Body

Philadelphia, Pa. - (November 18, 2019) - An upcoming clinical trial at Children's National Hospital will harness cardiopulmonary bypass as a delivery mechanism for a novel intervention designed to stimulate brain growth and repair in children who undergo cardiac surgery for congenital heart disease.

The NIH has awarded Children's National $2.5 million to test the hypothesis that mesenchymal stromal cells (MSCs), which have been shown to possess regenerative properties and the ability to modulate immune responses in a variety of diseases, collected from allogeneic bone marrow, may promote regeneration of damaged neuronal and glial cells in the early postnatal brain. If successful, the trial will determine the safety of the proposed treatment in humans and set the stage for a Phase 2 efficacy trial of what could potentially be the first treatment for brain damage in children with congenital heart disease. The study is a single-center collaboration between three Children's National physician-researchers: Dr. Jonas, Catherine Bollard, M.B.Ch.B., M.D., and Nobuyuki Ishibashi, M.D.

Dr. Jonas, chief of cardiac surgery at Children's National, will outline the trial and its aims on Monday, November 18, 2019, at the American Heart Association's Scientific Sessions 2019. Dr. Jonas was recently recognized by the Cardiac Neurodevelopmental Outcome Collaborative for his lifelong research of how cardiac surgery impacts brain growth and development in children with CHD.

Montreal, November 14, 2019 -- In Canada, 171,900 people injected drugs in 2016, up from 130,000 in 2011. In a study published in the American Journal of Public Health, researchers at the University of Montreal Hospital Research Centre (CRCHUM) estimated, using multiplier methods, the number of people who injected drugs in 11 of the 13 Canadian provinces (Nunavut and Northwest Territories not included) and reported a 30-per-cent increase in the period studied. The researchers also estimated how many people received medication for opioid use disorder and how many needle syringes were distributed.

Previous studies that estimated the number of people who inject drugs in Canada either reported for the whole country or for select cities only. This new study goes further and provides provincial and territorial estimates on the annual delivery of harm-reduction services for the prevention of HIV and the hepatitis C virus.

In its guidelines, the World Health Organisation suggests that at least 40 people should receive medication for opioid use disorder for every 100 people who inject drugs, and that each person who injects drugs should receive at least 200 sterile needle syringes per year.

"In 2016, we calculated that, for all of Canada, 66 people received medication for opioid use disorder for every 100 people who inject drugs, and that 291 needle syringes were distributed for each person who injects drugs. These data show that, overall, Canada is achieving targets set out by the World Health Organisation for harm-reduction delivery, but that success varies across the country," said first author Dr. Brendan Jacka, who at the time of the study was a postdoctoral research fellow in Dr. Julie Bruneau's lab at the CRCHUM.

Wide differences between provinces and territories

There was wide variation in service coverage across the country. The highest coverage of medication for opioid use disorder was found in Alberta and Prince Edward Island, where more than 150 people received it for every 100 people who injected drugs, while Manitoba provided the lowest, with 40 for every 100. Likewise, Alberta and Saskatchewan provided over 700 needle syringes per person who injected drugs in 2016, whereas Quebec, Yukon and Newfoundland and Labrador provided fewer than 200.

"In addition to greater investment in providing opioid agonist therapy and needle-syringe programs, we urgently require increased capacity and funding to measure and monitor injection drug use, harm-reduction coverage and treatment options for cocaine and methamphetamine-use disorder," said Dr. Jacka.

According to Dr. Bruneau, a researcher at the CRCHUM, "the study demonstrates the importance of harmonizing and implementing a set of indicators to prospectively follow progress. Indicators should be developed to document coverage, service access and delivery for populations most in need at the local, provincial and territorial, and national levels." She added that the study will also help measure stigma and barriers to care, in order to inform policies.

According to the researchers, a better understanding of the number of individuals possibly at risk was long needed to help provinces and territories more appropriately respond to epidemics of opioid overdose, methamphetamine and cocaine injection, and blood-borne virus transmission occurring across Canada.

An innovative strategy called Teens Against Tobacco Use showed promise as an effective strategy to deter tobacco use in middle and high school students, according to a research study by The University of Texas Health Science Center at Houston (UTHealth) School of Public Health.

The study appeared today in the American Journal of Preventive Medicine.

"The most important takeaway message is that Teens Against Tobacco Use is a promising model in tobacco prevention," said senior author Louis Brown, PhD, assistant professor of health promotion and behavioral sciences at UTHealth School of Public Health in El Paso, Texas.

The program, developed by the American Lung Association, the American Cancer Society, and the American Heart Association, partners teachers with youth interested in educating others about the dangers of tobacco.

Brown worked with the El Paso Independent School District to bring the tobacco prevention program to El Paso's teens with the help of the nonprofit Paso del Norte Health Foundation.

As part of the project, high school and middle school youth were trained to develop and present tobacco prevention messages to students in fourth through eighth grade in nine schools serving predominantly low-income Hispanic students in central El Paso. A total of 2,257 students took part in the evaluation. Classrooms were matched, with one classroom receiving the presentation first and the matched classroom receiving the presentation later, after the program had been evaluated.

Teachers from participating schools provided sample activities and coaching, but the students put together their own presentations. Some were particularly moving because they were taken from real life.

One student described growing up in a smoking household with the smell of tobacco smoke in her hair and clothes. Once someone had doused a cigarette butt in an open soda can, which she discovered when she took a drink. Another presenter described how his mother's smoking during pregnancy stunted his growth.

After sharing their stories, presenters were successful in getting many children in the classrooms to talk about smokers in their families, many of whom had chronic illnesses or had died because of the habit.

The students in the program took their advocacy further, speaking to the city council about a clean air ordinance.

"Their message was very persuasive, in part because of their passion, but also because adults are supposed to protect the health of our youth," said Brown. The city council passed the ordinance the students supported.

Students also did a cleanup event at a city park, flagging the places they found cigarette butts to highlight the problem of tobacco litter on playgrounds.

The results showed that students in the classrooms that received the tobacco prevention presentation had significantly lower tobacco susceptibility scores than classrooms that had not received the presentation - 12% in the early presentation group versus 17% in the latter group.

DUARTE, Calif. -- The first CAR T cell therapy targeting the B cell-activating factor receptor on cancerous cells eradicated CD19-targeted therapy-resistant human leukemia and lymphoma cells in animal models, according to City of Hope research published today in Science Translational Medicine. The new therapy will be used in a clinical trial next year for patients who relapsed after CD19 immunotherapy treatments and may potentially be used as a first-line of CAR T cell therapy treatment.

An estimated 20 to 30% of leukemia and lymphoma patients who achieve remission after receiving CD19 CAR T therapy will relapse after a few years. The effectiveness of those CAR T cells, which target the CD19 protein on cancerous B cells, starts to wear off and the cancer returns.

But there new hope for those patients who relapse after receiving axicabtagene ciloleucel (commercial name: Yescarta) or tisagenlecleucel (commercial name: Kymriah), the Food and Drug Administration-approved CD19 CAR T cell therapies, as well as another type of CD19-targeted immunotherapy, blinatumomab (commercial name: Blincyto).

"One major obstacle to current CAR T therapy is that in up to a third of these patients, the tumor is actually smart and comes back because it has learned how to no longer express the target that's recognized by the original immunotherapy," said Larry Kwak, M.D., Ph.D., vice president and deputy director of City of Hope's comprehensive cancer center and the study's principal author, who leads the research with Hong Qin, Ph.D., a research professor in City of Hope's Department of Hematology & Hematopoietic Cell Transplantation. "To combat that, City of Hope research has found a new, and potentially more effective, target for CAR T cell therapy against B cell leukemias and lymphomas. We plan to open a clinical trial next year using the BAFF-R CAR T cell therapy."

"This new treatment could change the face of leukemia and lymphoma treatment in the U.S. and worldwide," added Kwak, the Dr. Michael Friedman Professor in Translational Medicine.

CAR T cell therapy involves taking a patient's T cells from the bloodstream. The immune cells are then genetically engineered in a laboratory to recognize and attack a specific cancer-associated protein, such as BAFF-R, and reintroduced into the patient's bloodstream, where they get to work destroying tumor cells.

For this study, animal models with CD19 therapy-resistant human-tumors (including Burkitt, mantel cell, and other non-Hodgkin's lymphoma subtypes and acute lymphoblastic leukemia) received BAFF-R CAR T therapy. Remarkable tumor regression and prolonged survival were observed after treatment with these CAR T cells. In animal models with human Burkitt lymphoma, BAFF-R CAR T therapy achieved a cure (complete tumor regression with 100% long-term survival) after a single treatment.

For another part of the study, the animal models had a mixed population of CD19-positive and negative human tumors. They then received either CD19 CAR T cell therapy or BAFF-R CAR T cell therapy; the BAFF-R CAR T cells were able to eradicate both tumor populations while treatment failed in those receiving CD19 CAR T cells.

Tumor samples from patients who relapsed after receiving CD19-targeted immunotherapy (blinatumomab) were also investigated. The study demonstrated that BAFF-R CAR T cells were consistently active against these tumors, whereas CD19 CAR T cells had greatly diminished responses to each patient's relapse tumor compared to the pre-therapy samples.

"We did a head-to-head comparison of two new therapies, and our data showed that our BAFF-R CAR T therapy actually did a better job than FDA-approved CD19 CAR T therapies," Qin said. "If these results continue, we will pursue BAFF-R CAR T therapy as a kind of frontline CAR T therapy treatment for lymphoma and leukemia patients."

City of Hope plans to open a clinical trial next year using the BAFF-R CAR T cell therapy for B cell leukemia and lymphoma patients who have relapsed after receiving CD19 CAR T cell therapies or blinatumomab.

When the BAFF-R CAR T trial opens, City of Hope will manufacture the CAR T cells using in its own facility, the Cellular Therapy Production Center. This process includes a critical step: collecting patients' T cells and genetically engineering the T cells with viruses also produced at a City of Hope GMP facility, the Center for Biomedicine & Genetics. These two facilities, coupled with the Chemical GMP Synthesis Facility, make City of Hope one of the few cancer centers in the world with the ability to produce GMP cellular, genetic and drug-based therapies for its patients.

City of Hope licensed the BAFF-R CAR T to Pepromene Bio Inc.

Web-based and digital-app services that offer oral contraception appear to be overall safe and efficient, according to the findings of a secret-shopper-style study conducted by researchers at Harvard Medical School and UC Davis that analyzed the birth control prescription services of nine U.S. vendors.

The results, published Sept. 26 in The New England Journal of Medicine, offer a measure of reassurance amid concerns over the safety and reliability of a rapidly growing model of care delivery that gives individuals online access to treatments ranging from birth control and erectile dysfunction medication to hair-loss drugs.

"For most health conditions, a visit to the doctor remains essential, but there are certain clinical scenarios for which this model appears to be overall safe and efficient," said study senior author Ateev Mehrotra, an associate professor of health care policy and of medicine in the Blavatnik Institute at Harvard Medical School and a hospitalist at Beth Israel Deaconess Medical Center.

Yet, despite the overall safety and efficiency of the services, some gaps do remain, the study found.

While the providers adhered closely to CDC prescribing guidelines and were efficient at delivering oral contraceptive pills, they failed to counsel patients about other forms of birth control, such as long-lasting, reversible contraception, which do require an in-person clinical visit. Also, none of the providers included questions in their screening checklists to ensure the patients could comply with a daily pill regimen. Another improvement, the authors said, could be augmenting the questionnaire to screen for several rare health conditions that would render birth control unsafe.

These are all important features that could optimize both the safety and efficacy of the services offered, the researchers said.

"Business innovators have an important role to play in improving our health system, as they move quickly to find new ways to meet unmet needs with new technology and new ways of thinking about care delivery," said study first author Tara Jain, a student at Harvard Medical School. "But it's also crucial to have physicians involved to help think about how these new tools and models can best be used to increase access safely and to help people get the best care possible."

The advent of new forms of care delivery, including Web-based and smart phone medication prescription services, has left many public health researchers and practicing physicians both wary and hopeful. Questions have lingered over the safety of online providers and their ability to adhere to established guidelines. At the same time, these providers have the potential to address an unmet need by expanding access to medications, particularly for populations that are underserved in the current health care system, such as women who don't have access to reproductive health services or those living in "contraceptive deserts"--communities without health centers that provide birth control.

"Many women are turning to these apps and websites for contraceptives, but not much was known about the process of using them or whether they're doing a good job of providing safe, appropriate care," Jain said. "We wanted to take a look to see how these vendors really work."

For their study, the researchers recruited volunteers to assume the roles of patients and purchase birth control online. Some of the "patients," were taking medications or had characteristics or medical conditions that would rule them out as candidates for oral contraception. The secret shoppers presented to nine online contraception vendors that offered services in the United States. Between October 2018 and March of 2019, the "patients" completed a total of 63 visits requesting oral birth control.

The online visits lasted, on average, between seven and eight minutes. If a patient presented with a contraindication for oral birth control--certain medical conditions including history of deep-vein clots or migraine, for example--they would receive a text message, a phone call or a video call from the prescriber to discuss further. Some prescriptions were sent to a local pharmacy for immediate pickup. In other instances, pills were mailed directly to the customer, arriving within a week, on average.

Many of the vendors accepted health insurance. For an uninsured customer, the average cost of a 12-month prescription, including the cost of initial visits, was $313 (ranging from $67 to $519). This is slightly less than the cost of obtaining the prescription through a doctor's visit, the researchers said.

The analysis also showed that online vendors adhered to CDC prescribing guidelines 93 percent of the time. These guidelines ensure that oral birth control is not given to patients with certain medical conditions or to those receiving medications that may interfere with the safety and efficacy of birth control medications. Patients with contraindications for oral birth control received prescriptions in three of 45 instances, sometimes because they presented with relatively rare conditions not highlighted in the guidelines that might easily be missed during an in-person visit, too, the researchers said.

The robust adherence to guidelines observed in the study likely stems from the use of automated checklists, the researchers said.

Deployed properly, automation and checklists have great potential to improve clinical care, the researchers added. For example, computer algorithms that conduct the initial screening for certain routine conditions could alleviate physician workload and ease flow in clinics and offices, allowing clinicians to spend time on more complex tasks and cases.

"People aren't good at checklists, but computers are very good at checklists, and for certain conditions and certain scenarios, checklists may greatly optimize performance," Mehrotra said. "Our findings are yet another example that medicine can learn a great deal from other industries that have seen great leaps in productivity by introducing automation."

UCLA RESEARCH ALERT

FINDINGS

Researchers at the UCLA Jonsson Comprehensive Cancer Center have identified a new drug delivery pathway that may help stop tumor growth and keep cancer from coming back in mice. In the preclinical study, the team found that they could reengineer adipocytes -- fat cells that feed fatty acids energy needed to promote tumor growth and metastasis -- to reverse their malignant role on tumor development and deliver cancer-fighting drugs directly to the tumor microenvironment.

BACKGROUND

The course of treatment for many people with a solid tumor includes surgery with chemotherapy, radiotherapy, or immunotherapy. Well there have been many improvements in treatment techniques over the past decade, the cancer often comes back after therapy and can be even more aggressive. In order to stop the cancer from recurring, drugs need to be delivered directly to the diseased site. Since fat cells are widely present in the human body and can be easily isolated and purified, the UCLA-led team thought they might be able to serve as a highly efficient drug delivery system. However, tumor cells trigger the fat cells to release the fatty acid to support tumor growth. To overcome this problem, researchers added anticancer therapeutics to fat cells to make them work as a Trojan horse once delivered into the tumor site.

METHOD

The team tested the new drug delivery system by using UCLA-engineered fat cells to carry lipid-linked doxorubicin, a chemotherapy drug commonly used to treat cancer, and found the drug was able to successfully load into the lipid droplets consisting of an anticancer fatty acid within the fat cells. Linking the fat-soluble lipid molecule to doxorubicin can help reduce toxicity of the drug toward fat cells and enhance drug loading capability inside the fat cells. Once injected such fat cells into the tumor site or surgical site with residual tumor tissues, the encapsulated anticancer doxorubicin and fatty acid can be gradually released toward the tumor cells through lipid metabolism, subsequently inhibiting tumor growth and recurrence. Inside tumor cells, the lipid linked to doxorubicin can be effectively cleaved to show the killing effect of doxorubicin.

IMPACT

By utilizing fat cells with a therapeutic capsule, the team was able to demonstrate that the lipid metabolism pathway can be utilized for tumor specific drug delivery and drug development. This research also indicated that tumor supportive cells within the tumor tissue could serve as Trojan horse for cancer therapy. The approach could not only be useful for delivering cancer drugs to tumors, but could potentially be applied to other lipid metabolism related diseases.

Bottom Line: Among 123,000 patients in the U.S. Department of Veterans Affairs health system with newly diagnosed diabetes, 23% had mental health or substance use disorder diagnoses and that prior engagement with the health care system may be associated with a lower severity of complications for a few years after the onset of diabetes. More than 90% of patients with mental health or substance use disorders had primary care visits before diabetes was diagnosed compared with 58 percent of patients without those disorders. Patients with already diagnosed mental health and substance use disorders had lower overall, but more quickly progressing, complication severity scores through seven years after a diabetes diagnosis than those patients without, even after accounting for other mitigating factors such as coexisting illnesses. Study authors speculate patients with diagnosed mental health or substance use disorders likely were already being treated for other conditions, such as hypertension, when diabetes was diagnosed. Limitations of the study include missing data.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Eric Schmidt, Ph.D., Veterans Affairs Palo Alto Health Care System, Menlo Park, and Stanford University, Stanford, California, and coauthors

(doi:10.1001/jamanetworkopen.2019.112060)

Editor's Note: The article contains funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

 #  #  #

Media advisory: To contact corresponding author Eric M. Schmidt, Ph.D., email Kim Betton at Kim.Betton@va.gov">Kim.Betton@va.gov. The full study is linked to this news release.

Embed this link to provide your readers free access to the full-text article This link will be live at the embargo time: http://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2019.12060?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=092519

About JAMA Network Open: JAMA Network Open is the new online-only open access general medical journal from the JAMA Network. Every Wednesday and Friday, the journal publishes peer-reviewed clinical research and commentary in more than 40 medical and health subject areas. Every article is free online from the day of publication.

Men who became fathers through assisted reproduction techniques seem to be at higher risk for prostate cancer and early onset prostate cancer compared with men achieving fatherhood naturally, concludes a study published by The BMJ today.

The findings suggest that these men may benefit from early screening and long term monitoring for prostate cancer.

Prostate cancer and male infertility are both very common disorders, affecting approximately 10% and 8%, respectively, of all men in Western societies.

As prostate cancer and many forms of infertility are male sex hormone related, a possible link between them has been investigated previously. But study weaknesses have so far prevented researchers from drawing any firm conclusions.

So a team of researchers based in Sweden set out to compare the risk and severity of prostate cancer between men achieving fatherhood for the first time by assisted reproduction and men conceiving naturally.

Their findings are based on data from national registers for over one million children born alive in Sweden during 1994-2014 to the same number of fathers.

Fathers were grouped according to fertility status by mode of conception: 20,618 (1.7%) by in vitro fertilisation (IVF), 14,882 (1.3%) by sperm injection (ICSI), and 1,145,990 (97%) by natural conception.

The average age at childbirth was 37 years for both IVF and ICSI treated fathers, and 32 years for fathers who conceived naturally. Cancer registries were used to identify new cases of prostate cancer up to 20 years after childbirth.

After adjusting for factors that could have affected the results, such as age and education level, the researchers found that men becoming fathers through IVF and ICSI had a significantly higher risk of prostate cancer than men who fathered children naturally.

Among men achieving fatherhood naturally, 3,244 (0.28%) were diagnosed as having prostate cancer, compared with 77 (0.37%) in the IVF group and 63 (0.42%) in the ICSI group.

The risk of early onset prostate cancer (diagnosed before age 55 years) was also particularly high for men fathering children through ICSI, a technology used for men with the most severe forms of infertility.

These increased risks remained after excluding men with a previous cancer diagnosis or who received testosterone replacement therapy.

This is an observational study, and as such, can't establish cause, and the authors point to some limitations. For example, they did not include infertile men who were unable to father children, and who may have a higher risk of prostate cancer than those who managed to become fathers.

What's more, with an average age of 45 years at end of follow-up, these results cannot quantify prostate cancer risk over a lifetime.

Nevertheless, they conclude: "Men who achieved fatherhood through assisted reproduction techniques, particularly through ICSI, are at high risk for early onset prostate cancer and thus constitute a risk group in which testing and careful long term follow-up for prostate cancer may be beneficial."

How male infertility could be linked biologically to risk of prostate cancer is not yet clear, but abnormalities on the Y chromosome linked to both infertility and prostate cancer, are a possibility, say researchers in a linked editorial.

However, screening is controversial owing to lack of survival benefit and the harms from overdiagnosis and overtreatment that can follow a positive screening test, they warn.

"In the absence of a plausible mechanism of action or proof of causation, justifying screening for prostate cancer in all infertile men is difficult," they write. "However, further research on the possible future complications of male infertility would be welcomed by patients and will help clinicians to counsel all infertile men about their future health."

Immunodeficiency is the condition where the capability of the immune system to fight against diseases has been compromised. Immunocompromised people have a higher chance of contacting diseases compared to people with healthy immune systems. Immunodeficiency usually occurs as a consequence of several factors, such as diseases like AIDS and diabetes, chemotherapy, and organ transplant. Recently, doctors have noted an increased trend in the occurrence of life-threatening fungal infections--also called mycoses--in immunocompromised patients. In such cases, treatment requires the use of some special compounds with antifungal properties. Unfortunately, antifungal drugs currently available are very limited.

In 2006, a lead compound "eushearilide," derived from fungi, was discovered. It was found to have antifungal and antiyeast properties, and could tackle several fungi that were known to cause infections in humans. A team of scientists from the Tokyo University of Science had previously explored the unique chemical structure and the method of synthesis of eushearilide. Now, this research group, led by Prof. Isamu Shiina of the Tokyo University of Science--which also includes Takayuki Tonoi (Tokyo University of Science), Katsuhiko Kamei (Medical Mycology Research Center, Chiba University) and Naruhiko Ishiwada (Medical Mycology Research Center, Chiba University)--has used their previous findings to derive compounds from eushearilide that may have improved beneficial effects. This study is published in the journal Molecules. Their aim, Prof. Shiina explains, was "to look at the antibacterial effects on various fungi and bacteria of the new antibacterial lead compound 23-demethyleushearilide, colloquially called 'usharelide,' derived from eushearilide."

For this, first, usharelide had to be derived from eushearilide. This was achieved through a set of reactions involving the alteration of molecules attached at the 23rd carbon atom of eushearilide. Once usharelide and its structural variations were derived, they were tested for their antibiotic properties, specifically against fungi and bacteria. The researchers found that these compounds had significant promising antibiotic properties. In particular, two of the several variations of usharelide showed antimicrobial properties against Candida albicans, a fungus that is the instigator of yeast infections. Meanwhile, most of the variations showed antimicrobial properties against Cryptococcus neoformans, which causes lung infections, meningitis, and encephalitis, particularly in AIDS patients. This finding echoed the previous findings on the antifungal properties of eushearilide. However, what was even more interesting is that these usharelide variations also showed good antibacterial properties against several disease-causing bacterial species, including methicillin-resistant Staphylococcus aureus (MRSA), which is known to be a particularly difficult bacterium to tackle due to its resistance to several antibiotics and causes potentially fatal infections, particularly in people with weak immune systems.

These findings emphasize the unique status and importance of eushearilide and its derivative usharelide in the treatment of several fungal diseases in immunocompromised people. More significantly, these findings also shed light on the possible antibacterial properties of these compounds, which have not been adequately explored in research before. Usharelide has the potential for application in the treatment for patients with fungal diseases such as candidiasis, and in the elimination of hospital-origin infections caused by MRSA and vancomycin-resistant enterococci. Prof. Shiina stresses on the importance of further studies, stating, "Antibiotic properties of eushearilide derivatives are not only against various fungi but also against bacteria, especially important drug-resistant bacteria such as MRSA. This is a novel finding that definitely warrants deeper research, given the urgent need for MRSA treatment options."

This study definitely promises to be a step in the right direction for treating recalcitrant infections in immunocompromised people caused by dangerously pathogenic bacteria, which were once thought to be unconquerable.

New data from TAILORx, the federally funded, phase three clinical trial, will be presented as late-breaking information at the European Society for Medical Oncology (ESMO) 2019 Congress in Barcelona, Spain.

Concurrently, JAMA Oncology will publish the results. Reporters may access the original manuscript under embargo through https://media.jamanetwork.com/. The data is under strict embargo until Monday, September 30, 2:45 PM, Central European Time.

This secondary analysis of the prospective TAILORx trial will focus on the arm that received chemotherapy plus endocrine therapy to prevent recurrence, based on a score of 26-100 on the 21-tumor gene recurrence score assay.

TAILORx was designed and conducted by the ECOG-ACRIN Cancer Research Group with primary funding from the National Cancer Institute, part of the National Institutes of Health.

ESMO presentation information is as follows:

Session Type: Late-Breaking Abstract, Proffered Paper Session

Session Title: Proffered Paper - Breast Cancer, Early Stage

Title: Clinical Outcomes by Chemotherapy Regimen in Patients with RS 26-100 in TAILORx (ID 6136)

Presentation Number: LBA18

Date and Time: Monday, September 30, 2:45 - 3:00 PM Central European Time

Location: Cordoba Auditorium (Hall 7)

Speaker: Joseph Sparano, MD (Albert Einstein Cancer Center and Montefiore Health System, Bronx, NY, USA)

The federal trial record for TAILORx is (NCT00310180).

How and Why Does Parkinson's Disease Effect Women and Men Differently?

Scientists review the different clinical features, risk factors, responses to treatments, and mechanisms underlying the disease pathophysiology of Parkinson's disease in women and men in the Journal of Parkinson's Disease

Amsterdam, NL, September 25, 2019 - There is growing evidence that Parkinson's disease (PD) affects women and men differently. In this insightful review, published in the Journal of Parkinson's Disease, scientists present the most recent knowledge about these sex-related differences and highlight the significance of estrogens, which play an important role in the sex differences in PD.

PD is a slowly progressive disorder that affects movement, muscle control, and balance. It is the second most common age-related, neurodegenerative disorder, affecting about 3% of the population by the age of 65 and up to 5% of individuals over 85 years of age. The risk of developing PD is twice as high in men than women, but women experience a more rapid disease progression and a lower survival rate.

"It is becoming increasingly evident that PD differs in women and men," explained lead author Fabio Blandini, MD, Scientific Director of the IRCCS Mondino Foundation, National Institute of Neurology, Pavia, Italy. "Recent research findings suggest that biological sex also impacts on disease risk factors and, potentially, on molecular mechanisms involved in the pathogenesis of PD."

This review meticulously examines the most recent knowledge concerning differences between women and men with PD including:

* Motor and non-motor symptoms

Quality of life

Genetic and environmental risk factors

Pharmacological therapy of motor and non-motor symptoms

Surgical procedures

PD and steroids

Impact of biological sex on pathophysiology

Recent research has shown that women and men have distinctive motor and non-motor symptoms as their PD progresses. Motor symptoms emerge later in women: tremor is a common first presenting symptom associated with recurrent falls and more severe pain syndromes with specific characteristics such as reduced rigidity, a higher propensity to develop postural instability, and elevated risk for levodopa-related motor complications. Conversely, male PD patients show more serious postural problems and have worse general cognitive abilities: freezing of gait - the most disabling motor complication of PD - develops later in men; however, men have a higher risk of developing camptocormia (abnormal severe forward flexion of the trunk when standing or walking). An ongoing clinical trial is evaluating the prevalence in PD and the biological sex impact on other postural abnormalities, such as Pisa syndrome (a reversible lateral bending of the trunk with a tendency to lean to one side), antecollis (dystonia of the neck resulting in excessive forward flexion), scoliosis (a sideways curvature of the spine), and deformities related to hands and/or toes.

Non-motor symptoms have been the subject of a study of over 950 PD patients, which concluded that symptoms such as fatigue, depression, restless legs, constipation, pain, loss of taste or smell, weight change and excessive sweating are more common and severe in women. Other studies have demonstrated that male PD patients have worse general cognitive abilities and male sex is the primary predictive factor for mild cognitive impairment and its more rapid progression in the severe stage of the disease. A diagnosis of PD with dementia has a greater impact on life expectancy of women than men; in addition, women show distinctive symptoms as well as differences in the response to pharmacological therapies and deep brain stimulation, and in their personal evaluation of the quality of life compared to men.

The authors note that the distinctive clinical features as well as the contribution of different risk factors support the idea that PD development might involve distinct pathogenetic mechanisms (or the same mechanism but in a different way) in women and men. They highlight the significance of estrogens, which play an important role in the sex differences in PD, providing disease protection as demonstrated by the similar incidence of the disease in men and post-menopausal women.

"Sex hormones act throughout the entire brain of both males and females and sex differences are now highlighted in brain regions and functions not previously considered as subjected to such differences, opening the way to a better understanding of sex-related behavior and functions," added Silvia Cerri, PhD, head of the Laboratory of Cellular and Molecular Neurobiology of the IRCCS Mondino Foundation and first author of the article. She commented: "Neuroinflammation is an important piece of the pathogenic puzzle of PD. Current evidence suggests that the physiological role exerted by microglial and astrocytic cells could become compromised during aging, thus contributing to PD onset and progression. Since estrogens have anti-inflammatory properties, their actions throughout the lifespan could partially account for sex-related risk and manifestation of PD."

By drawing attention to sex-related differences and disparities in PD, Dr Blandini and colleagues hope this will further encourage the scientific community and policy makers to foster the development of tailored interventions and the design of innovative programs - for example in care practices - that meet the distinct requirements of women and men with PD. "Women diagnosed with PD are a sizable portion of the PD population, but their specific needs are still partially overlooked. The differences between women and men strongly suggest the need for a personalized (sex-related) therapy in PD," concluded Dr. Blandini and Dr. Cerri.

Researchers at the University of Luxembourg have discovered a flaw in the security standard used in biometric passports (e-passports) worldwide since 2004. This standard, ICAO 9303, allows e-passport readers at airports to scan the chip inside a passport and identify the holder.

Most passports today use the standard ICAO 9303, which is issued by the International Civil Aviation Organization (ICAO). The standard is designed to ensure that the privacy and unlinkability of the passport holder is protected to the highest degree. Unlinkability ensures that an attacker could not distinguish if two elements are closely related.

Dr. Ross Horne, Prof. Sjouke Mauw, PhD candidate Zach Smith and Master student Ihor Filimonov tested the standard. They discovered a flaw which allows specific non-authorised equipment to access passport data. "With the right device, you can scan passports in close vicinity and reidentify previously observed passport holders, keeping track of their movements", Dr. Horne explains. "Thus, passport holders are not protected against having their movements traced by an unauthorized observer."

Limits and implications of the flaw

An unauthorised device scanning a passport within several meters can identify and keep track of that passport, even though it cannot read the passport. Thus, the privacy of the passport holder are vulnerable to potential attacks, even though the flaw does not allow attackers to read all information from a given passport or to compromise biometric information stored in a chip inside the passport.

"As most passports today use the same standard, this security flaw potentially has global impact," continues Dr Horne. In Europe, such a security breach likely violates requirements from the EU data protection framework. Governments have the responsibility to protect individual privacy and to ensure that official documents are bulletproof against such attacks.

The team of researchers shared their test results with ICAO in June 2019. They also outlined several approaches for restoring privacy protection, based on the assumption that the manufacturers of e-passport readers must take responsibility for ensuring privacy protection of passport holders.

Cancer cells appear to adapt to treatment with checkpoint blocker drugs by altering a metabolic process, leading to shorter survival for patients

The findings could help identify patients who might benefit from combination therapy with a checkpoint blocker and another inhibitor

BOSTON -- A metabolic imbalance in some cancer patients following treatment with a checkpoint inhibitor drug, nivolumab, is associated with resistance to the immunotherapy agent and shorter survival, report scientists from Dana-Farber Cancer Institute, in collaborative work with the Broad Institute of MIT and Harvard.

The chemical change, which the investigators say reflects an "adaptive resistance mechanism" by cancer cells or the immune system in response to treatment with the PD-1 antibody drug nivolumab, was linked to worse survival in patients with advanced melanoma and kidney cancer. The greater the change - the conversion of the amino acid tryptophan to a metabolite called kynurenine - the larger the impact on survival.

"The main message is that metabolic adaptations in cancer immunotherapy may be relevant after immune checkpoint blockade," said Toni K. Choueiri, MD, co-senior author of the paper with Marios Giannakis, MD, PhD. Their report is published in Nature Communications. Metabolic processes are those chemical reactions in the body necessary to sustain life, such as the conversion of food to energy to run cellular processes.

Checkpoint blockers such as nivolumab are drugs that release the molecular brakes on the immune response that cancer often uses to escape attack by immune T cells. One such molecular brake is known as PD-1. In some patients and some cancer types the drugs have proven highly effective in unleashing the T cell attack on tumors, but overall, the drugs help only a minority of patients. "One of the most important questions in oncology is who responds and who doesn't to modern PD-1 inhibitors," said Choueiri, Director of the Lank Center for Genitourinary Oncology at Dana-Farber.

Scientists have studied cancer tissue specimens to look for factors that may be associated with greater or lesser effect of checkpoint inhibitors: among them are the number of cancer-related mutations found in the tumors' DNA, and other genetic "signatures" associated with response to checkpoint blockers. The metabolic alteration the scientists found in the current study could be measured in the bloodstream - a significant advantage over tissue-based tests.

"This is an attractive option for identifying biomarkers of metabolic changes" related to treatment with checkpoint blockers, said Giannakis, assistant professor of medicine at Dana-Farber and Harvard Medical School. "We know that metabolism is important in immunity, and kynurenine [the chemical found to be elevated in a majority of the patients treated with nivolumab] is known to be immunosuppressive."

In this study, the researchers analyzed blood samples from three independent immunotherapy trials and measured changes in metabolites [chemicals involved in metabolic reactions] before treatment started and at several points during treatment. In melanoma patients, 78% had increases in the tryptophan to kynurenine conversion and 26.5% had increases of greater than 50% at week four of treatment. In the kidney cancer patients, nivolumab treatment was also associated with increases in kynurenine.

The analysis showed that melanoma and kidney cancer patients with higher levels of tryptophan to kynurenine conversion on nivolumab had worse survival: In particular, individuals with melanoma whose blood tests showed a greater than 50% increase in the kynurenine and tryptophan ratio had a median survival of 15.7 months, while those with decreases in this ratio had a median survival time of more than 39 months whereas the respective number for patients with kidney cancer were 16.7 versus 31.3 months.

Exactly how treatment with PD-1 checkpoint blockers causes tryptophan to be converted to kynurenine isn't known. However, an enzyme known as IDO, which has been implicated in many forms of cancer, plays a major role in synthesizing kynurenine from tryptophan. The Dana-Farber researchers noted that a randomized clinical trial in which advanced melanoma patients were treated with IDO inhibitors alone did not yield positive results. However, that study did not look at the kynurenine levels of these patients. The researchers said their results suggest that combining checkpoint blockers with IDO inhibitors might "benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation."

BEER-SHEVA, ISRAEL...September 25, 2019 - In a new study of adolescent and adult athletes, researchers at Ben-Gurion University of the Negev, Stanford University and Trinity College in Dublin have found evidence of damage to the brain's protective barrier, without a reported concussion.

For the first time, the researchers were able to detect damage to the blood-brain barrier (BBB), which protects the brain from pathogens and toxins, caused by mild traumatic brain injury (mTBI). The results were published this month in the Journal of Neurotrauma.

The researchers studied high-risk populations, specifically professional mixed martial arts (MMA) fighters and adolescent rugby players, to investigate whether the integrity of the blood-brain barrier (BBB) is altered and to develop a technique to better diagnose mild brain trauma.

"While the diagnosis of moderate and severe TBI is visible through magnetic resonance imaging [MRI] and computer-aided tomography scanning [CT], it is far more challenging to diagnose and treat mild traumatic brain injury, especially a concussion which doesn't show up on a normal CT," explains Prof. Alon Friedman, M.D., Ph.D. Dr. Friedman is a groundbreaking neuroscientist and surgeon, who established the Inter-Faculty Brain Sciences School at BGU.

The study shows that mild impact in professional MMA and adolescent rugby can still lead to a leaky BBB. If in a larger study the results are similar, the brain imaging techniques being developed could be used to monitor athletes to better determine safer guidelines for "return to play."

In this study, MMA fighters were examined pre-fight for a baseline and again within 120 hours following competitive fight. The rugby players were examined pre-season and again post-season or post-match in a subset of cases. Both groups were evaluated using advanced MRI protocol developed at BGU, analysis of BBB biomarkers in the blood and a mouthguard developed at Stanford with sensors that track speed, acceleration and force at nearly 10,000 measurements per second.

Ten out of 19 adolescent rugby players showed signs of a leaky blood-brain barrier by the end of the season. Eight rugby players were scanned post-match and two had barrier disruptions. The injuries detected were lower than the current threshold for mild head trauma. The researchers were also able to correlate the level of blood-brain barrier damage seen on an MRI with measurements from the mouthguard sensors.

"The current theory today is that it is the outer surface of the brain that is damaged in a concussion since, during an impact, the brain ricochets off of skull surfaces like Jell-O," Dr. Friedman says. "However, we can see now that the trauma's effects are evident much deeper in the brain and that the current model of concussion is too simplistic."

In the next phase of research, the group plans to conduct a similar study in a larger cohort to determine whether BBB disruptions heal on their own and how long that takes.

"It is likely that kids are experiencing these injuries during the season but aren't aware of them or are asymptomatic," Dr. Friedman says. "We hope our research using MRI and other biomarkers can help better detect a significant brain injury that may occur after what seems to be a 'mild TBI' among amateur and professional athletes."

DALLAS - Sept. 25, 2019 - The psychiatry field has long sought answers to explain why antidepressants help only some people.

Is a patient's recovery due merely to a placebo effect - the self-fulfilling belief that a treatment will work - or can the biology of the person influence the outcome?

Two studies led by UT Southwestern provide evidence for the impact of biology by using artificial intelligence to identify patterns of brain activity that make people less responsive to certain antidepressants. Put simply, scientists showed they can use imaging of a patient's brain to decide whether a medication is likely to be effective.

The studies include the latest findings from a large national trial (EMBARC) intended to establish biology-based, objective strategies to remedy mood disorders and minimize the trial and error of prescribing treatments. If successful, scientists envision using a battery of tests such as brain imaging and blood analyses to increase the odds of finding the right treatment.

"We need to end the guessing game and find objective measures for prescribing interventions that will work," said Dr. Madhukar Trivedi, who oversees EMBARC and is founding Director of UT Southwestern's Center for Depression Research and Clinical Care. "People with depression already suffer from hopelessness, and the problem can become worse if they take a medication that is ineffective."

Brain activity

The studies - which each included more than 300 participants - used imaging to examine brain activity in both a resting state and during the processing of emotions. Both studies divided the participants into a healthy control group and people with depression who either received antidepressants or placebo.

Of the participants who received medication, researchers found correlations between how the brain is wired and whether a participant was likely to improve within two months of taking an antidepressant.

Dr. Trivedi said imaging the brain's activity in various states was important to get a more accurate picture of how depression manifests in a particular patient. For some people, he said, the more relevant data will come from their brains' resting state, while in others the emotional processing will be a critical component and a better predictor for whether an antidepressant will work.

"Depression is a complex disease that affects people in different ways," he said. "Much like technology can identify us through fingerprints and facial scans, these studies show we can use imaging to identify specific signatures of depression in people."

Improving outcomes

Data from both studies derive from the 16-week EMBARC trial, which Dr. Trivedi initiated in 2012 at four U.S. sites. The project evaluated patients with major depressive disorder through brain imaging and various DNA, blood, and other tests. His goal was to address a troubling finding from another study he led (STAR*D) that found up to two-thirds of patients do not adequately respond to their first antidepressant.

EMBARC's first study, published in 2018, focused on how electrical activity in the brain can indicate whether a patient is likely to benefit from an SSRI (selective serotonin reuptake inhibitor), the most common class of antidepressant.

The finding has been followed by related research that identifies other predictive tests for SSRIs, most recently the resting-state brain imaging study published in the American Journal of Psychiatry and the second imaging study published in Nature Human Behaviour.

AI and depression

The Nature research used artificial intelligence to determine correlations between the effectiveness of an antidepressant and how a patient's brain processes emotional conflict.

Participants undergoing brain imaging were shown photographs in quick succession that offered sometimes conflicting messages such as an angry face with the word "happy," or vice versa. Each participant was asked to read the word on the photograph before clicking to the next image.

However, rather than observe only neural regions believed to be relevant to predicting antidepressant benefits, scientists used machine learning to analyze activity in the entire brain. "Our hypotheses for where to look have not panned out, so we wanted to try something different," Dr. Trivedi explained.

AI identified specific brain regions - for example in the lateral prefrontal cortices - that were most important in predicting whether participants would benefit from an SSRI. The results showed that participants who had abnormal neural responses during emotional conflict were less likely to improve within eight weeks of starting the medication.

Ongoing research

Dr. Trivedi has initiated other large research projects to further understand the underpinnings of mood disorders, among them D2K, a study that will enroll 2,500 patients with depression and bipolar disorders and follow them for 20 years. In addition, RAD is a 10-year study of 2,500 participants (ages 10-24) that will uncover factors for reducing the risk of developing mood or anxiety disorders.

Utilizing some of these enrollees, Dr. Trivedi's research team will study the results from several other tests to augment brain imaging and more accurately assess patients' biological signatures to determine the most effective treatment. Dr. Trivedi has had preliminary success developing a blood test but acknowledges it may only benefit patients with a specific type of inflammation.

Combining blood and brain tests, he said, will improve the chances of choosing the right treatment the first time.

"We need to look at this issue in several ways to identify the many different signatures of depression in the body," he said. "The findings from these new studies are significant and bring us closer to using them clinically to improve outcomes for millions of people."