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WINSTON-SALEM, N.C. - April 14, 2021 - Investigators at Wake Forest School of Medicine, part of Wake Forest Baptist Health, have identified a set of new genetic markers that could potentially lead to new personalized treatments for lung cancer.

The study appears online in Cancer Research, a journal of the American Association for Cancer Research.

This study was built on a previous discovery by the precision oncology team at Wake Forest Baptist's Comprehensive Cancer Center, directed by Wei Zhang, Ph.D., professor of cancer biology at Wake Forest School of Medicine and a co-corresponding author of this study. Using DNA sequencing technologies, Zhang's team found that tumors with mutated KMT2 genes, a family of proteins, exhibit a feature of genetic instability with numerous mutations in the genome.

"These findings suggest that KMT2 genes may be required for the repair of DNA damages caused by carcinogen exposure such as excess tobacco smoking. We speculate that tumor cells containing mutations in KMT2 genes are unable to repair these DNA damages, causing accumulation of mutations in the genome," said Peiqing Sun, Ph.D., co-corresponding author of the study and professor of cancer biology at Wake Forest School of Medicine.

In the current study, the researchers found that KMT2C, a member of the KMT2 family of proteins, is indeed capable of regulating DNA damage responses and DNA damage repair. It directly binds to DNA damage sites, where it mediates methylation of histones, proteins responsible for wrapping DNA into compact chromosomes. This histone modification process relaxes the chromosome structure in the vicinity of the damaged DNA, which in turn, makes room for other key proteins needed for repairing damaged DNAs.

These findings reveal a novel mechanism for the repair of damaged DNA, Sun said.

This study also provides a basis for potential new personalized treatments for lung cancer. Researchers found that mutations in KMT2C and KMT2D (other members of the KMT2 family) make non-small cell lung cancer more sensitive to Poly (ADP-ribose) polymerase (PARP) inhibitors. PARP inhibitors are already approved for treating prostate, pancreatic, ovarian and breast cancer patients whose tumors have mutations in BRCA1 and BRCA2 genes, which are also known to be essential for the repair of DNA damages.

BRCA1 and BRCA2 mutations occur at relatively low frequencies in lung cancer. Researchers in this study suggest that mutations of KMT2C and KMT2D may play a similar role as BRCA1 and BRCA2 mutations as an indicator for improved response to PARP inhibitors.

"In our study, we demonstrated a novel role of KMT2C in DNA damage responses and identified KMT2C and KMT2D mutations as the much-needed biomarkers that could guide PARP inhibitor therapies for non-small cell lung cancer," Sun said.

He added that further clinical studies are planned to test the efficacy of PARP inhibitors in lung cancer patients.

Research by Australian scientists could pave the way to a new treatment for a currently incurable brain cancer in children called Diffuse Intrinsic Pontine Glioma, or DIPG. Affecting about 20 children in Australia each year, DIPG is a devastating disease with an average survival time of just nine months after diagnosis.

The research, led by scientists at Children's Cancer Institute and published this week in the international journal, Cell Reports, offers an exciting new therapeutic approach for the treatment of DIPG by using a new anti-cancer drug.

The new drug, CBL0137, is an anti-cancer compound developed from the antimalarial drug quinacrine. The researchers found that CBL0137 directly reverses the effects of the key genetic drivers in DIPG, and has a profound effect against DIPG tumour models. They also foundCBL0137 is even more effective when combined with a second drug, panobinostat, a new type of drug known as a histone deacetylase (HDAC) inhibitor. When used in combination, the two drugs were found to work synergistically, each enhancing the others effects against DIPG.

Associate Professor David Ziegler, Group Leader at Children's Cancer Institute and paediatric oncologist at the Kids Cancer Centre, Sydney Children's Hospital, said there is a desperate need for a new and more effective way to treat DIPG.

"Over the years, many different types of treatments have been tried for DIPG, but none so far have proven effective in clinical trials of children with the disease," he said. "Part of the problem is that the genetic driver in DIPG is a master gene that controls thousands of other genes. Until now, we have not known how to switch it off. Our data shows that CBL0137 acts to reverse the effects of this master gene, and then switch off the growth of the DIPG tumour cells."

In the newly published study, Associate Professor Ziegler and his colleagues in the Brain Tumours Group at Children's Cancer Institute built on earlier research carried out by the Institute's Experimental Therapeutics Group, who found that CLB037 was effective against neuroblastoma. Taking a similar approach with DIPG, the Brain Tumours Group confirmed that CBL0137 interferes with the growth of DIPG tumours by inhibiting an important molecule known as FACT (needed for DNA transcription, replication and repair). They found that FACT binds with the key genetic driver in DIPG - a mutation called K27M. By treating DIPG cells with CBL0137 they were able to target this gene and stop tumour cells from growing. Next, they tested CBL0137 in 'patient-derived xenografts' ? mice specially bred to grow DIPG cells taken directly from children with the disease ? showing it effectively penetrated the blood-brain barrier and increased survival time.

When the researchers added panobinostat to the mix, they found that the CBL0137-panobinostat combination was even more effective at killing DIPG cells and further improved the survival time of mice with DIPG.

"K27M is the Achilles heel of DIPG tumour cells," said Associate Professor Ziegler. "The finding that CBL0137 indirectly acts against this genetic driver is very exciting, and gives us great hope for this treatment strategy."

A/Prof Ziegler will lead an international clinical trial of CBL0137 for children with DIPG that will open in the top children's hospitals in the US and Australia. Plans to launch the trial are boosted by the fact that CBL0137 has recently successfully completed testing in phase I clinical trials in adults with solid tumours.

CLEVELAND, Ohio (April 14, 2021)--Despite all the advances in medicine, some basic questions remain. For example, people cannot be told with any certainty how long they'll live. Nor can it be predicted exactly when a woman's childbearing years will end. However, a new study offers insights into factors that might predict a woman's age at natural menopause. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Factors that affect age at natural menopause are one of the most frequently studied topics in menopause-related research in recent decades, and with good reason. Knowing when a woman will enter menopause could be valuable for family-planning purposes. Such information also could help to identify those women who are most likely to experience early menopause and be at greater risk for health issues such as cardiovascular disease, depression, and osteoporosis. Another big issue for women is how long they will experience bothersome bleeding, which affects how they choose to manage it (ie, with hysterectomy, an oral contraceptive pill, or deciding to "wait it out.")

Despite all the research, the ability to accurately predict a woman's age at natural menopause remains challenging because of the individual variations in women's reproductive lifespans, as well as the long duration of the menopause transition. Previous research in this area has focused on a few predetermined biomarkers. This new study, however, used a comprehensive set of potential predictors to help identify factors affecting age at natural menopause and develop models for pinpointing it.

Researchers in the study concluded that higher levels of estradiol and follicle-stimulating hormone, irregular menstrual cycles, and menopause symptoms are strong indicators that a woman is approaching menopause. The study additionally denotes the contributions of life habits and socioeconomic factors such as alcohol consumption, smoking, relationship status, physical activity, and the use of hormone contraception, when assessing the time to natural menopause.

Understanding these factors and a woman's overall risk level could help guide clinicians when choosing contraceptive options and treatments for menopause symptoms, although larger, more in-depth studies are still necessary to adequately advance such understanding.

Results are published in the article "Predicting the age at natural menopause in middle-aged women."

"This study, although conducted in a small number of women, adds to our knowledge regarding what factors are important in a prediction model for the age at which a woman will enter menopause. Accurately predicting age at natural menopause would better inform how we counsel women regarding multiple issues, including cardiovascular risk, family planning and contraception, and management of perimenopause issues such as irregular or heavy menstrual bleeding, vasomotor symptoms, and mood changes," says Dr. Stephanie Faubion, NAMS medical director.

Combining immune-boosting drugs with radiation and surgery increased the survival and anticancer immune response in mouse models of mesothelioma in preclinical research by Princess Margaret Cancer Centre researchers.

In a series of exciting experiments using mouse models of mesothelioma cancer, researchers found that combining two immunotherapy drugs can amplify the anti-tumour response first triggered by a short course of radiation, conferring long-lasting control and resistance against cancer. These response rates are improved further by adding surgery to remove the remaining tumour.

Better treatments are urgently needed for mesothelioma patients, as quality of life and prognosis of patients are still extremely poor with the majority of patients dying between six and 18 months after diagnosis.

The results are published today in Science Translational Medicine.

"It's a new paradigm in cancer treatment that offers the potential of cure even in late stage cancer," says thoracic surgeon Dr. Marc de Perrot, senior author of the study. He explains that by combining three complementary treatments, we can take advantage of each one, while limiting the toxicity of each.

"The goal is to cure patients who would otherwise die from this aggressive and recurring cancer," says Dr. de Perrot, who is Professor of Surgery and Immunology at the University of Toronto, the Canadian Mesothelioma Foundation Professor in Mesothelioma Research, and leads the Mesothelioma Program at University Health Network.

"These research results offer exciting, new hope and provide the evidence to test this approach in mesothelioma patients who have too often been told in the past that they may only have six months to live," adds Dr. de Perrot.

Exposure to asbestos is the main cause of mesothelioma in the 600 new cases reported in Canada each year, a number that has doubled in the past decade.

"This has the potential to change the way in which we treat this cancer," says Dr. John Cho, one of the authors and a radiation oncologist at Princess Margaret Cancer Centre, University Health Network. Dr. Cho is also an Assistant Professor, Department of Radiation Oncology at the University of Toronto.

"We're taking advantage of the body's own immune system to fight against the cancer."

The study builds on previous research of Drs. de Perrot and Cho which showed that a short course of radiation before surgery boosted the anticancer effects of the immune system in the short-term. Their goal since that work was to discover how to activate and amplify the anticancer immune effects for the long-term.

In their latest laboratory research, the scientists treated mice with mesothelioma with well-tolerated, short-course radiation (consisting of three days of treatments over one week), as well as two immunotherapy drugs. Acting in concert, the two drugs - an interleukin-15 superagonist (IL-15SA) and a glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) agonist (DTA-1) - stimulate and enhance the adaptive immune response, which provides long-term protection against specific tumour markers.

The two drugs work together to select and expand the numbers of highly specific killer T-cells in the immune system, which then seek, precisely target and destroy any remaining mesothelioma cancer cells. This selectivity makes this treatment more effective, and potentially less toxic.

"To cure a patient, we need to eliminate all the cancer cells," says Dr. Cho. "That's particularly difficult to do in mesothelioma where the fluid in the pleural cavity, which surrounds the lungs, is contaminated with cancer cells. That's why a precision treatment is so vital for this cancer."

The authors showed that the combination treatment extended survival, and provided a durable immune response, in about 40% of the mice. Surgically removing the irradiated tumour, in combination with the drugs, extended survival in all the mice.

Moreover, the anti-tumour immune response was shown to be robust. Re-injecting tumour cells into the mice up to 12 weeks after the initial treatment of radiation, immune-boosting drugs and surgery conferred long-lasting immunity against the cancer.

"The immune system remembered the cancer cells, and destroyed them," says Dr. de Perrot. "This combination therapy increased the 'memory effect' of the T-cells in the immune system so that they are able to recognize the tumour cells anywhere in the body for months, or possibly years after the treatment is completed."

Adds Dr. Cho: "The treatment acts like a vaccine against the tumour. Vaccination as a cure for cancer is a goal that is challenging. This work shows that it is possible."

As the countdown to the Tokyo Olympic and Paralympic games reaches 100 days, plans to hold the games this summer must be reconsidered as a matter of urgency, argue experts in The BMJ today.

Kazuki Shimizu at the London School of Economics and Political Science and colleagues say huge uncertainty remains about the trajectory of the pandemic and they warn that international mass gathering events such as Tokyo 2020 "are still neither safe nor secure."

Instead, they say "we must accelerate efforts towards containing and ending the pandemic by maintaining public health and social measures, promoting behaviour change, disseminating vaccines widely, and strengthening health systems."

They acknowledge that substantial scientific advancements have occurred over the past year, but say vaccine roll-out has been inequitable, reducing access in many low and middle income countries.

And although a special scheme for vaccinating athletes - marshalled by the International Olympic Committee - may help save lives, they argue that "it could also encourage vaccine diplomacy, undermine global solidarity (including the Covax global access scheme), and promote vaccine nationalism."

They point out that, unlike other countries in the Asia-Pacific region, Japan has not yet contained covid-19 transmission.

"Even healthcare workers and other high risk populations will not have access to vaccines before Tokyo 2020, to say nothing of the general population," they write.

To properly protect athletes from covid-19, "Japan must develop and implement a clear strategy to eliminate community transmission within its borders, as Australia did before the Australian Open tennis tournament."

Japan and the International Olympic Committee must also agree operational plans based on a robust science and share them with the international community, they add.

Waiving quarantine for incoming athletes, officials, broadcasters, press, and marketing partners "risks importing and spreading covid-19 variants of concern" and while international spectators will be excluded from the games, "cases could rise across Japan and be exported globally because of increased domestic travel - as encouraged by Japan's official campaigns in 2020."

An overwhelmed healthcare system combined with an ineffective test trace and isolate scheme "could seriously undermine Japan's ability to manage Tokyo 2020 safely and contain any outbreak caused by mass mobilisation," they write.

Finally, they point out that very little has been said officially about the Paralympic games and how to protect the health and rights of people with disabilities during international competition.

"The whole global community recognises the need to contain the pandemic and save lives. Holding Tokyo 2020 for domestic political and economic purposes - ignoring scientific and moral imperatives - is contradictory to Japan's commitment to global health and human security," they argue.

"We must reconsider this summer's games and instead collaborate internationally to agree a set of global and domestic conditions under which international multisport events can be held in the years ahead. These conditions must embody both Olympic and Paralympic values and adhere to international principles of public health," they conclude.

BOSTON - The anti-diabetic drug phenformin may prompt stronger cancer-fighting activities than its sister compound metformin, a finding that could have major implications for current and future clinical trials investigating both agents for their anti-cancer potential, according to researchers at Massachusetts General Hospital (MGH). In a review article in Trends in Cancer, the team presented evidence that immunotherapies such as immune checkpoint inhibitors (which enable T cells to attack and kill cancer cells) in combination with phenformin may also be a promising way to repurpose this diabetic drug as an anti-cancer agent.

Metformin was approved by the U.S. Food and Drug Administration in 1995 and has since become the most prescribed drug for diabetes in the United States. Phenformin was first prescribed for type 2 diabetes in the 1950s but was withdrawn from use in the late 1970s due to the risk of lactic acidosis, a potentially dangerous condition caused by excess buildup of lactic acid in the blood, which can disrupt the body's pH balance. Metformin and phenformin are members of a class of anti-diabetic drugs known as biguanides that originated from compounds in the French lilac, a plant known for its hypoglycemic properties since medieval times. Preclinical studies over the past ten years by MGH and others have demonstrated that both forms of biguanides possess anti-tumor activity, spurring efforts to repurpose them for cancer prevention and treatment.

"While the outcomes of various clinical studies of metformin in cancer patients have been underwhelming, research from our laboratory and others suggests that phenformin may have greater potential, particularly in combination with immunotherapies," says Bin Zheng, PhD, the study's senior author and an investigator in the Cutaneous Biology Research Center at MGH. "We have found, for example, that phenformin, but not metformin, enhances the efficacy of BRAF inhibitors in suppressing the proliferation of BRAF-mutant melanoma cells and BRAF-driven tumor growth in animal models." BRAF mutations are changes in cellular DNA that are found in about half of all melanomas.

After years of preclinical research, MGH has partnered with Memorial Sloan Kettering Cancer Center to launch a phase 1 clinical trial evaluating phenformin with a combination of inhibitors (dabrafenib/trametinib) in patients with BRAF-mutated melanoma. "If the safety of phenformin is confirmed in this trial, combinations of phenformin with targeted immunotherapies such as anti-PD-1 (programmed cell death 1 antibodies, which stimulate anti-tumor immunity) could be explored for patients with various types of solid tumors," says Zheng. Another retrospective study has shown improved clinical outcomes in patients with non-small-cell lung cancer who received immune checkpoint inhibitors in combination with metformin, compared to the inhibitors alone.

With respect to mechanisms of action governing the anti-tumor activity of biguanides, the MGH team noted that gut microbiota - the trillions of cells, including bacteria, viruses and fungi, that reside in the gut and are vital to normal health - could play a key role. They suggested that biguanides may affect the anti-tumor efficacy of therapies by modulating gut microbiota, in the same way metformin may lower blood glucose levels in diabetes patients in part by interacting with the microbiome.

"Scientists have shown a tremendous interest in biguanides as potential anti-cancer agents, and we believe our work will help the field to focus on the most promising ways forward, particularly phenformin," says Zheng. "Phenformin demonstrates more metabolic and pharmacologic potential than metformin, and its toxicity, which might be a problem for certain people with diabetes, is actually lower than some current chemotherapies."

While people may expect suicide rates to rise during a worldwide crisis such as the COVID-19 pandemic, a University of Michigan study suggests the onset of the pandemic and state of emergency executive orders likely did not increase suicide-related behavior in the early months of the outbreak.

The report, led by U-M researchers Rachel Bergmans and Peter Larson, found that emergency room visits related to suicide attempt and self-harm decreased by 40% during the first eight months of Michigan's lockdown. Their results are published in the Journal of Epidemiology and Community Health.

The study compared emergency room reports of suicide attempt and intentional self-harm at a hospital in Michigan's Washtenaw County during the first 8 months of the COVID-19 pandemic. The researchers used what's called a time-series analysis to look at what happened to suicide attempt and self-harm trends before and after the COVID-19 pandemic.

They compared the rate of suicide attempt and self-harm from Oct. 1, 2015, to March 9, 2020, to the rates between March 10, 2020, to October 31, 2020, and found that average daily visits to the ER because of suicidal behavior decreased from 8.6 visits per day to 5.5 per day.

Bergmans, a research fellow in the Survey Research Center at the U-M Institute for Social Research, says a strengthened social structure could be the reason for the decline in these visits.

"More research is needed to confirm why there was a decrease, but the earlier phase of the pandemic came with a lot of communitywide and individual changes including changes in unemployment. These types of factors can increase the risk of suicide," she said. "However, it's possible that things like financial assistance from stimulus checks, the eviction moratorium and student loan support that people are receiving might have buffered against some of these other effects."

The specific method Bergmans and Larson used, called an autoregressive integrated moving average modeling approach, also took into account seasonal variations of suicide rates, which are higher in the spring and fall.

"Models are designed to be informative but sometimes reality might differ from predicted," said Larson, a research fellow in the Survey Research Center at the Institute for Social Research and a lecturer in the U-M School of Public Health. "I think the COVID-19 crisis is unique among the crises we've seen in the past few decades, so we should expect that the response in mental health also to be somewhat unique."

Although the researchers focused on one hospital in Michigan, they say other regions report decreases in death by suicide as well. Their data also appears to be consistent with data from other hospital systems across the country. In Japan, suicide mortality was 20% lower in April 2020 compared to April 2019--however, suicide rates in Japan began growing after the government stopped being proactive about coronavirus measures, the researchers said.

There were a total of 3,002 individuals in the study data--62% female and 78% white, with a median age of 26.4. There were 10,753 emergency room visits for the study period, with 1,438 occurring after the onset of the pandemic.

The analysis shows that the number of ER visits remained consistent until March 17, 2020, at an average number of 8.6 per day. After March 17, they dropped to 5.5 per day. Although ER visits for suicide attempt and self-harm declined overall, there were some differences across groups.

Suicide-related behavior among men increased compared to women. The proportion of patient encounters decreased among people of Asian descent compared to whites and among married compared to unmarried patients. The suicide attempt and self-harm rate among those 18-65 increased compared to those under 18, while typically suicide-related behavior is higher among those under 18.

Bergmans and Larson suspect this may be because the closure of schools decreased exposure to psychological stressors at schools--and that young people had fewer opportunities for suicide-related behavior while their parents worked from home.

The researchers say one limitation of their study is the different ways people sought care during the pandemic, such as through telemedicine.

"This is one small study looking at one type of mental health outcome in a hospital system. Our findings are certainly consistent with places elsewhere, but I think this is really just the start of the type of work that needs to be done," Bergmans said. "This also points to the need for a greater understanding of how different populations were affected. We're really interested in exploring the potential health disparities as well, because COVID-19 has not treated all communities equally."

Berkeley -- Engineers at the University of California, Berkeley, have created a tiny wireless implant that can provide real-time measurements of tissue oxygen levels deep underneath the skin. The device, which is smaller than the average ladybug and powered by ultrasound waves, could help doctors monitor the health of transplanted organs or tissue and provide an early warning of potential transplant failure.

The technology, created in collaboration with physicians at the University of California, San Francisco, also paves the way for the creation of a variety of miniaturized sensors that could track other key biochemical markers in the body, such as pH or carbon dioxide. These sensors could one day provide doctors with minimally invasive methods for monitoring the biochemistry inside functioning organs and tissues.

"It's very difficult to measure things deep inside the body," said Michel Maharbiz, a professor of electrical engineering and computer sciences at UC Berkeley and a Chan Zuckerberg Biohub Investigator. "The device demonstrates how, using ultrasound technology coupled with very clever integrated circuit design, you can create sophisticated implants that go very deep into tissue to take data from organs."

Maharbiz is the senior author of a new paper describing the device, which appears in the journal Nature Biotechnology.

Oxygen is a key component to cells' ability to harness energy from the food that we eat, and nearly all tissues in the body require a steady supply in order to survive. Most methods for measuring tissue oxygenation can only provide information about what is happening near the surface of the body. That is because these methods rely on electromagnetic waves, such as infrared light, which can only penetrate a few centimeters into skin or organ tissue. While there are types of magnetic resonance imaging that can provide information about deep tissue oxygenation, they require long scanning times, and so are unable to provide data in real time.

Since 2013, Maharbiz has been designing miniaturized implants that use ultrasonic waves to wirelessly communicate with the outside world. Ultrasonic waves, which are a form of sound too high in frequency to be detected by the human ear, can travel harmlessly through the body at much longer distances than electromagnetic waves and are already the basis of ultrasound imaging technology in medicine. One example of such a device is Stimdust, designed in collaboration with UC Berkeley electrical engineering and computer sciences assistant professor Rikky Muller, which can detect and stimulate electrical nerve firings in the body.

Soner Sonmezoglu, a postdoctoral researcher in engineering at UC Berkeley, led the effort to expand the implant's capabilities to include oxygen sensing. Incorporating the oxygen sensor involved integrating both an LED light source and an optical detector into the tiny device, as well as designing a more complicated set of electronic controls to operate and read out the sensor. The team tested the device by monitoring the oxygen levels inside the muscles of live sheep.

Sonmezoglu points out that this type of oxygen sensor differs from the pulse oximeters that are used to measure oxygen saturation in the blood. While pulse oximeters measure the proportion of hemoglobin in the blood that is oxygenated, the new device is able to directly measure the amount of oxygen in tissue.

"One potential application of this device is to monitor organ transplants, because in the months after organ transplantation, vascular complications can occur, and these complications may lead to graft dysfunction," Sonmezoglu said. "It could be used to measure tumor hypoxia, as well, which can help doctors guide cancer radiation therapy."

Study co-authors Jeffrey Fineman and Emin Maltepe, who both are pediatricians at UCSF and members of the Initiative for Pediatric Drug and Device Development, became involved in the work because of its potential for monitoring fetal development and caring for premature babies.

"In premature infants, for example, we frequently need to give supplemental oxygen but don't have a reliable tissue readout of oxygen concentration," Maltepe said. "Further miniaturized versions of this device could help us better manage oxygen exposure in our preterm infants in the intensive care nursery setting and help minimize some of the negative consequences of excessive oxygen exposure, such as retinopathy of prematurity or chronic lung disease."

The technology could be further improved, Sonmezoglu said, by housing the sensor so that it could survive long term in the body. Further miniaturizing the device would also simplify the implantation process, which currently requires surgery. In addition, he said, the optical platform in the sensor could be readily adapted to measure other biochemistry in the body.

"By just changing this platform that we built for the oxygen sensor, you can modify the device to measure, for example, pH, reactive oxygen species, glucose or carbon dioxide," Sonmezoglu said. "Also, if we could modify the packaging to make it smaller, you could imagine being able to inject into the body with a needle, or through laparoscopic surgery, making the implantation even easier."

As older teens and young adults become eligible for COVID-19 vaccination across the country, and younger teens await their turn, new survey data suggest a strong readiness that has grown since fall.

But just as with older generations, a shrinking but still sizable minority of people age 14 to 24 say they're not willing to get vaccinated, or that their decision will depend on safety.

That makes it crucial for public health authorities, health care providers and others to create vaccination-related materials that reach young people in ways that are relevant to them.

The data, from the text-message-based MyVoice national survey of youth based at the University of Michigan, are published in a new paper in the Journal of Adolescent Medicine, and supplemented by new polling data just received in the past week.

Eric Brandt, M.D., M.H.S., lead author of the new paper, notes that in the first MyVoice survey in October 2020, 76% of the 911 teens and young adults said they were willing to get vaccinated, though that included 33% who said their ultimate decision would depend on additional information. At that time, 20% of young people said they were unwilling to get a COVID-19 vaccine.

Brandt's colleague Stephen Gorga, M.D., has just finished analyzing data from MyVoice respondents who answered a repeat survey in late March 2021.

The percentage who say they're willing to get vaccinated, or already have been vaccinated, has risen to 84%. Nine percent of the total say they're willing but that their decision still depends on what they learn about the vaccine. That means that 75% are unconditionally willing to get the vaccine when it becomes available to them, or already have been vaccinated.

The percentage of people age 14 to 24 who say they are not willing or intending to get vaccinated is down to 15%.

"These data reassure us that most youth are willing to get vaccinated against COVID-19 if they feel the vaccine is safe and effective," says Brandt. "But concerns about vaccine safety are still very much alive in this group."

He notes that the newest data were gathered before the U.S. Food and Drug Administration announced its "pause" of use of the Johnson & Johnson/Janssen vaccine due to a small number of cases of a rare blood clot condition in younger women who were among the first 6.7 million Americans to get the vaccine. The Astra-Zeneca vaccine, which is not available in the United States, has been paused in some countries because of clot concerns, too.

Currently, the Pfizer/BioNTech vaccine has emergency approval for use in Americans age 16 and up, while the Moderna and J&J vaccines have such approval for people age 18 and up. The new MyVoice data were also gathered before Pfizer announced results from its study of its vaccine in people age 12 to 15, and its intention to see approval in this age group soon. Moderna has also just announced that enrollment in its clinical trial for ages 12 to 17 has been completed.

Other findings

In the new paper, Brandt and colleagues - including MyVoice director Tammy Chang, M.D., M.P.H., M.S., share other findings from the October poll.

At that time, Black young people were more than three times more likely than their white peers to say they weren't willing to get the vaccine when it became available. Meanwhile, young people of Asian descent were more likely than white or Black young people to say they'd get vaccinated.

As communications efforts shift to younger people, the study finds that organizations such as the Centers for Disease Control and Prevention, and the World Health Organization, are the preferred sources of vaccine information for 42% of young people, and that 32% said they would prefer to learn about the vaccine from a health professional such as a doctor, pharmacist or other provider or health care organization.

Among those who said in October that they weren't willing to get the vaccine, safety was the top concern, especially what some saw as an inadequate amount of time in testing. Only 2% mentioned conspiracy theories.

The role of younger people in spreading COVID-19, even if they generally have a lower risk of developing severe disease, makes it important to reach them with effective messages and transparent information and answers to their questions, Brandt says.

Special efforts to reach Black teens and young adults may be needed, because of the disproportionate risk they and their family members face. Otherwise, racial disparities already well-documented in COVID-19 outcomes may continue to increase.

EXPLOITING BACTERIAL 'SWEET TOOTH' MAY HELP IMAGE AND DIAGNOSE INFECTIONS

Media Contact: Michael E. Newman, mnewma25@jhmi.edu

In the movie Mary Poppins, the title character sings that "a spoonful of sugar helps the medicine go down." Now, Johns Hopkins Medicine researchers have shown how a radioactive sugar -- combined with a widely used imaging technology -- could soon help physicians make the medicine work better by enabling them to rapidly detect and monitor infections from the largest group of bacterial pathogens threatening humans.

The new imaging tool uses positron emission tomography -- commonly known as a PET scan -- to noninvasively find and track dangerous infections from the microbial family Enterobacterales, a group that includes the Escherichia coli strains that cause food poisoning; Klebsiella pneumoniae, a cause of pneumonia and a severe threat to patients weakened from COVID-19; and Yersinia pestis, the scourge behind the "Black Death" pandemic of plague in the 14th century that wiped out 75% of the world's population.

Enterobacterales bacteria also have been tagged by the U.S. Centers for Disease Control and Prevention as "urgent and serious antibiotic resistance threats" because of their frequent mutations to drug-resistant strains.

The new diagnostic tool is described in a paper published April 14, 2021, in Science Translational Medicine. It emerged from a creative combination of existing PET scan technology -- a sophisticated 3D visualization system for imaging diseases such as cancer -- with sorbitol, a molecule used in making sugar-free foods. The method capitalizes on the fondness for sorbitol of Gram-negative bacteria (a classification of bacteria based on their resistance to a specific staining procedure) such as Enterobacterales and the fact that other microorganisms, cancers and human cells do not absorb it.

"We converted an already available radioactive imaging tracer into an isotope-tagged sorbitol molecule that would light up clusters of Gram-negative bacteria within the body during a PET scan," says study senior author Sanjay Jain, M.D., professor of pediatrics, and radiology and radiological medicine at the Johns Hopkins University School of Medicine; and professor of international health at the Johns Hopkins Bloomberg School of Public Health.

In a previous study, the researchers demonstrated that PET scans using their novel sugar tracer -- chemically known as 2-deoxy-2 [18F] fluoro-D-sorbitol (18F-FDS) -- successfully detected Enterobacterales infections in mice. This time, the team conducted a clinical study to evaluate the safety and effectiveness of the 18F-FDS PET technique. The work was done in collaboration with scientists from the Fundación Cardiovascular de Colombia-Hospital Internacional de Colombia (Piedecuesta, Colombia).

A total of 71 PET scans were performed in 31 patients, 18 of whom had previously confirmed Enterobacterales infections using traditional blood cultures. The 18F-FDS PET imaging technique was able to detect and localize Enterobacterales infections at multiple body sites, and distinguish them from the patients with infections caused by other bacteria and the ones whose infection-like symptoms were the result of cancer.

The tracer was well tolerated by all of the participants and showed no adverse effects.

Because the 18F-FDS PET imaging technique has shown that it can immediately detect the presence of Enterobacterales bacteria deep inside the body -- compared with laboratory tests which can take two to three days to confirm an infection -- the researchers feel that their method can play an important role in optimizing antibiotic treatments and preventing the rise of dangerous antibiotic-resistant bacteria strains.

"Using broad-spectrum antibiotics to treat a suspected bacterial infection before an infection is confirmed is sometimes like firing a cannonball to kill a fly," says study lead author Alvaro Ordonez, M.D., assistant professor of pediatrics at the Johns Hopkins University School of Medicine. "While such treatment is clinically justified in patients with serious infections of unknown origin, it can promote bacterial resistance to the drugs. Knowing quickly which organism is causing the problem can enable clinicians to target the antibiotic best suited for that bacteria, and that is where our new imaging system could make a difference."

The researchers also say that the 18F-FDS PET imaging technique also can be used to monitor the effectiveness of antibiotic therapy, as they showed for 13 of their clinical trial participants with Enterobacterales infections.

"We scanned the patients before and after their course of treatment," says Ordonez. "In those who did not respond well because of the presence of drug-resistant bacteria, the 18F-FDS signal remained high with the final scans. On the contrary, it decreased in those patients whose infections were significantly treated."

Jain says that larger clinical trials are needed to validate the findings of his team's latest study. "However, we're excited that our data support the role of 18F-FDS PET as a viable diagnostic and treatment monitoring tool," he says.

Jain and Ordonez are available for interviews.

SEEING IS BELIEVING, EVEN FOR THE EARS: VIDEO GOGGLES DIAGNOSE BALANCE AND MOVEMENT LOSS

Media Contact: Michel Morris, melben1@jhmi.edu

Our ears are not just organs for hearing; they also sense head motion, coordinate balance and enable us to move safely in different environments. Now, Johns Hopkins Medicine researchers have found that a test using commercially available, high-speed video goggles can help diagnose vestibular loss -- weakness in the balance mechanism of the inner ear -- more effectively.

In a study published March 25, 2021, in JAMA Otolaryngology-Head & Neck Surgery, Amir Kheradmand, M.D., director of research at the Johns Hopkins Medicine Neuro-Visual and Vestibular Disorders Center, and his team determined that the use of high-speed video goggles and automated analysis software can provide immediate feedback of vestibular loss during a clinical evaluation of patients with dizziness and balance problems.

Their findings show the test can be easily applied with a simple tilt of the head and torso together while the patient is seated and looking straight ahead.

"Imagine watching a video on a cell phone, and when you turn it from vertical to horizontal orientation, the screen adjusts accordingly," says Kheradmand, who also is an associate professor of neurology, and of otolaryngology-head and neck surgery at the Johns Hopkins University School of Medicine, and an adjunct faculty member of the Johns Hopkins University Laboratory for Computational Sensing and Robotics. "That's what our ears do; they sense the movement of our head, so that when you move your head to the right side, your eyes automatically move to the left. This helps keep the world steady in front of you."

"So, what we're measuring with the goggles is the rolling of the eyes relative to the head tilt so that we may do a comprehensive evaluation of the inner ear balance function," Kheradmand explains

Kheradmand says that the oculography (video recording of eye movements) goggles capture moving images of a patient's iris, the colored portion of the eye that controls the amount of light reaching the retina. The goggles also feature sensors that can track head motion and measure the balance function of the ear.

"You don't need complicated laboratory equipment," he says. "We can do the test in seconds to determine any loss of function."

The clinical trial described in the study compared data from the goggles for patients who had lost vestibular ability because of surgery with others who have normal inner ear function. Kheradmand says his team found that the test could accurately detect loss of vestibular function 83% of the time. Future studies, he says, will need to include patients with other causes and varying degrees of vestibular loss to better establish the test's diagnostic ability.

Kheradmand says the test not only uncovers past loss of vestibular function, but also can define if the loss is recent or chronic. However, he adds, the ability to detect loss varies with the length of time a patient has had the condition. In the study, patients who had a long history of loss were harder to identify, while those with very recent loss were easily found.

Kheradmand says that he and his team are excited about the potential use of their test to measure and track recovery from vestibular loss, as well as one day being able to track a patient's response to vestibular physical therapy.

Kheradmand is available for interviews.

GEORGE MASON UNIVERSITY JOINS JOHNS HOPKINS CLINICAL RESEARCH NETWORK

Media Contact: Danny Jacobs, danny.jacobs@jhu.edu

George Mason University's College of Health and Human Services has joined the Johns Hopkins Clinical Research Network (JHCRN). Developed by the Johns Hopkins Institute for Clinical and Translational Research (ICTR), JHCRN is designed to bring together academic- and community-based clinical researchers to provide new opportunities for research collaborations and accelerate the transfer of new diagnostic, treatment and disease-prevention advances from the research arena to patient care.

George Mason is the first university to join the JHCRN, which was established by Johns Hopkins Medicine in 2009 and includes the clinical health systems of Luminis Health in southern Maryland, TidalHealth in eastern Maryland and Reading Hospital, an affiliate of Tower Health, in Pennsylvania.

The network creates a bridge for research between Johns Hopkins and community-based medical centers by linking physician-scientists and staff members from Johns Hopkins Medicine with various centers in the region. It serves several purposes, the most important of which is making clinical trials available to patients who may not otherwise have access to them.

"The JHCRN is a unique research resource that increases patient access to innovative therapies and outcomes research in their own local communities. It also empowers physicians to design and conduct a broad array of research projects relevant to their communities," says Adrian Dobs, M.D., JHCRN director and professor of medicine and oncology at the Johns Hopkins University School of Medicine. "It is a premier network of affiliated medical institutions which can carry out efficient, collaborative clinical research to achieve high-quality innovative patient care. I am very impressed with the depth and excellence of research being done within the GMU enterprise, and believe our overall network will benefit from this great work."

George Mason is the one of the fastest-growing Research I institutions in the country, and its College of Health and Human Services has more than 1,900 undergraduate students and 1,370 graduate students.

"We are proud to join this highly-respected network of health care delivery organizations to bring research discoveries into clinical practice in a timely manner to improve the health of those we serve," says Germaine Louis, Ph.D., dean of the college. "It is only through partnerships such as these that we can improve health equity and make health visible and accessible for all people."

The JHCRN directly addresses the many complexities of conducting multisite and multi-institutional studies by providing investigators with a larger patient pool and a seamless platform that uses common research protocols. The goal of the network is to speed the approval of new protocols while ensuring careful oversight of patient safety. Rapid startup and timely completion of research studies, aided by widespread access to clinical trials, will make promising therapies available for patient use more quickly.

Initially, the JHCRN focused on expanding cancer-related clinical trials (including medical, surgical and radiation-therapy aspects of cancer treatment), as well as diabetes and surgical studies. Collaborations have facilitated expanded work, including a wide range of research areas, such as pediatrics and intensive care; COVID-19 studies; neuropsychiatric, brain and spine diseases; and radiology and nuclear medicine studies. Present sponsors include federal and industry sources, along with private foundations.

The JHCRN is a program within ICTR, which is a part of a national consortium dedicated to transforming how clinical and translational research is conducted at academic health centers around the country.

For more information about the JHCRN, visit http://ictr.johnshopkins.edu/JHCRN.

Dobs is available for interviews.

LOS ANGELES (April 13, 2021) -- The Lundquist Institute (TLI) Investigator Dong W. Chang, MD, and his colleagues' study on critically ill patients and ICU treatments was published in JAMA Internal Medicine. The study - "Evaluation of Time-Limited Trials Among Critically Ill Patients with Advanced Medical Illnesses and Reduction of Nonbeneficial ICU Treatments" - found that training physicians to communicate with family members of critically ill patients using a structured approach, which promotes shared decision-making, improved the quality of family meetings. This intervention was associated with reductions in invasive ICU treatments that prolonged suffering without benefit for patients and their families.

"Invasive ICU treatments are frequently delivered to patients who have very little chance of benefit. This leads to prolonged suffering for our patients and their families. We believed that poor communication was one of the key causes for this problem. In our study, we found that training physicians to use time-limited trials of ICU treatments engages families to make decisions together with the physicians and reduces unnecessary ICU treatments." said Dr. Chang.

The published study can be assessed here.

First study to examine suicides occurring around the world during the COVID-19 pandemic finds that - in high-income and upper-middle-income countries - suicide numbers have remained largely unchanged or have declined in the early months of the pandemic, compared with expected levels.

However, the authors stress that governments must remain vigilant as the longer-term mental health and economic effects of the pandemic unfold and be poised to respond if the situation changes.

Study looked at numbers of suicides in 21 countries between 1 April and 31 July 2020 and compared these with trends in the previous one to four years.

A new observational study is the first to examine suicides occurring during the early phase of the COVID-19 pandemic in multiple countries and finds that suicide numbers largely remained unchanged or declined in the pandemic's early months. The study is published in The Lancet Psychiatry journal.

The authors note that - while their study provides the best available evidence on the pandemic's effects on suicide so far - it only provides a snapshot of the first few months of the pandemic and effects on suicide might not necessarily occur immediately.

Lead author, Professor Jane Pirkis, Director of the Centre for Mental Health at the University of Melbourne, Australia, says: "We need to continue to monitor the data and be alert to any increases in suicide, particularly as the pandemic's full economic consequences emerge. Policymakers should recognise the importance of high-quality, timely data to support suicide prevention efforts, and should work to mitigate suicide risk factors associated with COVID-19, such as the heightened levels of stress and financial difficulties that some people may experience as a result of the pandemic. Increasing mental health services and suicide prevention programmes, and providing financial safety nets may help to prevent the possible longer-term detrimental effects of the pandemic on suicide." [1]

Professor Pirkis also stresses: "We know that many people have had their lives changed dramatically by the pandemic, and the journey for some of them is ongoing. We need to recognise that suicide is not the only indicator of the negative mental health effects of the pandemic - levels of community distress are high, and we need to ensure that people are supported." [1]

It is likely that mental health effects of the pandemic will vary between and within countries, and over time, depending on factors such as the extent of the pandemic, the public health measures used to control it, the capacity of existing mental health services and suicide prevention programmes, and the strength of the economy and relief measures to support those whose livelihoods are affected by the pandemic.

Few studies have examined the effects of any widespread infectious disease outbreaks on suicide. The new study included around 70 authors from 30 countries who are members of the International COVID-19 Suicide Prevention Research Collaboration (ICSPRC), which was created to share knowledge about the impact of the pandemic on suicide and suicidal behaviour, and advise on ways to mitigate any risks.

The study used real-time suicide data obtained from official government sources to determine whether trends in monthly suicide counts changed after the pandemic began. They compared numbers of monthly suicides before COVID-19 (estimated using modelling of available data from at least 1 January 2019 to 31 March 2020, and in some cases ranging from 1 January 2016) with numbers observed in the early months of the pandemic (from 1 April 2020 to 31 July 2020) to determine how suicide trends changed during the pandemic. The study included 21 countries and regions (16 high-income, and 5 upper-middle-income), including whole-country data in 10 countries and data for 25 specific areas in 11 countries.

The authors found no evidence of an increase in suicide numbers in the early months of the pandemic in any of the countries included. In 12 areas there was evidence of a decrease in suicide, compared to the expected numbers [2].

The authors note that their findings could be explained by some of the steps that governments took in the various countries. For example, in many countries mental health services were increased or adapted to mitigate the potential impact of lockdown measures on mental health and suicide. Similarly, fiscal measures were put in place to buffer the financial hardship experienced by people who lost jobs or had to close their businesses as a result of stay at home orders. They also note that the pandemic might have heightened some factors that are known to protect against suicide (such as community support of vulnerable individuals, new ways of connecting with others online, and strengthened relationships through households spending more time together), a beneficial collective feeling of 'being in it together', as well as a reduction in everyday stresses for some people.

Professor Pirkis says: "Many countries in our study put in place additional mental health supports and financial safety nets, both of which might have buffered any early adverse effects of the pandemic. There is a need to ensure that efforts that might have kept suicide rates down until now are continued, and to remain vigilant as the longer-term mental health and economic consequences of the pandemic unfold. The effect of the pandemic on suicide might vary over time and be different for different groups in the population." [1]

The authors note that their study did not include low or lower-middle-income countries, which account for 46% of the world's suicides and might have been particularly hard hit by the pandemic. They say that there are some concerning signs that the pandemic might be adversely affecting suicide rates in these countries, but that it is difficult to verify as very few of these countries have good quality death registration systems and fewer collect real-time suicide data. In addition, they note that data quality for all countries may have been less reliable if the pandemic disrupted data collection processes, but that sensitivity analyses to test for this in their study yielded similar results.

They also highlight that their data does not explore the association between the pandemic and suicide in different age groups, for males versus females, or for people of different ethnicities. It also does not explore the effects of various public health measures to contain the pandemic or economic support packages on suicide patterns. The authors have plans to study this in future research.

Writing in a linked Comment, Dr Stella Botchway and Professor Seena Fazel, University of Oxford, UK, say: "[...] despite this initial snapshot, governments and services need to remain vigilant for a possible delayed increase in suicides as a result of the pandemic. Suicide can be a lagging indicator of psychosocial difficulties, influenced by medium-term and longer-term disruptions to civic life and the economy. Other work has shown that suicides can increase following economic recession, and such increases can be sustained for several years. Without counter-measures, ongoing reductions in economic activity can translate into individual financial and personal problems, such as job losses, reduced social status, housing instability, and relationship breakdowns. Alongside social isolation and disruption of normal routines, these factors can, in turn, increase the incidence of suicide through rises in mental health conditions such as depression as well as drug and alcohol misuse. Similar mechanisms might be relevant during the COVID-19 pandemic and its aftershocks."

They continue: "Reducing the global impact on mental health of the COVID-19 pandemic will involve continued monitoring alongside early intervention and investment into mental health services. Local, regional, and national strategies should not overlook at-risk groups, including those that might be hidden from view, such as people who are homeless, living in prison, or in abusive relationships. These strategies will be informed by consortia, such as the International COVID-19 Suicide Prevention Research Collaboration, allowing for ongoing surveillance, particularly of populations at higher risk. This collaboration can also lead to more consistent collection of high-quality suicide data across different countries. Pirkis and colleagues' results are reassuring in that there has not been an initial clear increase in suicide deaths, but will need to be followed up across a wider set of countries over the next few years to investigate whether suicide will be one of the health-related aftershocks of the pandemic."

PITTSBURGH, April 13, 2021 - Wheezing, coughing that doesn't stop, a pale and sweaty face: clinically, severe asthma attacks look very similar from patient to patient. But biologically, not all severe asthma is the same--and a team of scientists has, for the first time, identified the key difference in people, a finding that has important implications for treatment.

In a paper published today in Cell Reports, a group of scientists led by immunologists and pulmonologists at the University of Pittsburgh, in collaboration with Stanford University, used advanced tools of immunology, molecular biology and unbiased computational and bioinformatic approaches to characterize immune profiles of patients with severe asthma. These findings invite a new appreciation for the complexity of disease mechanisms and can lead to improved treatments.

"We started this study to better understand immune mediators of inflammation in asthma," said lead author Matthew Camiolo, M.D., Ph.D., clinical instructor of medicine at Pitt. "We found that despite being grouped broadly as 'clinically severe,' these asthma patients actually had very different and distinct immune profiles."

Asthma is a debilitating condition that affects millions of people each year. According to the Centers for Disease Control and Prevention, 25 million Americans, or 1 in 13 people suffer from asthma. And while current standards of treatment--inhaled immunosuppressive corticosteroids, such as beclomethasone and budesonide--are effective in most patients, clinical markers that can help identify those who are likely to be resistant to treatment are lacking.

For patients who do not respond to standard corticosteroid treatment or respond to it poorly, there is no 'one size fits all' approach to treat severe disease. Because of that, while severe asthma accounts for 5 to 10 percent of all asthma cases, it consumes 50 percent of associated health care costs, amounting to $28 billion annually.

"Although breakthroughs in asthma therapy have greatly improved our ability to treat patients, many people still continue with disease that greatly diminishes their quality of life," said co-senior author Sally Wenzel, M.D., director of Pitt's Asthma and Environmental Lung Health Institute, and chair of Pitt Public Health's Department of Environmental and Occupational Health.

To characterize immune cells within the airways of severe asthma patients, the researchers, in collaboration with Kari Nadeau, M.D., Ph.D., director of the Sean N Parker Center for Allergy & Asthma Research at Stanford University School of Medicine, used mass cytometry, RNA-sequencing and machine learning, and established a novel algorithm that links immune cells to cellular pathways potentially related to disease pathogenesis.

The research team found that lung aspirates from one group of patients were enriched with T cells polarized to fight infections, while the other group had a much lower level of T cells. At the same time, the second group had an increased number of innate immune cells expressing an inflammatory molecule IL-4--a cytokine known to be elevated in asthma.

"We have identified two clusters of severe asthma patients with very similar biomarkers but with strikingly distinct immune profiles and associated biological pathways," said senior author Anuradha Ray, Ph.D., professor of medicine and immunology at Pitt. "These findings identify new targets for therapy, which are distinct in the two subgroups of severe asthma patients who otherwise would be indistinguishable based on biomarker profiles."

"We believe that the cell types expressing IL-4 in the airways of one of the groups have not been previously identified in humans in any setting," Ray added.

Researchers are optimistic that these findings will enhance precision medicine approaches to treating severe asthma patients.

"These important findings are the result of a successful team effort among physician-scientists and basic scientists across institutions that has established a new frontier in asthma research," said Ray. "We hope the new knowledge gained will be used to develop new therapeutics to treat severe asthma patients and also allow improved stratification of patients for better efficacy of existing therapies."

A new study finds that brachytherapy, a common procedure that delivers radiation directly to cancer cells, may continue safely, potentially without delay or antibiotics, in cervical cancer patients following uterine perforation.

According to the World Health Organization, cervical cancer is the fourth most common cancer in women. Treatment for cervical cancer often involves brachytherapy combined with daily radiation therapy. Brachytherapy delivers radiation directly to cancer cells through a tube placed within the uterus.

"At times this tube can pierce the uterus and lead to a perforation," said William Small, Jr., MD, lead study author and professor and chair of radiation oncology at Loyola Medicine and Loyola University Chicago Stritch School of Medicine. "Many clinicians will not proceed with the treatment when a perforation occurs. This can lead to delays in therapy that may increase the recurrence risk and potentially lead to worse survival rates."

In the new study, "Uterine perforation during brachytherapy for cervical cancer: Complications, outcomes, and best practices for forward treatment planning and management," researchers sought to determine the incidence of uterine perforations, review associated complications, and propose guidelines for the management of perforations after brachytherapy.

Researchers conducted a retrospective review of 123 patients with cervical cancer who received single or multiple high-dose therapy implants between April 2006 and May 2017 at Loyola University Medical Center. Patient CT and MRI images were reviewed to identify uterine perforation caused by the tandem, the tube placed within the uterus to deliver radiation. Acute and long-term complications during and after treatment were scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4.0.

Perforations were observed in 22 patients (17.9%) and 31 (6.4%) of the 482 total implants. Three patients developed acute infectious complications; two of these patients had mild urinary tract infections, which resolved without complications or treatment delays. The third patient had a complex perforation, received antibiotics and required a one-week treatment delay. Of the different categories of adverse events, only the rate of acute infectious complications among those with perforations (13.6%) versus those without perforations (3%) was significant.

"Our study notes that when perforation occurs, treatment can proceed without delay, potentially improving survival," said Dr. Small, who is also director of Loyola's Cardinal Bernardin Cancer Center. Treatment also may proceed without prophylactic antibiotics.

"If confirmed with additional data, the findings could lead to a new standard of care with the potential to save significant lives around the world," said Dr. Small.

The study first appeared online March 17, 2021 in the journal Brachytherapy.

New research led by the Garvan Institute of Medical Research has revealed how breast cancer cells that develop during or after pregnancy change their environment to form more aggressive tumours.

In experimental models of pregnancy-associated breast cancer, researchers found that cancer cells send signals to the connective tissue around them to trigger uncontrolled inflammation and remodel the tissue, which in turn helps the cancer to spread.

"Breast cancers that arise during or shortly after pregnancy are highly aggressive as they often become resistant to standard therapies. With 50% of cases being fatal, better treatment options are urgently needed," says Dr David Gallego-Ortega, Leader of the Tumour Development Group at Garvan and co-senior author of the new study published in Cell Reports.

"Our study has revealed a crosstalk between these breast cancer cells and their environment that is fuelling the right conditions for cancer to metastasise, and reveals the inflammation itself as a potential new therapeutic target for the disease."

Breast cancer during pregnancy

While a breast cancer diagnosis is devastating for any patient, the prognosis is far worse for pregnant women and new mothers. One in every two women diagnosed with pregnancy-associated breast cancer, which affects up to 40 of every 100,000 women giving birth, will lose their battle within five years of diagnosis.

"Breast cancer survival rates reduce from 80% to just 52% for young mothers who develop breast cancer while pregnant," says co-first author Dr Fatima Valdes-Mora from the Children's Cancer Institute, who conducted the research at the Garvan Institute.

"We set out to understand the cellular basis of how pregnancy triggers a more aggressive breast cancer and how current treatment could be improved."

Using next-generation cellular genomics technology, the researchers analysed a snapshot of gene activity of the individual cells found within the tumours of an experimental model of pregnancy-associated breast cancer. Interestingly, the researchers observed a number of changes not just in the cancer cells themselves, but in the surrounding connective tissue cells.

An environment for cancer to thrive

"In normal breast tissue cells, when mothers stop breastfeeding, changes in hormonal signals tell the connective tissue around milk-producing cells to revert to its pre-pregnancy form. But we found when similar signals were sent by breast cancer cells, they triggered changes that enabled inflammation and faster cancer spread," says Dr Gallego-Ortega.

"The genomic data showed us that as they received pregnancy cues, breast cancer cells transitioned to the more malignant 'basal' breast cancer subtype. At the same time, the cells were 'tweaking' their environment, signalling to cells around them to turn on inflammation within the tumour tissue."

In their model, the researchers found that cells in the tumour environment drove changes that make pregnancy-associated breast cancer highly aggressive - uncontrolled inflammation, tissue remodelling and the generation of new blood vessels.

Path to improving therapy

The findings have prompted the researchers to explore new therapeutic targets for pregnancy-associated breast cancer. In experimental models, the team is next aiming to test whether treating the inflammatory pathways in the tumour environment - some of which can be targeted with existing medication such as ibuprofen - could reduce the spread of pregnancy-associated breast cancers and improve outcomes of current treatments.

"Pregnancy can provide cancers with a route of escape from therapy and from their location in the breast," explains Prof Chris Ormandy, co-senior author and Head of the Cancer Biology Lab at Garvan. "Our study suggests that targeting inflammation is one way to stay a step ahead of the disease."