Body

Lugano, Switzerland, 20 September 2020 - Adding abemaciclib to hormonal therapy reduces the risk of cancer recurrence by 25% in patients with high-risk early hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) breast cancer, according to results from a study at ESMO 2020. (1)

"This is the first time in more than 20 years that we have seen an advance in the adjuvant treatment of this form of breast cancer," said lead author Prof Stephen Johnston, from the Royal Marsden Hospital NHS Foundation Trust, London, UK. He explained that hormone receptor positive breast cancer is the commonest form of breast cancer, affecting 70% of patients, with most being diagnosed with early disease.

"Many of these patients can be cured with currently available treatments: surgery, radiotherapy, chemotherapy and hormone treatment. But about 20% have high-risk disease and will develop a recurrence either locally in the breast or elsewhere in the body over the first ten years of treatment," he explained.

"These patients with high-risk early breast cancer show a degree of resistance to hormone therapy, relapsing early despite everything we currently give them," said Johnston. "CDK4/6 inhibitors, such as abemaciclib, have transformed the way we treat metastatic breast cancer over the last few years, overcoming primary endocrine resistance and improving survival. So it was an obvious step to see whether adding abemaciclib to hormone treatment in patients with high-risk early breast cancer could reduce the risk of their cancer returning."

The international phase 3 monarchE study included 5637 patients with HR+ HER2- early breast cancer with clinical and/or pathological risk factors putting them at high risk for relapse. After completing their primary treatment they were randomised on an open-label basis to abemaciclib (150mg twice daily for two years) plus endocrine therapy or endocrine therapy alone.

"We found a 25% reduction in recurrence of cancer with the first two years when abemaciclib was added to hormone therapy compared to hormone therapy alone," reported Johnston. During this time 11.3% of patients in the control group had a relapse of their cancer compared to 7.8% of those in the abemaciclib group, an absolute difference of 3.5% which translates to a 25.3% reduction in risk. Most of the reductions occured in sites of distant metastases, especially to liver and bone.

"This is the first study to show that adding a CDK4/6 inhibitor to endocrine therapy significantly improves invasive disease free survival in the adjuvant setting," said Giuseppe Curigliano, Associate Professor of Medical Oncology at the University of Milan, Italy, and Chair of the ESMO Guidelines Committee.

"This is a very important trial and the findings will change practice. Once approved for high risk HR+ HER2- early breast cancer the new standard of care for these patients will be to add two years of abemaciclib to endocrine therapy," he suggested.

Curigliano suggested it would have been interesting to have included genetic signature into the assessment of patients at high risk, in addition to number of positive lymph nodes, tumour size, histologic grade and Ki-67 (a marker of proliferation). Johnston said that tissue and plasma samples had been collected from all of the study participants for translational research that will include looking at genomic signatures and response to abemaciclib.

"The safety data are important, particularly the number of patients treated with abemaciclib who had to discontinue or required dose reductions due to side-effects," said Curigliano. A total of 463 (16.6%) of patients discontinued abemaciclib due to adverse events, most commonly diarrhea; 306 of these continued on endocrine therapy. The protocol allowed dose reduction from 150 to 100mg twice daily if required. He noted: "Adherence to treatment will be an important issue to be considered in the real life population of patients when this treatment is approved and used in clinical practice."

Curigliano added, "For the future it will be important to understand if we can potentially spare chemotherapy in this group of patients treated with a CDK4/6 inhibitor. This would need to be investigated in a randomised clinical trial."

A drug used to treat breast and ovarian cancer can extend the lives of some men with prostate cancer and should become a new standard treatment for the disease, concludes a major trial which is set to change clinical practice.

Final results from the trial showed that olaparib - a pioneering type of drug called a PARP inhibitor and the first ever cancer drug to target an inherited genetic fault - can be used successfully to treat prostate cancers with a weakness in their ability to repair damaged DNA.

The innovative drug was more effective than the modern hormone treatments abiraterone and enzalutamide at slowing down the growth and spread of prostate cancer in patients with advanced disease.

Prior results from the PROfound trial published earlier this year led to olaparib's approval by the US Food and Drug Administration (FDA) - making it one of the first genetically targeted drugs available for prostate cancer.

The trial had already reported an improvement in disease development and outcome for this group of men with DNA repair faults in their tumours - but the final results published at this stage offer a longer follow-up and conclusively demonstrate an improvement in survival for men who were given olaparib.

The PROfound trial studied 387 men with advanced prostate cancer who had defects in one or more of 15 DNA repair genes. It was funded by AstraZeneca (LSE/STO/NYSE: AZN) and co-led by The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, alongside international collaborators including Northwestern University in Chicago, US.

Scientists at The Institute of Cancer Research (ICR) were the first to discover how olaparib could be targeted at tumours with faults in their ability to repair DNA. They now expect the concluding results from the PROfound trial - presented at the European Society for Medical Oncology today (Sunday) and published in the journal The New England Journal of Medicine at the same time - to pave the way for regulatory approval of olaparib in prostate cancer in Europe and in the UK.

Men whose tumours had genetic changes were assigned to two groups: one group for those with changes in BRCA1, BRCA2 or ATM, and another group for men with genetic changes in any other of the DNA repair genes studied. Men were then randomly assigned to olaparib or standard hormone therapy.

DNA damage is the basic cause of cancer - but it is also a key weakness of cancer that can be exploited, since cancer cells need to be able to repair their own DNA too.

In the final analysis of data from the PROfound trial, researchers found that olaparib blocked prostate cancer growth more effectively than the modern targeted hormone treatments abiraterone and enzalutamide in men with faulty DNA repair genes.

Patients with genetic alterations in the DNA repair genes BRCA1, BRCA2 or ATM who received olaparib had a median overall survival of 19.1 months, compared with 14.7 months for those on targeted hormone treatments. Meanwhile, patients with genetic alterations in any other of the DNA repair genes studied had an overall survival of 14.1 months with olaparib or 11.5 months with the targeted hormonal drugs.

During the trial, patients were allowed to 'cross over' - meaning that they were able to switch treatments and start taking the experimental treatment, olaparib, once their disease progressed. Overall, 66 per cent of men who received the targeted hormone treatments - 86 out of 131 - crossed over to receive olaparib. Researchers analysed the impact on survival of crossing over from targeted hormone treatments and found that those who crossed over to olaparib were less likely to die sooner.

Thanks to the trial's results, researchers now hope to see olaparib approved in the UK once it gains approval from the European Medicines Agency (EMA) and NICE - so that it can benefit men with advanced prostate cancer with faults in the BRCA1, BRCA2 or ATM genes who have been previously treated with modern targeted hormone treatments like abiraterone or enzalutamide.

There were trends that favoured the use of olaparib in men with DNA repair faults other than BRCA or ATM, but the data is not definitive. Next, researchers will be studying new drug combinations which could make olaparib more effective and help men with prostate cancer and faulty DNA repair genes live even longer.

Study co-leader Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

"I'm confident that our results will transform prostate cancer treatment - hopefully very soon. We have shown that olaparib, a drug already approved for use in breast and ovarian cancer, can extend the lives of men with advanced prostate who have defects in the genes BRCA1, BRCA2 or ATM and who have been treated with enzalutamide or abiraterone.

"The FDA has already approved olaparib for prostate cancer in the US and I hope that the final results of our trial will bring the authorisation of this innovative drug to Europe and the UK as soon as possible. This will enable more men with the disease to take advantage of this targeted treatment so that they can have more precious time with their loved ones."

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

"I'm really excited to see the genetically targeted drug olaparib making such a difference to men with prostate cancer. One of the benefits of this innovative drug is that it has far fewer side effects than chemotherapy, as it can target an Achilles heel in prostate cancers instead of also attacking healthy cells in the body.

"Olaparib is the perfect example of a smarter, kinder personalised therapy for patients - and it's great that it has been an advance led here in the UK, including pioneering ICR science and practice-changing clinical trials like this.

"The next step for our researchers is to study new treatment combinations that can take us a step further and help us prevent or overcome drug resistance - the central aim of our new Centre for Cancer Drug Discovery."

Lugano, Switzerland, 19 September 2020 - The results of the phase 3 CheckMate 9ER trial have provided a new first-line treatment option for patients with metastatic kidney cancer. The late breaking results are presented at ESMO 2020. (1)

The trial took two drugs used as monotherapies in the second line, nivolumab and cabozantinib, and combined them for use as a first-line treatment against standard of care, sunitinib. The combination was superior to sunitinib for progression-free survival, overall survival, and response rate. There was a consistent benefit of the combination over sunitinib in numerous subgroups including age, sex, PD-L1 expression, bone metastases, International Metastatic RCC Database Consortium (IMDC) risk group, and region of the world.

More than 50% of patients in the combination arm needed a dose reduction of cabozantinib due to adverse events. But only 3% had to stop both drugs because of toxicity compared to 9% of patients in the sunitinib arm. The overall rate of serious adverse events was similar between arms, but liver toxicity was more common in the combination arm. As for immune-related side-effects, 19% of patients in the experimental arm needed corticosteroids; just 4% needed corticosteroids for 30 days or longer.

The findings add to mounting evidence showing the advantages of combination therapy over single drugs. Similar to the CheckMate 9ER trial, the KEYNOTE-426 and JAVELIN Renal 101 trials (2,3) combined an immune checkpoint inhibitor with an anti-angiogenic drug, whereas CheckMate 214 combined two immune checkpoint inhibitors. (4)

Study author Dr Toni K. Choueiri, Director, The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and The Jerome and Nancy Kohlberg Chair and Professor of Medicine, Harvard Medical School, Boston, US said: "The results with combination therapy were statistically significant and clinically meaningful. The risk of progression or death was cut by almost 50%, death was cut by 40%, and the response rate doubled. This will become an important treatment option to choose from. The various combination treatments will unlikely be compared head-to-head, but I think quality of life could differentiate this new therapy, as there was a statistical significance favouring the combination arm with both questionnaires we used. (5) Another factor to consider is that clinicians are familiar with both of these drugs."

Commenting on the findings, Dr Dominik Berthold, Head, Specialised Consultation for Urological Cancers Medical Oncology Service, Department of Oncology, Lausanne University Hospital, Switzerland said: "CheckMate 9ER met its efficacy endpoints and the combination can be considered a new first-line treatment option. However, the medical community is divided about whether two immunotherapies or immunotherapy plus an anti-angiogenic drug is the better choice, since the different combinations appear to have similar effectiveness."

He said longer-term data are needed for CheckMate 9ER: "The 18 months of follow-up is still quite short. The question is whether the responses to treatment are durable or patients progress at some point."

"It would also be useful to learn whether the combination of cabozantinib and nivolumab is effective in non-clear cell carcinoma," added Berthold. "This is a minority of patients with advanced kidney cancer which are not well studied and were excluded from this trial."

Berthold noted that when using drugs with specific mechanisms of action, the first-line treatment choice will also determine the selection of second-line therapy. He explained: "If you start with a combination of immune therapy only, it becomes an automatic choice to use an anti-angiogenic drug in the second line. But if you begin with a combination of two mechanisms of action, such as immune therapy and an anti-angiogenic drug, then the second-line choice is less clear. More data are needed on the most suitable order of therapy for the entire population as well as specific groups such as high tumour burden versus slow-growing disease."

Based on reported cases, Unverricht-Lundborg disease, also known as progressive myoclonic epilepsy-1A, EPM1, is more common in Finland than anywhere else in the world, a new study finds. The researchers combined data from various registers and hospital records to explore the prevalence and disease course of EPM1 in Finland. Published in Neurology, the study was carried out in collaboration between the North Karelia Central Hospital, the University of Turku, Kuopio University Hospital, the University of Eastern Finland, and Turku University Hospital.

EPM1 is part of the Finnish disease heritage and it is estimated to be more common in Finland than anywhere else in the world. The disease is caused by a mutation in the cystatin B (CSTB) gene, and it is autosomal recessively inherited. This means that both parents need to pass down a mutated gene in order for EPM1 to manifest. The majority EPM1 cases are linked to a repeat expansion mutation that is prevalent in the Finnish population. The gene mutation was discovered already in 1993, but the prevalence of EPM1 hasn't been studied systematically anywhere in the world until now, and this was also the first time in Finland.

The objective of the newly published study was to explore the prevalence and incidence of EPM1 in Finland, and to describe the disease course and the related life expectancy. Patients for the study were identified and the data collected by combining data from nationwide registers, hospital records and genetic studies. Recently, the same methods have also been used to explore the prevalence of certain other neurological diseases in Finland.

The study found that the prevalence of EPM1 in Finland is 1.9 cases per 100,000 inhabitants. However, a comparison of the different data sources showed that it is likely that the study did not reach all patients diagnosed with EPM1, and the real prevalence may be higher by up to one third. Earlier studies have shown that EPM1 may be underdiagnosed in many countries and, based on the results of this new study, this may also be the case in Finland.

The risk of premature death among Finnish patients with EPM1 started to grow significantly after they reached 40, making them nearly five times more likely to die prematurely than the general population. On average, the clinical picture and disease course of EPM1 in Finnish patients seemed to be slightly more severe than in patients from Italy, which has been reported in earlier studies. In some Finnish patients, however, the clinical picture was very mild, and they remained functional and capable of working until the end of the follow-up period, sometimes even up to their retirement age.

The findings indicate that EPM1 is more common in Finland than elsewhere in the world. Patients with EPM1 have a higher risk of premature death than the general population, but there is significant individual variation in the clinical picture and disease course.

As well as allowing us to communicate with other people, languages are the tool we use to convey our thoughts, identity, knowledge, and the way we see and understand the world. Mastering more than one language enriches us, provides a gateway to other cultures and, according to a team of researchers led by scientists from the Universitat Oberta de Catalunya (UOC) and Pompeu Fabra University (UPF), actively using them also brings us neurological benefits and protects us from cognitive impairment associated with ageing.

In a paper published in Neuropsychologia, the researchers conclude that speaking two languages on a regular basis - and having done so all one's life - enhances cognitive reserve and delays the appearance of symptoms associated with cognitive decline and dementia.

"The prevalence of dementia in countries where more than one language is spoken is 50% lower than in those regions where the population uses only one language to communicate," said researcher Marco Calabria, professor at the UOC Faculty of Health Sciences and member of the University's Cognitive NeuroLab research group and the Speech Production and Bilingualism research group, at the UPF.

Previous work had already found that the lifelong use of two or more languages could be a key factor in increasing cognitive reserve and delaying the onset of dementia, as well as offering advantages for memory and executive functions.

"We wanted to discover the mechanism through which bilingualism contributes to cognitive reserve in cases of mild cognitive impairment and Alzheimer's, and whether there were differences in terms of the benefit gained from different degrees of bilingualism, and not only between monolingual and bilingual people," said Calabria, who led the study.

Therefore, unlike in previous studies, the researchers established a bilingualism gradient: from people who speak only one language but are passively exposed to another, to individuals who have excellent proficiency in both and use them indiscriminately on a day-to-day basis. To create this gradient, several variables were taken into account, including the age of acquisition of the second language, the use made of each language, and switching between languages in the same context.

The researchers focused on the population of Barcelona, where the use of Catalan and Spanish is highly variable, with some predominantly Catalan-speaking neighbourhoods and others where Spanish is the main language. "We wanted to take advantage of this variability, and instead of comparing monolingual and bilingual people, we looked at whether in Barcelona - where everyone is more or less bilingual - there was a certain degree of bilingualism that had neuroprotective benefits," explained Calabria.

Bilingualism and Alzheimer's

They recruited 63 healthy individuals, 135 patients with mild cognitive impairment such as memory loss, and 68 people with Alzheimer's - the most prevalent type of dementia - in four hospitals in Barcelona and the metropolitan area. They used a questionnaire to establish proficiency in Catalan and Spanish and ascertain each person's degree of bilingualism. They then correlated this degree with the age of neurological diagnosis and the onset of symptoms.

To better understand the origin of cognitive advantage, they asked participants to perform various cognition tasks, focusing primarily on the executive control system, as previous studies have suggested that this is the source of the benefit. In total, the participants performed five tasks in two sessions, such as memory tests and cognitive control.

"We saw that the people with a higher degree of bilingualism received a diagnosis of mild cognitive impairment later than those who were passive bilinguals," said Calabria, who surely considers speaking two languages and regularly switching from one to the other to be lifelong training for the brain. According to this researcher, such linguistic gymnastics is related to other cognitive functions, such as executive control, which kicks in when we perform several actions at once, for example when we drive, to help us filter out relevant information.

The brain's executive control system is related to the system used to control two languages: it has to switch between them, making the brain focus on one and then the other, to avoid one language intruding into the other when we speak.

Calabria considers that "in the context of neurodegenerative diseases, this system could offset symptoms. So, when something is not functioning well due to the disease, thanks to the fact that it is bilingual, the brain has efficient alternative systems for resolving the problem," also stressing that "we have seen that the more you use both languages and the better your language skills, the more neuroprotective advantage you have. In fact, active bilingualism is an important predictor of delay in the onset of symptoms of mild cognitive impairment - a preclinical phase of Alzheimer's disease - because it contributes to cognitive reserve".

Now researchers want to see whether bilingualism is also beneficial for other diseases, such as Parkinson's and Huntington's disease.

Irvine, Calif. - Experiencing multiple stressors triggered by the COVID-19 pandemic - such as unemployment - and COVID-19-related media consumption are directly linked to rising acute stress and depressive symptoms across the U.S., according to a groundbreaking University of California, Irvine study.

The report appears in Science Advances, published by the American Association for the Advancement of Science.

"The pandemic is not hitting all communities equally," said lead author E. Alison Holman, UCI professor of nursing. "People have lost wages, jobs and loved ones with record speed. Individuals living with chronic mental and physical illness are struggling; young people are struggling; poor communities are struggling. Mental health services need to be tailored to those most in need right now."

In addition, the research highlights the connection between mental health and exposure to media coverage of the COVID-19 pandemic, suggesting the need to step away from the television, computer or smartphone to protect psychological well-being.

"The media is a critical source of information for people when they're faced with ambiguous, ongoing disasters," said Roxane Cohen Silver, professor of psychological science and one of the study's principal investigators. "But too much exposure can be overwhelming and lead to more stress, worry and perceived risks."

With funding from a National Science Foundation RAPID grant, Holman, Silver, and co-investigators Dana Rose Garfin and Rebecca R. Thompson conducted a national survey of more than 6,500 U.S. residents in March and April 2020, as illness and deaths were rising around the country. Using the NORC AmeriSpeak panel, the study was the first of its kind to examine early predictors of rising mental health problems across the nation. The design let researchers evaluate the effects of the pandemic as it was unfolding in real time.

"Over the course of the study, the size of the pandemic shifted dramatically," Holman said. Accordingly, people surveyed later in the study period reported the highest rate of acute stress and depressive symptoms.

The UCI team's findings offer insights into priorities for building community resilience in the face of the COVID-19 pandemic:

Those with pre-existing mental and physical conditions are more likely to show both acute stress and depressive symptoms.

Secondary stressors - job and wage loss, a shortage of necessities - are also strong predictors in the development of these symptoms.

Extensive exposure to pandemic-related news and conflicting information in the news are among the strongest predictors of pandemic-specific acute stress.

"It's critical that we prioritize providing resources to communities most in need of support right now - the unemployed, poor or chronically ill people, and young people," Holman said. "We also encourage the public to limit exposure to media as an important public health intervention. It can prevent mental and physical health symptoms and promote resilience."

A deadly combination of two mosquito-borne viruses may be a trigger for stroke, new research published in the The Lancet Neurology has found.

University of Liverpool researchers and Brazilian collaborators have been investigating the link between neurological disease and infection with the viruses Zika and chikungunya. These viruses, which mostly circulate in the tropics, cause large outbreaks of rash and fever in places like Brazil and India. Zika is widely known to cause brain damage in babies following infection in pregnancy, but the new research shows it can also cause nervous system disease in adults.

The study of 201 adults with new onset neurological disease, treated in Brazil during the 2015Zika and 2016 chikungunya epidemics, is the largest of its kind to describe the neurological features of infection for several arboviruses circulating at the same time.

The new research shows that each virus can cause a range of neurological problems. Zika was especially likely to cause Guillain-Barre syndrome, in which the nerves in the arms and legs are damaged. Chikungunya was more likely to cause inflammation and swelling in the brain (encephalitis) and spinal cord (myelitis). However, stroke, which could be caused by either virus alone, was more likely to occur in patients infected with the two viruses together.

Stroke occurs when one of the arteries supplying blood to the brain becomes blocked. The risk of stroke is known to be increased after some types of viral infection, like varicella zoster virus, which causes chickenpox and shingles, and HIV. Stroke is also being recognised increasingly as a complication of COVID-19. This has important implications for the investigation and management of patients with viral infection, as well as for understanding the mechanisms of disease.

In total 1410 patients were screened and 201 recruited over a two-year period at Hospital da Restauração in Recife, Brazil. Comprehensive PCR and antibody testing for viruses was carried out in Fiocruz laboratories.

Of the 201 patients admitted with suspected neurological disease linked to Zika, chikungunya or both, 148 had confirmation of infection on laboratory testing, around a third of whom had infection with more than one virus.

The median age of patients was 48, and just over half the patients were female. Only around 10% patients had fully recovered at discharge, with many having ongoing issues like weakness, seizures, and problems in brain function.

Of the stroke patients, who were aged 67 on average, around two thirds had infection with more than one virus. Many of the people who had a stroke had other stroke risk factors, such as high blood pressure, indicating that stroke following Zika and chikungunya viral infection may most often be seen in those who are already high risk.

Dr Maria Lúcia Brito Ferreira, neurologist and head of department at Hospital da Restauração, leading the Brazilian team said: "Zika infection most often causes a syndrome of rash and fever without many long-term consequences, but these neurological complications - although rare - can require intensive care support in hospital, often result in disability, and may cause death."

Dr Suzannah Lant, a Clinical Research Fellow at the University of Liverpool, who worked on the study explained: "Our study highlights the potential effects of viral infection on the brain, with complications like stroke. This is relevant to Zika and chikungunya, but also to our understanding of other viruses, such as COVID-19, which is increasingly being linked to neurological complications."

Senior author Professor Tom Solomon, Director of the National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections at the University of Liverpool said: "Although the world's attention is currently focused on COVID-19, other viruses that recently emerged, such as Zika and chikungunya, are continuing to circulate and cause problems. We need to understand more about why some viruses trigger stroke, so that we can try and prevent this happening in the future."

Public health agencies need ethical guidelines for deciding what to do when anonymous student health surveys discover a very high local rate of suicide-risk, according to CU researchers.

In a report published today in the highly influential American Journal of Bioethics, the researchers describe a student health survey team that discovered a Colorado school with extremely high rates of suicide risk, and a lack of ethical guidance on whether or how to intervene.

The case came from the Healthy Kids Colorado Survey, a voluntary statewide anonymous survey completed by students in participating schools across Colorado. In addition to reporting results for the entire state, the survey team compiles and returns results to each school.

"While compiling school results, the HKCS team noticed that one school's suicide-risk rate was off the charts. They were alarmed but weren't sure how to proceed, since the survey promises confidentiality of results," said lead author Arnold H. Levinson, PhD, MJ, professor of Community and Behavioral Health at the Colorado School of Public Health.

In the end, the surveyors called the principal at the school, who said he would use the information to ask the district for extra resources to address suicide risks. The decision to call the principal was endorsed by a multidisciplinary team of CU researchers and ethicists from the CU Center for Bioethics and Humanities who examined the case.

But the authors of the new report note that the decision was not informed by ethical guidance.

"We searched for guidance from research ethics, medical ethics, public health ethics and education ethics," Levinson said. "And we couldn't find any directly applicable guidelines."

"We urge national public health and education associations to produce guidance that clarifies the ethical and legal duties owed to randomly chosen schools and students that participate in anonymous surveys when surveillance activities identify high-risk clusters."

Adolescent suicide is at epidemic levels in Colorado and the nation, noted a research team member, M. Franci Crepeau-Hobson, PhD, associate professor and director of clinical training, University of Colorado School of Education and Human Development.

"Schools should be conducting suicide-prevention programs, and administrators are responsible for ensuring their students' health and safety," she said. "Screening for suicide is the best approach, but at a minimum, school personnel should be trained to see signs of risk and appropriate ways to respond."

New Rochelle, NY, September 18, 2020—Gene therapy was successfully used to overcome the cardiac effects of Freidreich’s ataxia (FA) in a mouse model of the disease, as reported in the peer-reviewed journal Human Gene Therapy. Click here to read the full-text article free online through October 18, 2020.

Researchers at Weill Cornell Medical College created a unique, cardiac-specific mouse model of FA that is similar to early stage human disease. The mice are normal at rest but exhibit stress-induced cardiac symptoms, such as when they exercise on a treadmill. 

In the article “Stress-induced Mouse Model of the Cardiac Manifestations of Friedreich’s Ataxia Corrected by AAV-mediated Gene Therapy,” the treated mice received a one-time intravenous dose of adeno-associated virus (AAV) gene therapy to deliver the frataxin gene, which is deficient in FA. These mice exhibited exercise performance on a treadmill that was indistinguishable from their healthy littermates. 

“The complexity of single gene disorders often complicates the strategies approached to clinical gene therapy,” according to Editor-in-Chief of Human Gene Therapy Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School. “The demonstration by these authors that FA may require a systemic delivery method to correct both the cardiac and neurologic manifestations of the disease could be of critical importance in future FA gene therapy.”

About the Journal
Human Gene Therapy, the Official Journal of the European Society of Gene and Cell Therapy and eight other international gene therapy societies, was the first peer-reviewed journal in the field and provides all-inclusive access to the critical pillars of human gene therapy: research, methods, and clinical applications. The Journal is led by Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, and an esteemed international editorial board. Human Gene Therapy is available in print and online. Complete tables of contents and a sample issue are available on the Human Gene Therapy, website.

About the Publisher
Mary Ann Liebert, Inc., publishers is known for establishing authoritative peer-reviewed journals in many promising areas of science and biomedical research. Its biotechnology trade magazine, GEN (Genetic Engineering & Biotechnology News), was the first in its field and is today the industry’s most widely read publication worldwide. A complete list of the firm’s 90 journals, books, and newsmagazines is available on the Mary Ann Liebert, Inc., publishers website.

Mary Ann Liebert, Inc. 140 Huguenot Street New Rochelle, NY 10801 (914) 740-2100 or (800) M-LIEBERT Fax (914) 740-2101 www.liebertpub.com

Journal

Human Gene Therapy

DOI

10.1089/hum.2019.363

NARBONNE, France - The Pharmabiotic Research Institute (PRI), Europe's only regulatory expertise centre for the development of microbiome-based drug products, has announced the publication of a review titled "Live biotherapeutic products: the importance of a defined regulatory framework". Published in the journal Experimental & Molecular Medicine, it shines a light on the need for clear scientific and pharmaceutical standards when developing and registering live biotherapeutic products (LBPs), a new and innovative type of microbiome-based drug product. Many in the general public will have heard of 'probiotics', which according to the WHO definition are 'live microorganisms that when administered in adequate amounts confer a health benefit on the host...'; however the authors of this review have focused on live microorganisms as active pharmaceutical substances intended to be used in the treatment or prevention of disease in humans. It is an in-depth treatment of the latest regulatory innovations and 'quality-by-design' development principles which will be critical in the appropriate assessment of these biologic medicines' quality, efficacy and safety. This work draws on years of interactions with leading biotechs in the field, discussions with national and European health authorities (mainly through scientific advice), as well as extensive research of the existing European and other regions' relevant pharmaceutical frameworks. The PRI is a European non-profit organization, and this topic is a key example of the type of regulatory challenges that its members are striving to overcome in their pursuit of microbiome medicinal product development and registration for the EU Market.

"Ideally, this article will help stakeholders in the field of microbiome-based products understand that the active substance or the ingredient of a product does not define its regulatory status. Thus, 'probiotic' substances can be developed as dietary supplements, food ingredients or drugs, depending on what these substances are intended to do and to whom," says co-author Dr. Alice Rouanet (PRI).

Dr. Magali Cordaillat-Simmons, Executive Director of the PRI continues, "In a field where regulatory confusion often exists we perceived a strong need for clarification of the general concepts and specific constraints associated with 'probiotic strains' intended for prevention or treatment of a human disease, i.e. in the context of their registration as biological drug products."

Similar to all products intended to prevent or treat diseases, LBPs will have to be registered as medicinal products to reach market in the US and in Europe. LBPs under the current European legislative framework have no 'separate status', and "...are by nature considered biological medicinal products as the active substances are live microorganisms, which are biological substances...LBPs have to comply with the biological medicinal product legislative and regulatory framework." The authors address several aspects of pharmaceutical development principles, notably; 'How can the quality of LBPs be ensured and demonstrated?', 'How can the safety of LBPs be demonstrated?', and 'How can the efficacy of LBPs be demonstrated?'.

Pr. Bruno Pot, Science Director for Yakult Europe and PRI President concludes, "New medicinal products directed to the gut microbiota pose big scientific challenges, because of the complexity and variability of the microbiota. The regulatory challenge, however, is also real, maybe because of the complexity and variation of the possible paths to success! Time and money can be gained in making decisions as early as possible on the regulatory path to follow: it will help to decide on the study planning and result in the preparation of a valid and credible dossier for the evaluation by competent authorities. Our hope is that this paper could assist you somehow in this complex process."

New research to be presented at the ESCMID Conference on Coronavirus Disease (ECCVID, held online from 23-25 September) shows that one quarter of hospitalised younger patients with COVID-19 aged 18-39 years developed pneumonia, underlining the danger the disease respresents to young people. The study is by Assistant Professor Hyun ah Kim, Keimyung University Dongsan Hospital, Daegu, and Dr Hyo-Lim Hong, Daegu Catholic University Medical Center, Daegu, South Korea, and colleagues.

Many countries that had been controlling their COVID-19 pandemic are now seeing a resurgence of the virus, especially among young people.The authors say: "The low alertness of young people has become a social problem around the world, since it is known that the progress toward severe cases is low in young people."

In this study, the authors analysed the incidence of pneumonia and clinical characteristics of young patients. The retrospective study was conducted on adult patients aged 18 to 39 who were admitted to 6 hospitals in Daegu, South Korea (one of the earliest hotspots of the pandemic) from February 18 to March 31, 2020. The patient group without pneumonia and the patient group with pneumonia were compared.

A total of 315 hospitalised, isolated patients were analysed. Of these, 205 (65%) were female (65.1%) and 32 (10.2%) patients were asymptomatic. In South Korea, even asymptomatic patients were hospitalised and quarantined once confirmed COVID-19 positive if there were beds available in hospitals. Symptoms were presented in the following order: cough (168, 53%), sore throat (83, 26%), fever (82, 26%), rhinorrhoea/runny nose (99, 31%), myalgia (muscle pain) (62, 20%), chill (51, 16%), diarrhoea (46, 15%).

There were 71 (23%) confirmed cases of pneumonia on chest X-rays. Of the 85 patients who had a CT scan performed, 43 were confirmed to have pneumonia. Eleven cases of pneumonia were diagnosed in CT who had previously had normal X-ray results. Overall, pneumonia was confirmed in a total of 83 (26%) of patients.

In around a quarter (16/71, 23%) of cases, chest X-rays remained abnormal on the last chest X-ray before hospital discharge, which for asymptomatic patients was 10 days after diagnosis; for patients with symptoms hospital discharge occurred after two consecutive negative tests for COVID-19.

Severe pneumonia was reported in 7 (2.2%) cases, with one patient needing mechanical ventilation. Symptoms of fever, cough, diarrhoea and shortness of breath were statistically significantly more frequent in the pneumonia group. Blood test results showed particularly high C-reactive protein (a sign of systemic inflammation) in the pneumonia group: more than 8 times higher than in patients without pneumonia (2.47 vs. 0.3 mg/L). There was also one asymptomatic case that subsequently developed pneumonia.

The authors conclude: "Pneumonia occurred in 26% of young hospitalised patients. Severe pneumonia presented in 2% of cases, and one patient with no other medical history required mechanical ventilation. Young people should also be aware of the risk of pneumonia or severe pneumonia due to COVID-19."

It is better to invest in measures that make it easier for women to visit a doctor during pregnancy than measures to repair birth injuries. This is the conclusion from two mathematicians at LiU, using Uganda as an example.

A fistula is a connection between the vagina and bladder or between the vagina and the rectum. It can arise in women during prolonged childbirth or as a result of violent rape. The connection causes incontinence, in which the patient cannot control either urine or faeces, which in turn leads to several further medical problems and to major physical, mental and social suffering. The medical care system in Uganda is well-developed, particularly in metropolitan areas, but despite this the occurrence of fistulas during childbirth is among the highest in Africa. It has been calculated that between 1.63 and 2.25 percent of women of childbearing age, 15-49 years, are affected.

Betty Nannyonga, postdoc at LiU who also works at Makerere University in Kampala, Uganda, and Martin Singull, associate professor in mathematical statistics at the Department of Mathematics at LiU, have published an article in the scientific journal PLOS ONE that demonstrates how the available resources can be put to best use.

"We have tried to construct a mathematical model to show how to prevent (obstetric) fistulas in women during prolonged childbirth. This is hugely important in a country such as Uganda", says Martin Singull.

The study analysed data from the Uganda Demographic Health Survey 2016. This survey collected information from 18,506 women aged 15-49 years and living in 15 regions in Uganda. Some special clinics, known as "fistula camps", have been set up in recent years to provide surgery for affected women. Data from two of these, in different parts of the country, were also included in the study.

The research found that significantly fewer women have received surgery at the clinics than expected.

"Our results show that Uganda has a huge backlog of women who should be treated for fistula. In one of the regions we looked at, we found that for each woman who had undergone an operation, at least eight more should have received care", says Betty Nannyonga.

The researchers have looked at the relationship between the resources required to provide surgery for the women after being injured and the corresponding resources used to give the women access to professional care during the pregnancy, which includes the availability of delivery by Caesarean section if required. Another chilling statistic that must be considered is that not only do the women suffer from fistula, but that the baby survives in only 9% of such cases.

The mathematical models demonstrate that the number of women who suffer from fistula decreases most rapidly if the resources are put into preventive maternity care, and making it possible for the women to give birth in hospital.

The authors point out, however, that several difficulties contribute to the relatively high occurrence of fistula.

"Even if professional healthcare and medical care are available in Uganda, most women do not enjoy good maternity care during their pregnancy. In some cases, this is because the distance to the healthcare providers is too far. Other reasons are the women do not have the money needed, or that they require permission from their husbands. It won't do any good to invest money in health centres if the women don't attend", says Betty Nannyonga.

The regions differ considerably in how they provide care. It is twice as likely that a woman in a town will see a doctor than it is for someone who lives in rural areas. Another factor is education: those with upper secondary education are twice as likely as those without, and having higher education than upper secondary increases the probability by a further factor of two. Social status also plays a major role: the probability of seeing a doctor on some occasion during the pregnancy is directly linked to income.

One positive trend shown by the statistics is an increase in the fraction of women who receive professional care during the delivery itself (although the figures are for only those cases in which a child is born alive). This has risen from 37% in the period before 2001, to 42% in 2006, 58% in 2011 and 74% in 2016.

"Our results show that professional care and surgery by themselves cannot prevent all cases of fistula: other measures will be needed", concludes Betty Nannyonga.

September 17, 2020 - For Black women in the southern United States, mistrust of the health care system that is grounded in structural and systemic racism is a key factor affecting participation in HIV prevention and treatment services, reports a study in the September/October issue of The Journal of the Association of Nurses in AIDS Care (JANAC). The official journal of the Association of Nurses in AIDS Care, JANAC is published in the Lippincott portfolio by Wolters Kluwer.

"[Our] results indicate that there are barriers to the utilization of health services that are grounded in personal experiences, historical mistrust for the health care system and systemic racism," according to the qualitative study by Schenita D. Randolph, PhD, MPH, of Duke University School of Nursing and colleagues. "HIV programs serving Black women should include conversations around structural racism and trust for both providers and patients."

"Dr. Randolph's findings are critical because they demonstrate women's own views of the critical and sometimes subtle ways in which systemic racism can have dramatic effects on African-American women's health through multiple pathways," said Dr. Carol Golin, Professor of Medicine and Public Health at the University of North Carolina at Chapel Hill. "This suggests that working to dismantle racism is a fundamental step that is needed to fully address health disparities." Dr. Golin was Principal Investigator of the community-based parent study in which the data were collected.

New Insights on Obstacles to Black Women's Participation in HIV Care

Disparities in HIV risk are an important public health issue for Black women, particularly in the South. "Black women have nearly 20 times the risk of white women in being infected with HIV, and lifetime HIV risk is greatest for people living in the southern United States," according to the authors.

In a previous study, authors identified Black women's perceptions of structural racism and discrimination, and medical mistrust, as critical factors in the development of HIV prevention programs and interventions. The new study further explored those perspectives through a series of focus groups with African-American women living in low-income housing communities in one small city in the South.

Although they did not use those exact terms, the participants consistently communicated that the concepts of structural racism and discrimination, and medical mistrust, had a significant impact on their health care decisions and participation. From the focus group discussions, four subthemes emerged:

Decreased trust in health care advice and instructions. Based on their experiences, some of the women perceived that health care professionals give incomplete or even false medical information to Black patients. They also viewed some medical facilities as being more trustworthy or more receptive to Black patients than others.

Systems and structures placing Black women at a disadvantage. "Institutional and systematic regulations" - especially policies related to living in low-income housing - contributed to mistrust of the health care system. Participants perceived that that the combination of being Black and being a woman added "a layer of challenges" to accessing health care. The women felt there were "little to no resources in the community to access affordable health care."

Lack of effective communication. The women reported experiences with lack of communication in the health care system, including misinformation and not receiving details of the care being given. Some women did report effective communication with providers - showing that taking time to build good communication and relationships can lead to improved health behaviors.

Need for empowerment in clinical encounters. Perceived racial bias in dealings with health care providers motivated the women to be more assertive in advocating for their rights. They felt they should be able to question health care recommendations and demand more information from providers.

"These findings support the importance for health care providers, as well as researchers, to be aware of systematic racism and structural discrimination that may be overt or covert in our health care systems," Dr. Randolph and coauthors write. They note that the focus group participants voiced a strong preference for HIV-related messaging and programming to be delivered by "trusted individuals or gatekeepers" in the community, whom they viewed are more relatable than health care providers. The findings also highlight the need for "careful attention to interpersonal relationships and communication in the clinical encounter with Black women."

"Findings on the understanding of Black women's skepticism of medical providers and systems reinforced and expanded our view of the importance of addressing these trust issues in future HIV prevention efforts with this population," the researchers write. "More importantly," Dr. Randolph comments, "findings expanded our view of the importance of addressing how our systems that are grounded in historical racism, contribute intentionally or unintentionally to the inequities of care among Black women."

Dr. Randolph and coauthors conclude: "This long history will require that critical conversations about structural and systemic racism and health take place to begin breaking deeply ingrained cycles of discrimination."

By Maria Fernanda Ziegler | Agência FAPESP – The typical measures of the efficacy of a country’s response to COVID-19 are the contagion curve and the number of deaths from the disease. Indeed, the frequently expressed aim of “flattening the curve” refers to a perceived need to slow the rate of transmission so that healthcare systems are not overwhelmed. An international group of researchers have set out to go beyond these indicators by discussing how and why the strategies implemented by countries to deal with the pandemic succeeded or failed.

The study is supported by FAPESP and coordinated by researchers at Getúlio Vargas Foundation (FGV) in São Paulo, Brazil, and the University of Michigan in the United States. A book will be published with comparative analyses of countries and regions. The project also calls for primary data collection during the pandemic, and for the creation of a repository as a basis for future studies, with news stories and data on political leaders, government communication, and public policies.

“I’m going to contribute to the comparative analysis of countries and the chapter on how Brazil has addressed the crisis. Brazil was very well positioned to deal effectively with the pandemic but unfortunately failed to do so. Its research and health infrastructure is relatively robust, and it has a strong track record in combating epidemics such as AIDS and zika. One of the main problems may have been science denialism, which was already advancing in response to climate change,” Elize Massard da Fonseca, a professor in FGV’s Department of Public Administration and principal investigator for the project, told Agência FAPESP.

According to Fonseca, the Brazilian government’s actions in the sphere of international relations and its reaction to the disclosure of deforestation data had already pointed to a degree of science denialism. “It’s possible to discern similarities between the response to the pandemic and environmental policy,” she said. “There was already a great deal of climate denial, and with regard to the Amazon, more importance has been placed on economic development than conservation. The emphasis is on contempt for science and a hypothetical opposition between these factors and the economy, which is groundless in both cases.”

Data is another issue and one that has become crucial. “Trustworthy data and information are essential for the planning and transfer of resources in the healthcare sector,” Fonseca said. “In the case of COVID-19, this is even more important. You need data almost in real-time for fast decision making on matters such as whether to end lockdown or buy equipment.”

Since Brazil restored democracy after the end of the military dictatorship (1964-85), the country has had reliable epidemiological and health surveillance data, Fonseca added. This is a sound basis for mapping regional differences and needs, including policies and programs to combat diseases such as AIDS.

“Brazil has various regionalized infectious disease monitoring systems that include planning information, so there was no doubt which regions would face the greatest difficulties in dealing with the pandemic and it was possible to formulate specific public policies for these regions,” she said.

It is very hard to obtain data, she continued, but one of the advantages of doing research in Brazil is the reliability of the data available. “In the case of the Health Ministry, this period is an exception. Since redemocratization, the ministry has been staffed by highly qualified professionals, although it also has many political appointees. That isn’t just an impression. It’s one of the findings from our group’s research, which includes profiling ministers, executive secretaries, and divisional heads since the 1980s. They’ve almost all been medics or other kinds of health professionals who know the health system well and understand the importance of having good data.”

Eye of the storm

A first paper with findings from the research project is published in the journal Global Public Health, arguing that the different responses to COVID-19 and their effects cannot be understood without an in-depth analysis of policy and politics in the various countries concerned. The authors propose four key focuses to understand the reasons for COVID-19 responses: social policies to manage the economic crisis and recovery, political regime (democracy or authoritarianism), formal political institutions including subnational governments, and state capacity, especially control of health care systems and public administration.

“The measures taken to deal with the pandemic tend to be similar because of the profile of the disease, the recommendations of the World Health Organization [WHO] and observation of what worked in the first countries affected, such as lockdown in Wuhan, or mass testing and tracing in South Korea,” Fonseca said. “We’re going to look at the fit between what worked well and the characteristics of the countries concerned, in a comparative analysis focusing on regional and institutional variables.”

Countries that suffered signal failures in the past are now displaying higher levels of efficacy. “South Africa, for example, responded very wrongly to the AIDS epidemic. The president at the time actually denied the importance of public policy to deal with it. Now, however, all these years later in a different epidemic the country’s response has been relatively effective,” she said.

Analyzing the response to a pandemic, including possible resurgences and fresh waves, requires a certain temporal distance, but at the same time, there is an urgent need to collect primary data and find explanations for successes and failures in combating COVID-19.

“It’s a very hard time to do analysis of any kind. We’re in the eye of the storm. Everything is happening at once. Any attempt to analyze crises and do research in social science requires distancing. So this project is a daunting challenge,” Fonseca said. “The phenomena we’re studying are highly dynamic and change constantly, but collecting primary data is very important and we’re one of the first groups in Brazil to undertake a comparative study of this kind with the aim of explaining what’s happening.”

The article “The comparative politics of COVID-19: The need to understand government responses” (doi: 10.1080/17441692.2020.1783340) by Scott L. Greer, Elizabeth J. King, Elize Massard da Fonseca and André Peralta-Santos can be read at: www.tandfonline.com/doi/full/10.1080/17441692.2020.1783340.

Journal

Global Public Health

DOI

10.1080/17441692.2020.1783340

Lugano, Switzerland, 18 September 2020 - Access to cancer medicines is highly unequal across Europe both for new drugs in development because of uneven access to clinical trials and for currently approved drugs due to huge disparities in healthcare spending by different countries, according to results from studies presented at ESMO 2020. (1,2)

Countries in Western Europe run a higher number of clinical trials for novel cancer treatments than countries in Eastern and Central Europe, showed an analysis of clinical trials active in different countries (1) that indicated large differences in access to new treatments in development for cancer patients depending on where they live.

"Our study gives us proof of what we previously suspected, that there is a huge asymmetry in the number of clinical trials for cancer treatments in different countries," said study co-author Dr Teresa Amaral, from University Hospital Tubingen, Germany.

"Having access to clinical trials confers several benefits to cancer patients. It means they can potentially access novel therapies earlier during the trial phase rather than having to wait for licensing and reimbursement," she explained. "Also, all trial participants benefit from the regular follow-up and monitoring involved in taking part in a clinical study."

The researchers searched the Clinicaltrials.gov database for interventional clinical trials in adults with tumours between 2009 and 2019. Analysing the number of trials in 34 European countries revealed huge differences. Albania had the lowest number of active clinical trials for cancer (0.14 clinical trials per 100 000 population) while Belgium had the highest number (11.06 per 100 000).

Further results showed that the total number of oncology clinical trials performed in European countries increased by 33% between 2010 and 2018, with a much greater increase in early phase trials (61% increase in phase I-II trials) than late-phase trials (7% increase in phase 2-3 trials).

Amaral suggested that this might be due to a shift in clinical trial design: "There is no longer a clear progression from first-in-human studies to phase 1, phase 2 and then much larger phase 3 trials. Instead we tend to have more trials in earlier phases, namely phase II, which might expand to later phases."

The increase in early phase trials was again asymmetrical and the growth rate depended on the baseline number of trials. "Countries need to have the necessary infrastructure and expertise to conduct trials of any type, including early phase trials."

"A higher number of phase I trials is a sign of more active research going on in a particular country, with the appropriate infrastructure and necessary incentives to conduct clinical trials," said Thomas Cerny, Professor of medical oncology at the University of Berne, Switzerland and member of the ESMO Principles of Clinical Trials and Systemic Therapy Faculty. "And the only way to develop new cancer drugs is to be able to put patients into clinical trials," he added.

"The difference in the number of clinical trials per head of population, with more trials in wealthier countries, means access to clinical trials and innovative drugs is just not possible for cancer patients living in many less wealthy countries." Although the study is descriptive, he considered it made best use of the available data to evaluate differences in clinical trial availability in different countries.

He added: "Clinical studies require a solid infrastructure in terms of personnel and equipment, and this depends on a country's overall financial situation. These requirements are increasing so the gap in clinical trial capacity is not likely to reduce soon."

"There is still a lot to do to increase access to clinical trials for cancer patients in different countries," agreed Amaral. "The voluntary harmonisation procedure, in which trial sponsors can submit trial documentation to several countries at the same time, has streamlined the process and reduced the approval time for trials. But more is needed to increase access to clinical trials in countries where the number of trials is currently low." The research group is currently exploring the reasons for the asymmetry to inform potential solutions.

A health economics analysis also reported at ESMO 2020 showed that wealthier European countries spent ten times as much as poorer countries per inhabitant on cancer medicines in 2018, following a similar pattern to that seen for clinical trials. (2)

"There was a huge difference in spending on cancer medicines," said lead author Dr Nils Wilking, from the Karolinska Instituet, Stockholm, Sweden. "We found that inequalities are mainly related to countries' economic strength and not to the disease burden of cancer."

The researchers estimated cancer-specific health expenditure for 31 countries (EU-27 plus Iceland, Norway, Switzerland and the UK) using national figures for 2018. Results showed the top spenders on cancer medicines were Austria, Germany and Switzerland (Euros 90 to 108 per capita) while the lowest spenders were the Czech Republic, Latvia and Poland (Euros 13 to 16). The largest differences in spending between countries were seen for immuno-oncology drugs.

"There are two main factors accounting for the differences in spending on cancer medicines: one is shortage of money and the other is drugs not being approved for use by some healthcare systems," suggested Wilking. He noted that, although the study did not consider data at the individual patient level, the difference observed in access to cancer medicines would affect patient outcomes.

Cerny commented: "It is difficult to assess the real costs in any country because systems vary in different countries and there are many hidden costs not reflected in the databases used. But the study essentially shows the more a country has to spend, the more its inhabitants have access to cancer medicines."

Considering how to widen access to cancer medicines, Wilking suggested: "We need a model in which we incentivise innovation of valuable medicines through outcome-based payment models and consider a disease area and what a society is able to pay for treatment." He added: "The work of health technology assessment organisations has been important and a critical scrutiny and evaluation of new drugs should always be applied."