children overestimated the children's ability based on high confidence by the child - despite inhaler misuse."

The study surveyed 65 pairs of parents and children at four Chicago public charter schools. The age range of the children was 8 to 14 years, most were male and 90 percent were African American. Most parents (80 percent) were female. Nearly all children (97 percent) misused their inhaler. One child demonstrated mastery. A small proportion of children and parents accurately matched their confidence to their child's technique. Five percent of children who were confident in their inhaler technique used their inhaler without misuse, while 4 percent of children whose parents were confident properly used their inhaler. None of the parents underestimated the children's skills.

"It's not enough for an allergist or other health care provider to ask a child or their parents if the child knows how to use an inhaler," says allergist Todd Mahr, ACAAI president. "Simply asking is not a reliable screening tool to determine who needs additional education on how to properly use an inhaler. If your child has asthma, check with your allergist to make sure your child has proper inhaler technique. Bring the inhaler with you to your next appointment and have your allergist or one of their staff watch your child use it."

The study results showed parents may be less accurate in predicting their child's inhaler ability than their child. The authors thought potential reasons may be children's daily experience with inhalers, parents' lack of knowledge about proper inhaler technique or parents' limited supervision of care.

A major new review of the world literature has found that Fetal Alcohol Spectrum Disorder (FASD) is 10 to 40 times higher in certain susceptible groups than the general population. These groups include children in care, people in correctional services or special education services, Aboriginal populations, and people using specialized clinical services.

FASD is a serious, lifelong, disabling condition that affects individuals from all racial, ethnic and socioeconomic backgrounds. It is caused by alcohol consumed during pregnancy. Alcohol is a toxic substance that can readily cross the placenta, resulting in permanent damage to the brain and other organs of the developing embryo and fetus. An estimated one in every 13 infants prenatally exposed to any level or type of alcohol will develop FASD; about 630,000 infants are born with FASD in the world each year.

This study used data from 69 studies representing 17 countries across North and South America, Europe, Asia, and Australasia. The studies included five sub-populations: children in care, people in correctional services, Aboriginal populations, people in special education services, and people using specialized clinical services (genetic clinics and clinics for developmental disabilities or psychiatric care).

The estimated prevalence of FASD in these groups ranged from 10 to 40 times higher than the 7.7 per 1,000 global FASD prevalence in the general population. For example, FASD prevalence among children in care was 32 times higher in the United States and 40 times higher in Chile; prevalence among adults in the Canadian correctional system was 19 times higher; and prevalence among special education populations in Chile was over 10 times higher.

Lead author Dr Svetlana Popova says, "Public policy and clinical care for people with FASD needs to recognise the severity of the problem globally. Routine screening protocols should be established to identify people with FASD in child welfare, special education, justice system and other settings to provide appropriate support and early interventions. Service staff should be trained in FASD awareness, identification, and interventions to provide better care. Women should completely abstain from any type of alcohol during their entire pregnancy and while trying to get pregnant."

This review was restricted by the limited number of studies, some of which were dated and had methodological weaknesses. Countries need to conduct rigorous epidemiological studies to understand the size and severity of this serious but preventable alcohol-related neurodevelopmental disorder.

New research presented at this year's European Congress on Obesity (ECO) in Glasgow, Scotland (28 April - 1 May) reveals that the risk of a child becoming overweight or obese is more than trebled by maternal obesity prior to getting pregnant. The study is by Dr Nicola Heslehurst, Institute of Health & Society, Newcastle University, UK, and colleagues.

Efforts to prevent childhood obesity are recognised as being vital for public health, global health, and clinical practice, with a particular emphasis on early-life intervention. In order to inform clinical practice and public health policy, there needs to be an understanding of how the body mass index (BMI) of a mother can impact the risk of obesity faced by the child. This in turn can provide estimates of the potential health gains from channelling resources into early interventions focused on mothers to be.

The authors used five databases of scientific papers as their sources of data for the study (MEDLINE, Child Development & Adolescent Studies, CINAHL, Embase, PsycInfo), and looked for research into the association between maternal and child BMI or equivalent z-score (a numerical measure of how a value relates to the mean for that sample). Mothers were grouped using BMI categories: obese (BMI of 30 kg/m2 or higher), and overweight (BMI between 25 and 30). Children were grouped using BMI or z-score percentile categories: obese (?95th percentile), overweight or obese (?85th percentile) and overweight (85-95th percentile). Statistical analyses were then performed to explore the relationship between maternal weight and that of their child.

The researchers found that when a mother had obesity prior to becoming pregnant, the odds of her child also developing obesity was 3.64 times greater than for a mother whose weight was in the 'recommended' BMI range (18.5 - 25). When mothers had an overweight BMI, the odds of the child having obesity were 1.89 times higher.

When the team looked at children with either overweight or obesity (as a one combined group), they found that the odds of ending up in this group were 2.69 and 1.65 times higher when the mother had obesity or overweight respectively. For children in the overweight category, their odds of being so were 1.80 times higher if their mother had obesity, and 1.41 times higher if she had an overweight BMI prior to pregnancy.

The authors conclude: "This research has identified a more than three-times increased risk of child obesity when mothers have preconception obesity. This data provides substantial evidence for the need to develop interventions commencing prior to conception in order to support women of childbearing age with weight management and contribute towards prevention of intergenerational obesity."

It was 90 years ago that mould accidentally got onto a bacterial culture in Alexander Fleming's lab. The Scottish bacteriologist observed that the mould produced a substance that killed the bacteria on the cell-culture dish. He had discovered penicillin, one of the first antibiotics. There are now several dozen classes of antibiotics on the market, and scientists continue to search tirelessly for new antimicrobial agents because they are urgently needed in medicine. A large proportion of these drugs are natural products or take these as their origin. And the method of detection is still the same as it was in Fleming's day: if a substance can kill bacteria on a cell-culture dish, then it's an antibiotic.

Steven Schmitt and colleagues from ETH Professor Sven Panke's group in the Department of Biosystems Science and Engineering at ETH Zurich in Basel have now modernised and miniaturised Fleming's method, making it fit for high-throughput screening of microorganisms and the substances they produce. "While it currently takes up to a year to test around 10,000 producers of substances using conventional methods, we are able to examine millions of variants within just a few days," says Schmitt, who developed the method as part of his doctoral thesis at ETH.

The ETH scientists, together with Dutch and German colleagues, have successfully identified a number of new antibiotic candidates with the new technology. In a next step, the scientists will investigate whether some of these molecules are suited for medical application.

"Bubble tea" in the quest for active substances

Alexander Fleming used a cell-culture dish with a diameter of ten centimetres, but the new technique, called nanoFleming, employs tiny beads of gel just half a millimetre across - bringing to mind bubble tea or molecular gastronomy's imitation caviar. Inside these beads, scientists can test new substances for antibiotic activity. For this, they embed numerous sensor bacteria along with one microorganism that produces a substance with a potential antibiotic effect.

If the produced substance has an antibiotic effect, the sensor bacteria die. If it has no effect, they proliferate and form cell clusters. After labelling the sensor bacteria with a fluorescent dye, the scientists can use a high-throughput sorting method to isolate weakly fluorescent gel beads. These contain a microorganism producing an active antibiotic. The scientists can then proceed to identifying this substance.

More effective antibiotics

For their latest paper, which the scientists recently published in the journal Nature Chemical Biology, they tested a collection of 6,000 peptides (short proteins) for antibiotic effect. These molecules are similar to a group of known peptide antibiotics called lantibiotics. The scientists wanted to investigate whether it was possible to increase the efficacy of lantibiotics or bypass known resistance mechanisms by altering their molecular structure in intelligent ways.

Working with fellow Dutch and German scientists, they started from known lantibiotics and their structural and functional subunits. Taking a biotechnology approach, they combined these different subunits in all possible ways and created a collection of microorganisms that produce these recombinant peptides. Testing them with the nanoFleming method the team found 11 peptides that either are effective at smaller doses than the conventional lantibiotics or are able to bypass known resistance mechanisms.

Seeking substances in the natural world

"The method is also excellent for investigating whether microorganisms found in nature produce as yet undiscovered active substances," says Schmitt. He explained that microbes trying to eliminate their competitors with biochemical compounds is a natural and widespread mechanism. It is therefore possible that new antibiotic classes could be found in habitats such as soil samples or the microbiome found on human skin and in saliva, an area which has not yet been studied in detail. The new technology will be able to analyse microorganisms from these habitats very well. "And because we are now able to test many more producers of active substances in a much shorter time than was possible with previous methods, the chances of discovering active agents from rare microorganisms are far greater."

The technique could also be adapted to test for additional criteria already during the first screening, such as the stability of antibiotic substances in the human bloodstream or avoidance of resistance mechanisms. Furthermore, it could be possible to equip the gel beads with different kinds of sensor bacteria - those that an active substance absolutely should kill, such as pathogens, and others that it should most definitely not harm, such as beneficial bacteria found on healthy skin or in oral flora.

A study of nearly 50,000 women in Denmark, presented at this year's European Congress on Obesity in in Glasgow, Scotland (28 April-1 May), reveals that those with overweight or obesity in childhood were more likely to develop hypertensive disorders during pregnancy than women of normal weight in childhood. The study is by Dorthe Corfitzen Pedersen, PhD student, the Center for Clinical Research and Prevention at Bispebjerg and Frederiksberg Hospital in Copenhagen, Denmark and colleagues.

The findings build on two well-known observations: women with overweight or obesity are at greater risks of hypertensive disorders in pregnancy than women with normal-weight; and excess adiposity (severe overweight or obesity) takes time to develop. Hypertensive disorders in pregnancy are of particular concern since they can endanger the lives of both the mother and her unborn child.

For these analyses the authors used data on 49,615 girls from the Copenhagen School Health Records Register, born from 1930-1996 (and aged 23-90 years now). Annual height and weight measurements were collected from ages 7-13 years.

The researchers defined overweight and obesity at ages 7 and 13 years according to the International Obesity Task Force body mass index cut offs (BMI ?17.69 kg/m2 at age 7 years and 22.49 kg/m2 at age 13 years). Using national registers, they identified girls who later became pregnant and those who developed gestational hypertension or preeclampsia from 1978-2017. Women were included in the study if they were in the age-range of 18-45 years and gave birth to a single baby in their first recorded birth.

After estimating the odds ratios (OR) for the association between childhood BMI and hypertensive disorders during pregnancy, using a statistical technique called multivariate logistic regression, the team found that compared to girls with normal-weight, those with overweight at ages 7 or 13 years were significantly more likely to develop gestational hypertension (increased risk: 1.9 and 2.0 times, respectively) and preeclampsia (increased risk 1.6 and 2.3 times, respectively) when adjusted for maternal age at delivery and maternal birth cohort (all results were statistically significant).

When looking at patterns of change in BMI, girls with overweight at 13 years only or at both 7 and 13 years were around twice as likely to develop gestational hypertension and preeclampsia during pregnancy than girls with normal-weight at both ages.

The team concludes: "A high childhood BMI at ages 7 and 13 years in girls was significantly associated with the later risk of developing gestational hypertension and preeclampsia during pregnancy. These results suggest that preventive efforts aimed at helping girls attain a normal weight during these years may benefit both their own health and the health of children they may have in future."

New research presented at this year's European Congress on Obesity (ECO) in Glasgow, Scotland (28 April - 1 May) reveals that a quarter of patients have never had their body mass index (BMI) recorded by their GP. The study is by Kath Williamson and Professor Mike Lean of the Department of Human Nutrition and Dr Amy Nimegeer of the Institute of Health and Wellbeing, University of Glasgow, UK.

Providing effective and correctly targeted weight management services, including those aimed at the remission of type 2 diabetes relies on having accurate and up to date BMI data. National survey data shows that 29% of Scottish people are classed as obese (BMI of above 30kg/m2). The Quality and Outcomes Framework in the UK* aimed to incentivise BMI recording of BMI, especially for people with obesity. Despite this need, previous research has demonstrated significant under reporting, with only 37% of UK adults having had their BMI recorded in the last year and 79% having had their BMI ever recorded.

The extent of routine BMI recording and documentation in Scottish primary care has not been previously researched. In this new study, the authors conducted a review of the health records of 77,591 adults aged 16 years and over from 12 general practices covering a broadly socioeconomically representative sample of the Scottish population. The BMI fields of records were searched for any BMI recording, with a specific interest in any measurements taken during the previous 2 years.

The researchers found that a BMI had ever been recorded in 75% of individuals, while less than a third (31%) of patients had a recent BMI measurement (that was less than 2 years old). Up to date BMI recording rates also varied significantly across practices from 20% to 42%, although the team did note a marked increase in recording rates over the 2-year review period.

For those with a BMI recording in the previous 2 years, they were split into the following BMI categories: less than 18.5 (underweight): 2%; 18.5-24.9 (normal weight) 27%; 25-29.9 (overweight) 33%; 30-39.9 (obesity grades I and II) 31%; and 40+ (severe obesity) 7%. In the two highest BMI categories the figures were greater than those in the 2017 Scottish Health Survey (26% and 3% respectively), as well as the 2017 Health Survey England (25% and 4% respectively), suggesting that both obesity and severe obesity rates may be higher than previously thought.

The authors conclude: "More complete current routine BMI data is required for accurate planning and provision of weight management services. Underreporting may hinder stated public health aims of early detection and intervention of type 2 diabetes. It is important to monitor the quality of data in electronic health records given their increasing use as a source in research and to estimate variation between real life prevalence rates and national health survey rates."

The disconnect between perceptions of health care providers (HCPs) and people with obesity (PwO) is revealed in a new international study (the ACTION-IO study) presented at this year's European Congress on Obesity (ECO 2019) in Glasgow, UK, and published in the journal Diabetes, Obesity and Metabolism. Among the study's findings are that while 71% of HCPs believe PwO are not interested in losing weight, actually only 7% of PwO report they are not interested - a 10-fold difference.

ACTION IO is the largest study of its kind to investigate barriers to obesity management from the perspective of people with obesity and healthcare professionals. The study surveyed over 14,500 people with obesity and nearly 2,800 HCPs from 11 countries: Australia, Chile, Israel, Italy, Japan, Mexico, Saudi Arabia, South Korea, Spain, UAE and the UK. ACTION IO supplements the valuable insights gained from the previous ACTION studies conducted in the US and Canada, published in 2017.

Other key findings from the study include that 81% of PwO believe it is their sole responsibility to lose weight; and only 51% of PwO discussed their weight with their HCPs in the past five years, but only after a significant delay of a mean of six years from when their weight struggles began.

Reporting on actual attempts to lose weight were also very different between the two groups: 81% of PwO said they had made at least one serious weight-loss effort in the past, while HCPs reported that only 35% of their patients had done so, possibly indicating that PwO are not necessarily comfortable discussing the subject with HCPs or that HCPs were not aware of an attempt being made. That said, the study also found that 68% of PwO would like HCPs to start conversations around weight management during appointments.

"Our data suggest that PwO are motivated to lose weight and there is an opportunity for HCPs to initiate earlier, effective weight loss conversations with minimal fear of offence," says the study's lead author Professor Ian Caterson of the Boden Institute, Charles Perkins Centre, University of Sydney, NSW, Australia.

He adds: "PwO may not recognise the need to reduce excess weight until it has an impact on their health, further supporting the requirement for HCPs to raise the topic of weight before such obesity-related complications occur. Our study also reveals a global need for greater education for both PwO and HCPs on the biological basis and clinical management of obesity, and for a more positive HCP attitude towards initiating weight discussions and management."

He concludes: "We hope that these findings can help remove the barriers between people living with obesity and their health care providers and drive more positive engagement in the treatment of obesity."

Milan, Italy: Mesothelioma patients are twice as likely to survive for two years or longer, if they are treated with a high dose of radiation to the affected side of the trunk, according to research presented at the ESTRO 38 conference.

Mesothelioma is a rare but aggressive form of cancer that grows in the layers of tissues surrounding the lungs. It is usually caused by exposure to asbestos. Patients typically only live for a year or two following diagnosis and treatment options are very limited.

The study looked at patients whose cancers could not be completely removed with surgery and the researchers say their findings have the potential to change treatment and outcomes for this group of patients.

The study was led by Dr Marco Trovo MD, chief of the Radiation Oncology Department at University Hospital of Udine, Italy. He said: "There is an urgent need for more effective treatments for mesothelioma. Surgery can be given to these patients, but it is often impossible to remove all of the tumour.

"Patients with mesothelioma are sometimes given radiotherapy to help control their symptoms. However, radiotherapy has evolved dramatically in the last few years so we wanted to see if it could now be used to prevent the cancer from spreading to nearby tissue, hopefully bringing improvements in survival."

The study involved 108 patients with malignant pleural mesothelioma who were treated at the National Cancer Institute of Aviano, Italy, between 2014 and 2018. All were given surgery to remove some tumour tissue, followed by chemotherapy.

Half were randomly assigned to receive radical hemi-thoracic radiotherapy, meaning the radiation was delivered to either the left or right side of their trunk, depending on where the tumour was located. This involved 25 treatments delivering a total dose of 50 Gy to the left or right side of the trunk, as well as an extra 60 Gy dose to the precise location of the tumour. The other patients received a more typical palliative form of radiotherapy. This involved five to ten treatments delivering a total dose of 20-30 Gy to the precise location of the tumour.

Of the patients who received the aggressive radiotherapy treatment, 58% were still alive two years later. In the patients who received the palliative radiotherapy, 28% were still alive two years later.

Around 20% of patients receiving radical hemi-thoracic radiotherapy suffered radiation pneumonitis (inflammation of the lung). Other sides effects included weakness, nausea and mild inflammation of the oesophagus.

Dr Trovo said: "This research shows a clear survival benefit in using this type of radiotherapy for mesothelioma patients whose tumours can only partially be removed by surgery. We believe that this should be considered the new standard of care for these patients."

He hopes that even greater gains in survival could be made by treating patients with radiotherapy followed by targeted immunotherapy (where the body's own immune system is encouraged to fight cancer cells).

Professor Umberto Ricardi, President of ESTRO and head of the Department of Oncology at the University of Turin, Italy, who was not involved in the research, said: "This is an extremely positive result that brings good news to patients with this rare and difficult-to-treat cancer. To ensure these patients benefit from this type of treatment, it's important that they are referred to a specialist cancer centre with the right expertise and equipment to carefully plan and deliver the most effective radiotherapy treatment, and manage any side effects that occur."

Milan, Italy: Patients with advanced Hodgkin's lymphoma who have large tumours at the time of diagnosis may benefit from radiotherapy after chemotherapy even when all traces of the cancer appear to have gone, according to late breaking results presented at the ESTRO 38 conference today (Monday).

Approximately 65-70% of patients with advanced stage Hodgkin's lymphoma can be cured by receiving six cycles of ABVD chemotherapy (which includes doxorubicin, bleomycin, vinblastine and dacarbazine), with or without subsequent radiotherapy. Currently, however, the addition of radiotherapy is controversial.

In a statement before the conference, Dr Mario Levis, a co-author of the study, who is a radiation oncologist at the University of Turin, Italy, explained: "These patients can often have four or five decades of life expectancy ahead of them but, given this cure rate, the cancer treatment can result in a high risk of complications for many long-term survivors. For this reason, it's important that we give patients the most effective treatment for curing their cancer, while, at the same time, trying to keep the toxic side effects to a minimum."

To investigate whether radiotherapy after ABVD chemotherapy provided any benefit to these patients, researchers in several centres in Italy, led by Professor Pier Luigi Zinzani, of the Institute of Haematology at the University of Bologna, and Professor Umberto Ricardi, head of the Department of Oncology at the University of Turin and President of ESTRO, recruited 512 patients between 2008 and 2013 to a randomised clinical trial: HD0801.

Patients who had been treated successfully in the earlier, phase II part of the trial, and in whom PET scans showed no trace of cancer both during and at the end of chemotherapy, were randomised to the phase III part of the trial to receive either radiotherapy in order to mop up any remaining cancer cells, or no further treatment.

In total, 354 patients had PET scans showing they were clear of cancer after the initial treatment. Of these, 116 (32.7%) had had large lesions (greater than 5cm in diameter) at the time of their diagnosis and they were assigned to radiotherapy or no further treatment.

Dr Levis and Prof Ricardi found that more patients were alive three and five years later without their disease getting worse (known as progression-free survival) if they had been treated with radiotherapy than those who did not receive it.

Professor Ricardi told the conference: "We found that three years later 92% of patients who received radiotherapy were still alive without disease progression compared to 82% of patients who did not receive it. After five years, these figures were 89% and 82% respectively.

"This suggests that patients with large tumours, who have responded to six cycles of ABVD chemotherapy, may still benefit from the addition of radiotherapy, with a survival benefit ranging from 7% to 10% at three and five years.

"This is something that should be considered carefully when deciding whether or not to give radiotherapy to these patients. The omission of radiotherapy would guarantee the prevention of radiation-induced toxic side effects, but, on the other hand, it exposes 10% of our, frequently young, patients to an increased risk of relapse and of even higher toxicity due to the heavy salvage therapies required when the disease returns."

Nine patients who had been enrolled in the radiotherapy arm of the trial did not actually receive radiation treatment due to decisions made by their doctors, and the disease returned in five of them. This meant that when the data on the 116 patients were analysed according to "intention to treat" (i.e. regardless of whether or not they had actually received the radiotherapy), there was little difference between the two groups in progression free survival at three and five years. It was only when the researchers analysed the data according to the treatments the patients had actually received (a "per protocol" analysis) that it was possible to see the benefit on survival for those treated with radiotherapy, although this was not statistically significant. This was mainly because of the small number of patients in whom the disease returned: five in the radiotherapy arm and 13 in the 'no further treatment' arm of the trial.

"The results of this trial do not provide definitive evidence on the role of radiotherapy after chemotherapy for patients with advanced Hodgkin's lymphoma and large tumours. However, the improvement in survival among those who did receive radiotherapy is not negligible. We think that the next step is for a meta-analysis of this and similar randomised trials in order to increase the robustness of the information we have on the best way to treat this disease," concluded Prof Ricardi.

Professor Yolande Lievens, past-President of ESTRO and head of the department of radiation oncology at Ghent University Hospital, Belgium, said: "As physicians our main aim is to treat our patients effectively while keeping any adverse side-effects from the treatment to the minimum. This is especially important for patients with a disease such as Hodgkin's lymphoma, many of whom can expect to be cured and live long after their treatment has finished. The results from this trial provide us with additional, important information to take into account when advising our patients on what might be the best treatment."

A new study has shed light on the link between higher body mass index (BMI) and serious health outcomes and death in over 2.8 million adults representative of the UK population.

The new estimates, being presented at this year's European Congress on Obesity (ECO) in Glasgow, UK (28 April-1 May), indicate that adults with severe obesity class III (BMI of 40-45 kg/m2) are 12 times as likely to develop type 2 diabetes, and are at 22 times greater risk of sleep apnoea than their normal weight peers. Those individuals with obesity class I (30-35 kg/m2) are at 70% higher risk of developing heart failure.

Importantly, the risk of developing serious health problems was highly dependent on whether or not individuals had comorbidities at the start of the study. For example, a history of any cardiovascular event doubled the risk of unstable angina/heart attack, stroke, and heart failure.

The size of this study, as well as the ability to consider 12 different serious health outcomes in a single-population representative cohort in the UK makes this research different from anything that's been previously done, researchers say.

The study analysed BMI, health, and mortality data on over 2.8 million adults (average age 51 years) between January 2000 and July 2018 from the UK Clinical Practice Research Datalink--which is representative of the overall population demographic with regard to age, sex, and geographic distribution.

Study subjects were divided into five BMI groups: 18.5-25kg/m2 (normal weight; reference group); 25-30 (overweight); 30-35 (Obesity class I); 35-40 (Obesity class II) and 40-45 (Obesity class III), and linked with Hospital Episode Statistics data to estimate the risk for 12 serious health problems. The results were adjusted for age, gender, and smoking.

Compared with normal weight individuals, adults with Obesity class I (BMI 30-35) were more than five times as likely to develop type 2 diabetes and sleep apnoea--these risks were almost 8-fold and 12-fold higher respectively in those with severe Obesity class II (35-40).

Having Obesity class III tripled the risk of heart failure, high blood pressure, and dyslipidaemia (abnormal, usually high, levels of cholesterol and other fats in the blood), and these individuals also had a 50% higher risk of dying prematurely from any cause than their normal weight counterparts.

Importantly, the study found that comorbidities present at start of the study increased the risk of developing serious health problems. For instance, having high blood pressure at the start of the study was strongly associated with developing dyslipidaemia, chronic kidney disease, and type 2 diabetes. A previous cardiovascular event doubled the risk of unstable angina/heart attack, stroke/transient ischemic attack, and heart failure.

"Comparing BMI risk across a large number of outcomes in the same large population sample suggests that risk levels associated with BMI are different for different health outcomes. The health risks linked with having excess body weight are particularly high for type 2 diabetes and sleep apnoea", says author Christiane Haase from Novo Nordisk, Denmark.

"With the number of people living with obesity almost tripling worldwide over the past 30 years (105 million people in 1975 to 650 million in 2016), our findings have serious implications for public health. Body mass index represents an important modifiable risk factor for ameliorating the risk of a wide variety of serious health problems in the general population."

The authors acknowledge that their findings show observational differences, so no firm conclusions can be drawn about cause and effect, and they point to a number of limitations, including that referral bias (that is, the fact that the subjects must have been to their physician and had their BMI measured for a reason) and unmeasured confounding (meaning differences in unmeasured factors which may have affected the health outcomes of the study) may have influenced results.

BALTIMORE - A new study identifies antigens targeted by the antibody response of children with Kawasaki Disease (KD). Findings will be presented during the Pediatric Academic Societies (PAS) 2019 Meeting, taking place on April 24 - May 1 in Baltimore.

"To identify antigens targeted by the antibody response of children with KD, we identified plasmablasts that were clonally expanded in the peripheral blood of 11 children with KD and made monoclonal antibodies from these plasmablasts," said Anne Rowley, MD, one of the authors of the study. "Monoclonal antibodies from nine of the 11 patients identified intracytoplasmic inclusion bodies in ciliated bronchial epithelium of fatal KD cases. A subset of these antibodies recognizes peptides from a hepacivirus non-structural protein, and an optimized peptide blocked binding of these antibodies to the inclusion bodies, demonstrating the presence of a hepacivirus-like protein in the inclusion bodies. These results strongly suggest that a new human virus, closely related to the hepaciviruses and with a respiratory portal of entry, is etiologically related to KD."

The study isolated peripheral blood (PB) from KD children 1-3 weeks after fever onset, and characterized the response using single cell RT-PCR. It identified oligoclonal PB sets and highly mutated IgA PB, and generated monoclonal antibodies from these PB. It used the monoclonal antibodies to evaluate reactivity to KD tissues and to a peptide array comprising 29,939 peptides derived from 13,123 B cell epitopes of animal viruses reported in the Immune Epitope Database and Analysis Resource.

The study sequenced 1,156 PB from 11 KD patients, and identified 44 sets of oligoclonal PB in these patients. It prepared 61 monoclonal antibodies (Mab) from oligoclonal PB and from IgA PB that showed high levels of somatic mutation. Ten of these antibodies strongly bind to KD ICI, and 23 weakly bind. Animal virus peptide array revealed that Mab KD4-2H4 (from patient KD4), which strongly binds ICI, recognized multiple similar peptides from a nonstructural protein of hepacivirus C with an identified motif that was highly significant at e-118. Patient KD4 had negative hepatitis C serology. Peptide substitution analysis was performed to identify optimal amino acids for binding of KD4-2H4 at each position. ELISA using an optimized peptide revealed that four other KD Mab from two additional KD patients also recognized this peptide; all three patients had coronary aneurysms. The strong ICI binding of KD Mabs KD4- 2H4 and KD6-2B2 was completely blocked by pre-incubation with the optimized peptide.

Children with KD make antibodies to hepacivirus peptides, and KD ICI contain protein with a hepacivirus-like epitope. These results strongly suggest that a new human virus, closely related to the hepaciviruses and with a respiratory portal of entry, is etiologically related to KD. Identification of the specific etiology of KD could revolutionize KD diagnosis and treatment in the future.

Dr. Rowley will present findings from "Monoclonal Antibodies from Children with Kawasaki Disease (KD) Recognize Hepacivirus Peptides" on Monday, April 29 at 2 p.m. EDT. Reporters interested in an interview with Dr. Rowley should contact PAS2019@piercom.com. Please note that only the abstracts are being presented at the meeting. In some cases, the researchers may have additional data to share with media.

The PAS 2019 Meeting brings together thousands of pediatricians and other health care providers to improve the health and well-being of children worldwide. For more information about the PAS 2019 Meeting, please visit http://www.pas-meeting.org.

New research presented at this year's European Congress on Obesity in Glasgow, Scotland (28 April - 1 May) shows that individuals with obesity who commute by car have a 32% higher risk of death, from any cause, compared with those individuals with a normal weight and commute via cycling and walking. The study is by Edward Toke-Bjolgerud, University of Glasgow, UK, and colleagues.

Previous work, using UK Biobank data, has shown that active commuting, mainly cycling, was associated with a 50% lower risk of death, from any cause, and heart disease compared to car commuting. Since 57% of men and 66% of women in the UK are overweight or obese -- a condition linked with a range of poor health outcomes -- the authors of this new research aimed to investigate how different modes of active commuting (car, cycling, walking, mixed-mode) might alter the association between obesity and adverse health outcomes.

Their analysis includes 163,149 UK Biobank participants who have been followed up for a mean of 5 years. The age range was 37 to 73 years and 50.8% were women. Obesity was defined as a body mass index (BMI) (kg/m2) of greater than 30. Active commuting to and from work was self-reported and people classified in one of the following groups: car commuters, walking and cycling (active-mixed), cycling-only and walking-only. The health outcomes of interest were death from any cause, death due to heart disease and hospital admission due to non-fatal heart disease.

Dr Carlos Celis, from the British Heart Foundation Glasgow Cardiovascular Research Centre at the University of Glasgow and lead investigator of this work, reported that during the follow-up a total of 2,425 participants died and 7,973 developed heart disease. Compared with having a healthy body weight and reported mixed active commuting (walking and cycling to and from work; reference group), being obese combined with car commuting was associated with a 32% higher risk for premature death, a doubling of risk of heart disease mortality and a 59% increase in risk non-fatal heart diseases.

In contrast, those people with obesity who reported being active commuters had a risk of death from any cause that was similar to normal weight active commuters, suggesting that cycling or walking to and from work could reduce the detrimental effect of obesity. However, the risk of heart disease was still increased by 82% in active commuters with obesity compared with normal weight active commuters.

The authors conclude: "Our findings, if causal, suggest that people with overweight or obesity could potentially decrease the risk of premature mortality if they engage in active commuting."

They add: "Regardless of your body weight, being physically active could partly reduce the excess risk associated with obesity. However, compared to other forms of physical activity -- such as gyms and exercises classes -- active commuting can be implemented and fitted within our daily routines, often with no additional cost, but at the same time could increase our overall physical activity levels and therefore help to meet the current physical activity recommendations for health."

Researchers have shown that existing optical fibre technology could be used to produce microscopic 3D images of tissue inside the body, paving the way towards 3D optical biopsies.

Unlike normal biopsies where tissue is harvested and sent off to a lab for analysis, optical biopsies enable clinicians to examine living tissue within the body in real-time.

This minimally-invasive approach uses ultra-thin microendoscopes to peer inside the body for diagnosis or during surgery, but normally produces only two-dimensional images.

Research led by RMIT University in Melbourne, Australia, has now revealed the 3D potential of the existing microendoscope technology.

Published in Science Advances, the development is a crucial first step towards 3D optical biopsies, to improve diagnosis and precision surgery.

Lead author Dr Antony Orth said the new technique uses a light field imaging approach to produce microscopic images in stereo vision, similar to the 3D movies that you watch wearing 3D glasses.

"Stereo vision is the natural format for human vision, where we look at an object from two different viewpoints and process these in our brains to perceive depth," said Orth, a Research Fellow in the RMIT node of the ARC Centre of Excellence for Nanoscale BioPhotonics (CNBP).

"We've shown it's possible to do something similar with the thousands of tiny optical fibres in a microendoscope.

"It turns out these optical fibres naturally capture images from multiple perspectives, giving us depth perception at the microscale.

"Our approach can process all those microscopic images and combine the viewpoints to deliver a depth-rendered visualization of the tissue being examined - an image in three dimensions."

How it works

The research revealed that optical fibre bundles transmit 3D information in the form of a light field.

The challenge for the researchers was then to harness the recorded information, unscramble it and produce an image that makes sense.

Their new technique not only overcomes those challenges, it works even when the optical fibre bends and flexes - essential for clinical use in the human body.

The approach draws on principles of light field imaging, where traditionally, multiple cameras look at the same scene from slightly different perspectives.

Light field imaging systems measure the angle of the rays hitting each camera, recording information about the angular distribution of light to create a "multi-viewpoint image".

But how do you record this angular information through an optical fibre?

"The key observation we made is that the angular distribution of light is subtly hidden in the details of how these optical fibre bundles transmit light," Orth said.

"The fibres essentially 'remember' how light was initially sent in - the pattern of light at the other side depends on the angle at which light entered the fibre."

With this in mind, RMIT researchers and colleagues developed a mathematical framework to relate the output patterns to the light ray angle.

"By measuring the angle of the rays coming into the system, we can figure out the 3D structure of a microscopic fluorescent sample using just the information in a single image," Professor Brant Gibson, Chief Investigator and Deputy Director of the CNBP, said.

"So that optical fibre bundle acts like a miniaturised version of a light field camera.

"The exciting thing is that our approach is fully compatible with the optical fibre bundles that are already in clinical use, so it's possible that 3D optical biopsies could be a reality sooner rather than later."

In addition to medical applications, the ultra-slim light field imaging device could potentially be used for in vivo 3D fluorescence microscopy in biological research.

JUPITER, Fla. - April 29, 2019 - A new study challenges the presumption that people born with developmental brain disorders such as severe autism will benefit from medical interventions only if treated during a narrow window in infancy or early childhood.

Writing in the journal eLife, an open-access scientific journal, the Rumbaugh lab at Scripps Research in Florida reports improvement in measures of seizure and memory in adult mouse models of a genetic cause of autism, called SYNGAP1 disorder.

Children born with only one working copy of the SYNGAP1 gene don't make enough of the critical SynGAP protein. Two broken copies is lethal. Depending on the extent of their deficit, these children can develop a range of developmental challenges as they mature. This may include intellectual disability, autism-like behaviors, disordered sensory processing, and epileptic seizures that don't respond to medication. The disorder likely affects one to four individuals per 10,000, similar to the frequency of Fragile X syndrome, says Gavin Rumbaugh, PhD, an associate professor in the Department of Neuroscience at Scripps Research in Florida. However, patients can only be discovered through genetic tests. As a result, only a small fraction of patients with this disorder have been discovered.

To study whether treatment of SYNGAP1 disorder in adulthood could be beneficial, Rumbaugh's team genetically restored levels of the mice's SynGAP protein to normal. The treated adult mice showed multiple improvements. It suggests that having one broken copy of the gene not only harms the brain as it develops, but it also has effects in the adult brain, Rumbaugh says. There may be reason to treat at any stage of life once options become available, Rumbaugh adds.

"Our findings in mice suggest that neurodevelopmental disorders' disease course can be altered in adult patients," Rumbaugh says. "We can correct brain dysfunction related to seizure as well as memory impairments after restoring SynGAP protein levels in the adult animals."

Significantly, the paper offers a path to measure the effectiveness of potential medications or other therapies for neurodevelopmental disorders going forward. Electrographic spikes between seizures is an indicator of epilepsy. In their paper, the scientists looked at human EEG data collected from a SYNGAP1 disorder patient registry and found that the appearance of these spikes were much more likely to occur during sleep. Similar findings were observed from mouse models of SYNGAP1 disorder, offering a useful endpoint. Establishment of biomarkers that predict generalized improvements in brain function will be a critical step in advancing treatments for people with severe neurodevelopmental disorders, Rumbaugh says.

The need for a treatment option is clear, Rumbaugh says. Seizures typically become more frequent as children with SYNGAP1 disorders mature, and for many patients, those seizures do not respond to anti-epilepsy drugs.

"Getting to know families affected by this severe disorder has been invaluable, and drives us to develop treatments that will improve the lives of both children and adults," Rumbaugh says. "It is encouraging that gene therapy techniques that increase pathologically low protein levels for other types of brain disorders are showing promise in the clinic now."