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In their phase-2 study of tisagenlecleucel (marketed as KYMRIAH®), to be published on-line Dec. 1, 2018 in the New England Journal of Medicine, an international team of researchers evaluated 93 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). They found that 52 percent of those patients responded favorably to the therapy. Forty percent had a complete response and 12 percent had a partial response.

Sixty-five percent of those patients--recruited from 27 sites in North America, Europe, Australia and Asia--were relapse free one year later, including 79 percent of the complete responders. The median progression-free survival for patients in this trial, known as JULIET; NCT02445248, "has not been reached," the authors note.

This compares favorably with earlier studies based on chemotherapy. The retrospective SCHOLAR-1 study, published in 2017, found that only seven percent of patients with refractory DLBCL had a complete response. The median overall survival was a mere 6.2 months. "Outcomes were consistently poor across patient subgroups and study cohorts," the SCHOLAR-1 authors noted.

More promising data from the JULIET trial "led to the Food and Drug Administration's approval May 1, 2018 of tisagenlecleucel for treatment of DLBCL," said study co-author Michael Bishop, MD, Professor of Medicine and Director of the Cellular Therapy Program at the University of Chicago Medicine. "Our current results are a promising sign of the potential for long-term benefit."

Scott McIntyre, the first patient to receive CAR-T cell therapy for stage 3 DLBCL at the University of Chicago, was pleased to learn about the study results. He is now 30 months post treatment and has had no sign of recurrence. He still gets a transfusion of antibodies every two months to protect him from the risk of infection that comes with the loss of his normal B cells. But the South Bend, Indiana native quickly returned to his job and seldom misses a Notre Dame football game. He just returned from watching the undefeated team beat the University of Southern California.

The JULIET trial, based at the University of Pennsylvania, is a single-arm, open-label, global study in adults with relapsed or refractory DLBCL. Patients who were enrolled had received at least two previous lines of therapy.

The treatment process is complicated. The care team takes blood from the patient, extracts T-cells and returns everything else. The T cells were shipped to Novartis' Morris Plains facility in New Jersey. The team there modified the T lymphocytes, enabling them to find disease-causing B cells that display a surface protein called CD19 and destroy them.

Once the T cells are returned to the hospital and re-infused into the patient, they multiply rapidly, producing millions of offspring. They quickly launch a vigorous assault on cells that display CD19, leading to the rapid destruction of cancerous cells.

The process, a form of immunotherapy, can have severe but generally self-limited side effects. The most common adverse event is cytokine release syndrome (58 percent), which causes severe flu-like symptoms such as fevers, swelling and low blood pressure. It can also cause neurologic effects such as delirium, but physicians have learned how to control these side effects. No deaths in this trial were attributed to the treatment.

McIntyre experienced mild cytokine release syndrome and some neurologic effects, but responded quickly to drugs designed to limit these side effects.

"The median progression-free survival has not been reached for complete responders," the authors wrote. The probability of survival at month 12 "was 90 percent among complete responders."

"Overall, this is extremely exciting," Bishop said. "Relapses after 12 months are infrequent. Our first patient, treated in May 2016, has been back at work for two and a half years. This trial demonstrates that CAR-T cell therapy can provide a high rate of durable responses."

The FDA's approval of tisagenlecleucel in patients with relapsing or refractory DLBCL is based on the phase-2 JULIET clinical trial, the first multi-center global registration study for Kymriah in adult patients with DLBCL. JULIET is the largest study examining a CAR-T therapy in DLBCL. It has enrolled patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including: Austria, France, Germany, Italy, Norway and the Netherlands.

PHILADELPHIA - In an update to a global clinical trial stretching from Philadelphia to four continents, the chimeric antigen receptor (CAR) T cell therapy Kymriah® (tisagenlecleucel, formerly CTL019) led to long-lasting remissions in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The most recent results from the trial will be presented today at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego (Abstract #1684). Stephen J. Schuster, MD, director of the Lymphoma Program at the Abramson Cancer Center of the University of Pennsylvania, was the principal investigator on the trial, which is known as JULIET and has already led to approval by the U.S. Food and Drug Administration as well as by the European Commission, Health Canada, and Swissmedic. Another data set from the JULIET trial with an earlier cut-off date will also be published simultaneously in the New England Journal of Medicine (NEJM).

JULIET included 27 sites in 10 countries across North America, Europe, Australia, and Asia. According to the data presented at ASH, 115 patients with r/r DLBCL received an infusion of CAR T cells. The overall response rate of evaluable patients was 54 percent, with 40 percent achieving a complete response. The median duration of those responses was not reached at a median follow-up of 19 months.

"These findings are consistent with what we've shown in our single-site studies here at Penn, which is that the majority of patients who go into remission stay in remission," said Schuster, who is the senior author on the ASH abstract and is the lead author on the NEJM study. The data will be presented at ASH by Richard T. Maziarz, MD, a professor of Medicine at the Oregon Health and Science Knight Cancer Institute.

Two-thirds of DLBCL cases are successfully treated with frontline chemotherapy. When that fails, a high-dose chemotherapy combined with an autologous stem cell transplant can potentially lead to long-term disease-free survival. However, only half of r/r patients are candidates for this approach, and for those who are, the expected three-year event-free survival rate is just 20 percent.

"CAR T therapy represents a potentially life-saving alternative for these patients, who now have a therapy that can help them achieve durable remissions even after other therapies, including transplant, have failed," Schuster said.

The treatment modifies patients' own immune T cells, which are collected and reprogrammed to potentially seek and destroy the patients' cancer cells. After being infused back into patients' bodies, these CAR-expressing T cells both multiply and attack, targeting cells that express a protein called CD19. Tests reveal that this army of hunter cells can grow to more than 10,000 new cells for each single engineered cell patients receive, producing high remission rates. They can also survive in the body for years.

Grade 3/4 cytokine-release syndrome (CRS), a toxicity associated with CAR T therapy, which includes varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain, and can require ICU-level care, was reported in 23 percent of patients, 16 percent of whom required treatment with tocilizumab, which is the standard therapy for the toxicity. All patients recovered from their CRS. Other Grade 3/4 toxicities included infections (19 percent of patients), fever resulting from low blood count (15 percent), neurological events (11 percent), and a metabolic abnormality called tumor lysis syndrome (two percent). There were no treatment-related deaths.

In May 2018, Kymriah® was approved by the U.S. Food and Drug Administration for the treatment of adult patients with r/r large B-cell lymphoma after two or more lines of systemic therapy, including DLCBL, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. In August 2018, it was approved by the European Commission, making it the first cellular therapy approved for two different cancer indications. The original FDA approval came in August 2017 for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Penn and Novartis formed a global research and development collaboration in 2012.

The 60th Annual Meeting of the American Society of Hematology will feature research from St. Jude Children's Research Hospital on topics ranging from the genomic basis and vulnerabilities of leukemia to an update on gene therapy for hemophilia B to advances in sickle cell disease and beta-thalassemia.

St. Jude research will be highlighted at the Sunday plenary session and throughout the four-day meeting that begins Saturday in San Diego. St. Jude faculty and staff will also chair sessions, give talks, provide updates on clinical advances, participate in panels and moderate sessions on scientific and clinical topics throughout the meeting and in the Friday scientific workshops. The subjects include inherited predisposition to hematopoietic malignancies, how to establish a hematopoietic predisposition clinic and myeloid development.

At the plenary session, St. Jude researchers will lift the veil on the biology of acute erythroid leukemia (AEL) to reveal the genomic basis and therapeutic vulnerabilities of this high-risk leukemia. The findings will be presented by Ilaria Iacobucci, Ph.D., a scientist in the laboratory of Charles Mullighan, MBBS, M.D., a member of the St. Jude Department of Pathology. The plenary session begins at 2 p.m. PT in San Diego Convention Center Hall AB.

"This project marks a paradigm shift in our understanding and possible treatment of acute erythroid leukemia," Mullighan said. AEL is a rare subtype of acute myeloid leukemia (AML) that affects children and adults. AEL has a poor prognosis. Until this study, the genetic basis was poorly understood.

Researchers previously used integrated genomic analysis to compare 159 patients with AEL to 1,509 patients with AML or related red-blood disorders. Scientists identified five age-related subtypes of AEL, each with distinct genomic features and survival rates.

Using CRISPR/Cas9 genome editing, researchers developed mouse models of the AEL subtypes. This was done by simultaneously inactivating different combinations of nine genes in mouse blood stem and progenitor cells. The genes were frequently mutated in the AEL subtypes. The method helped to capture the genomic complexity of AEL and identify mutations driving the leukemia. For example, inactivating the genes Tp53, Bcor and Dnmt3a or Tp53, Bcor, Rb1 and Nfix promoted development of AEL. Inactivating a different constellation of genes--Tp53, Bcor, Tet2--promoted development of B-ALL.

The mouse models were then used to screen the subtypes for sensitivity to almost 200 chemotherapy agents and other compounds, including precision medicines that target specific pathways.

"We found that leukemic cells driven by different mutations have different sensitivities and vulnerabilities to drugs," Iacobucci said. For example, AEL subtypes with NUP98-fusions were highly sensitive to various classes of BET inhibitors and were resistant to common chemotherapeutic drugs. Tp53 wild-type tumors without gene fusions were highly sensitive to a variety of standard chemotherapy agents. In contrast, leukemia subtypes with Tp53 mutations resisted certain chemotherapy drugs, but were sensitive to compounds called PARP inhibitors.

Mullighan said: "These results make a strong case for using genomics to classify patients and then use the information to help guide therapies, since leukemic cells with different genotypes do not respond to treatment the same way."

Other St. Jude oral presentations:

Sunday

San Diego Convention Center, Room 25B

Abstract: 385

Noon PT

Leukemia risk gene revealed as an important regulator of B-cell development

Certain genetic variation in the gene ARID5B is linked to as much as a two-fold increased risk of childhood acute lymphoblastic leukemia (ALL), but until now the biology behind this association and the function of the ARID5B protein have been poorly understood.
Charnise Goodings-Harris, Ph.D., a St. Jude postdoctoral fellow in the laboratory of Jun J. Yang, Ph.D., an associate member of the Department of Pharmaceutical Sciences, will present evidence Sunday that ARID5B is an important regulator of B-cell development. "These results fill a knowledge gap regarding the roles this protein plays during blood cell development," Yang said. "That can then help us understand how variations in the gene influence risk of pediatric ALL."

For this study, researchers developed a mouse that overexpressed Arid5b and tracked how that affected development of B cells and other blood components. B-ALL is the most common childhood cancer.

Previous work by Yang and others identified inherited variations in ARID5B that were associated with elevated susceptibility to ALL in childhood and to a poor prognosis. Compared to children of European ancestry, children of Hispanic ethnicity had more of the high-risk variations and had an increased risk of developing the disease.

San Diego Convention Center, Room 25B

Abstract: 410

4:45 p.m. PT

Researchers home in on the mechanism to turn back the clock on hemoglobin production
Sunday, St. Jude researchers will offer new details of the mechanism by which red blood cells switch from producing fetal hemoglobin to adult hemoglobin. That change leaves individuals with the inherited blood disorders sickle cell disease and beta-thalassemia at risk for debilitating, sometimes life-threatening complications. Increasing fetal hemoglobin levels is proven to ease symptoms in affected individuals.

For this study, researchers identified the protein UHRF1 in a gene editing-based screen designed to find proteins that facilitate the fetal-to-adult hemoglobin switch.

"UHRF1 is the guardian of methylation throughout the genome," said senior author Mitchell Weiss, M.D., Ph.D., chair of the St. Jude Department of Hematology. Methylation, the process for adding or removing methyl groups from DNA, regulates gene expression.

"In this study, we detail efforts to pinpoint where methylation is most important for turning off fetal hemoglobin with the goal of reactivating it in individuals with sickle cell disease or beta-thalassemia to alleviate their symptoms. This study contributes to that effort," Weiss said.

Ruopeng Feng, Ph.D., a postdoctoral fellow in the Weiss laboratory, will present the results.

San Diego Convention Center, Room 25B

Abstract: 411

5 p.m. PT

Immunosuppression agent may offer new treatment of beta-thalassemia

An immunosuppressive drug best known for protecting organ transplants from rejection may also help to ease symptoms of beta-thalassemia, a common inherited blood disorder. The research will be presented Sunday by Christophe Lechauve, Ph.D., scientist in the laboratory of Mitchell Weiss, M.D., Ph.D., chair of the St. Jude Department of Hematology.

The drug is rapamycin. St. Jude researchers found that rapamycin reduced the effects of beta-thalassemia in mice and in cultured red blood cells of beta-thalassemia patients. Rapamycin combats -thalassemia by activating an enzyme (Ulk1) that reduces the toxic build-up of hemoglobin components.

Hemoglobin is the protein in red blood cells that carries oxygen. Normal hemoglobin has four protein chains--two alpha-globin and two beta-globin. Beta-thalassemia patients have too little beta-globin, which leads to a toxic build-up of ?-globin in red blood cells and the developing cells that give rise to them. Patients develop anemia and other, sometimes life-threatening, symptoms associated with the disorder.

"Rapamycin treatment significantly reduced and in some cases fully corrected the accumulation of ?-globin in the developing blood cells of patients with beta-thalassemia," Weiss said. Researchers hope the findings will lead to a clinical trial of the drug in beta-thalassemia patients.

San Diego Convention Center, Room 6B

Abstract: 491

5:30 p.m. PT

Gene therapy provides long-term relief for men with severe hemophilia

Eight years after the first men with severe hemophilia B received gene therapy developed in Memphis and London, researchers will report the therapy is still working. The therapy was pioneered by researchers at St. Jude, University College London and the Royal Free Hospital.

"This is the first report that gene therapy provides a safe, reliable supply of the blood clotting factor for such an extended period after a single infusion," said co-author Ulrike Reiss, M.D., of the St. Jude Department of Hematology. "The findings address lingering concerns that factor IX levels might decline with time."

Not only were the initial increased levels in clotting factor IX maintained in the 10 men enrolled in the study, but their bleeding episodes decreased 82 percent. Their use of clotting-factor concentrate to prevent or treat spontaneous bleeds dropped 66 percent.

A mutation in the factor IX gene leaves individuals with hemophilia B, who are mostly men, with sometimes dramatically reduced or absent levels of the clotting factor. That leaves patients at risk for painful episodes of spontaneous bleeding that can result in crippling joint damage early in life as well as potentially fatal bleeds in the brain.

For this study researchers modified the adeno-associated virus (AAV8) to serve as the delivery device (vector) to carry the genetic material for making factor IX in liver cells, where it is normally produced.

Researchers also reported that a new vector preparation method failed to prevent an asymptomatic increase in liver enzymes that some patients experienced. Enzyme levels returned to the normal range following steroid treatment. Investigators had tried removing empty viral particles before the gene therapy was infused into patients in case they were triggering an immune response. This finding suggests other factors are involved.

While this study is closed to new patients, St. Jude, University College London and the Royal Free Hospital have opened another gene therapy trial for patients with severe hemophilia B. This clinical trial involves a new vector that researchers believe is even more effective.

Monday

Marriott Marquis San Diego Marina, Pacific Ballroom 24

Abstract: 529

7 a.m. PT

Tumor suppressor protein also plays key role in red blood cell development

St. Jude researchers have identified an intriguing new role for the tumor suppressor protein FBXO11 and a new mechanism important for red blood cell maturation.

FBXO11 is a type of enzyme called ubiquitin ligase, which tags unneeded or unwanted proteins for degradation. Previous studies showed that loss-of-function mutations in the FBOX11 gene arrest the development of normal lymphoid cells and promote their transformation to cancer. In this study, researchers found that FBXO11 is essential for the development of human and mouse red blood cells.

"Evidence suggests that FBXO11 acts early in red blood cell development to degrade a repressor protein called BAHD1, thereby activating the expression of hundreds of genes essential for maturation of red blood cells," said Mitchell Weiss, M.D., Ph.D., chair of the St. Jude Department of Hematology. "The finding may help explain how FBXO11 works in other tissues and prevents cancer."

Peng Xu, Ph.D., a postdoctoral fellow in Weiss' laboratory, will present the research Monday.

San Diego Convention Center, Room 25B

Abstract: 565

7 a.m. PT

RNA sequencing helps uncover mutations that launch most common childhood cancer

Researchers led by St. Jude have identified eight new subtypes of the most common form of acute lymphoblastic leukemia (ALL), which is also the most common childhood cancer. The finding means that more than 90 percent of B-ALL cases can now be classified by subtype.

"Prior to this study, 30 percent of B-ALL cases could not be classified into subtypes," said corresponding author Charles Mullighan, MBBS, M.D., of the St. Jude Department of Pathology. "These patients lacked precision medicine approaches to treatment and commonly relapsed."

The research, which identified 23 B-ALL subtypes, involved integrated genomic analysis, including RNA sequencing, of almost 2,000 children and adults with B-ALL. The research highlighted RNA sequencing as a tool to recognize chromosomal rearrangements, gene-expression profiles, novel point mutations and other alterations that are difficult to detect using whole-genome or whole-exome sequencing.

The newly identified subtypes are strongly associated with prognosis in children and adults. The list includes two that involve the PAX5 gene, notably PAX5 P80R, the first point mutation identified that initiates leukemia. Researchers reported that the mutation blocked B cell differentiation and maturation, and in a mouse model created by CRISPR/Cas9 genome editing, resulted in the development of leukemia in mice. The PAX5 subtypes accounted for almost 10 percent of previously uncategorized B-ALL cases.

The study provides a new framework for classifying ALL in children and adults and shows the utility of RNA-sequencing to provide much of the information required for accurate diagnosis of B-ALL.

Zhaohui Gu, PhD, a postdoctoral fellow in Mullighan's laboratory, will present the results Monday. . St. Patient-derived samples of many B-ALL subtypes are available to researchers worldwide through a St. Jude resource called PROPEL (Public Resource of Patient-derived and Expanded Leukemias). The PROPEL data portal provides access to more than 200 human leukemia samples. The cancers were grown in mice and are known as patient-derived xenografts.

San Diego Convention Center, Room 10

Abstract: 550

7:45 a.m. PT

Gene rearrangement drives high-risk leukemia

Charles Mullighan, MBBS, M.D., of the St. Jude Department of Pathology, and his colleagues recently identified a subtype of acute leukemia defined by rearrangements involving the transcription factor gene ZNF384. These tumor cells typically have features of both B lymphocytes and myeloid cells, and may be diagnosed as B-ALL or mixed phenotype acute leukemia (MPAL).

Researchers had shown that the ZNF384 fusion proteins cause leukemia when expressed in mouse bone marrow, and that the fusions are first acquired in primitive human blood stem cells.

This study examined the effects of expressing the fusion in human blood stem cells. Using stem cells isolated from umbilical cord blood, the researchers showed that the TCF3-ZNF384 fusion, but not normal ZNF384, skewed blood cell development to resemble that of human leukemic cells. In addition, the stem cells resulted in development of B/myeloid leukemia in mice.

"This is the first human model of mixed phenotype leukemia, and provides the foundation to probe the mechanism, including associated epigenetic changes, induced by the fusion gene," Mullighan said. Patient-derived samples of the subtype are available to researchers through the PROPEL data portal.

Kirsten Dickerson, a graduate student in the Mullighan laboratory, will present the research Monday.

San Diego Convention Center, Room 29C

Abstract: 723

3:15 p.m. PT

Online resource offers rich source of genomic and clinical data on sickle cell disease

St. Jude researchers have developed a data portal to fuel collaboration and advance understanding of the genomic landscape of sickle cell disease, particularly genetic factors that contribute to disease severity and complications. Lance Palmer, Ph.D., of the St. Jude Department of Computational Biology, will outline the initiative during his presentation Monday.

The Sickle Cell Disease Portal includes whole-genome sequencing data and select clinical information from more than 800 individuals with the chronic inherited blood disorder. It is one of the first such sickle cell disease data sets available to researchers worldwide. The resource is expected to grow as whole- genome sequencing data from more individuals with sickle cell disease are added as well as visualization tools for scientists.

Each year about 300,000 infants are born worldwide with sickle cell disease. It is caused by inherited mutations in the HBB gene that results in stiff, brittle red blood cells with a characteristic sickle shape. Affected individuals are at risk for premature death and a variety of complications, including episodes of acute pain, stroke and progressive organ damage.

"Not every patient gets every complication," said Mitchell Weiss, M.D., Ph.D., chair of the St. Jude Department of Hematology. "Genetics plays a role in who develops which complications, but many of those genetic modifiers are unknown or poorly understood.

"The Sickle Cell Disease Portal is designed to complement existing resources and help address the knowledge gaps by fueling the collaboration that is essential to change the outcomes for patients," he said.

The portal includes whole-genome sequencing data of 503 St. Jude patients, primarily individuals enrolled in the Sickle Cell Clinical Research and Intervention Program (SCCRIP). This long-term St. Jude study follows individuals with sickle cell disease throughout their lives. The goal is to better understand how the disease progresses and assess treatment efficacy.

The site also includes whole-genome sequencing data from 304 sickle cell patients treated at Baylor College of Medicine in Houston.

Overall, more than 98 percent of the Sickle Cell Disease Portal data come from African-American participants. Along with whole-genome sequencing, the site includes such clinical information as hemoglobin and fetal hemoglobin levels as well as some known genetic modifiers of the disease. Identifying patient information has been removed.

The information is available through St. Jude Cloud, a data-sharing resource developed to make it easier for scientists worldwide to access raw sequencing data along with analytic and visualization tools for pediatric cancer and sickle cell disease.

Data-access requests will be handled by a data-access committee. Along with whole-genome sequencing data, access may include coded clinical and demographic information.

A new immunotherapy can greatly extend the lives of a proportion of people with advanced head and neck cancer, with some living for three years or more, a major new clinical trial reports.

Overall, the drug pembrolizumab had significant benefits for patients, with 37 per cent of patients who received it surviving for a year or more, compared with only 26.5 per cent of those on standard care.

But the results were particularly exciting among the group of people who did respond to pembrolizumab - with a median length of response of 18.4 months, compared with five months for standard care.

The large international clinical trial was led by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and involved 97 medical centres in 20 countries.

The trial was sponsored and funded by Merck & Co., Inc., known as MSD outside the United States and Canada, and the results are published in The Lancet today (Friday).

The drug was evaluated in a trial of nearly 500 patients with very advanced head and neck cancer that had spread around the body and had already become resistant to platinum chemotherapy, the first-line treatment for the disease. Some 247 patients were randomised to pembrolizumab and 248 to standard of care - chemotherapy or the targeted agent cetuximab.

When chemotherapy or targeted therapies stop working, treatment options for people with advanced head and neck cancer are limited, and they are normally expected to survive for less than six months.

Patients on the trial who received pembrolizumab survived for a median of 8.4 months with pembrolizumab, and 6.9 months with standard treatment.

But a minority of patients responded extremely well to pembrolizumab - 36 patients saw their cancer partially or completely disappear, and some are still cancer free three years after first receiving the drug.

Pembrolizumab also caused fewer serious side-effects than currently approved drugs - 13 per cent of people who received the immunotherapy experienced serious side-effects, compared with 36 per cent of people given standard treatment.

Researchers at The Institute of Cancer Research (ICR) and The Royal Marsden hope pembrolizumab could be a much needed smarter, kinder treatment option for people with advanced head and neck cancer.

Pembrolizumab works by taking the brakes off the immune system's ability to attack cancer cells, and is already approved for use in some people with lung cancer, skin cancer and lymphoma.

Professor Kevin Harrington, Professor of Biological Cancer Therapies at The Institute of Cancer Research, London, and Consultant at The Royal Marsden NHS Foundation Trust, said:

"Head and neck cancer is extremely hard to treat once it comes back or spreads, and the outlook for patients once other therapies have stopped working is very poor.

"Our findings show that the immunotherapy pembrolizumab extends the life of people with advanced head and neck cancer overall, and in a group of patients has really dramatic benefits. It is also a much kinder treatment than those currently approved.

"I would like to see pembrolizumab approved for use in the clinic, so that people with advanced head and neck cancer can be offered the chance of a longer life and improved quality of life. There is also an urgent need to work out how we can identify in advance which patients are likely to benefit, given that some of these people may do much better than they do on standard treatment."

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

"Immunotherapies are already revolutionising treatment for several cancer types, and I am excited to see the new drug pembrolizumab now showing benefit in advanced head and neck cancer.

"The next big challenge is to design immunotherapies that can work for many more people, so that more patients can benefit from the kinds of dramatic responses that we saw in some patients in this trial."

Derek Kitcherside, 69, is alive and well after two years of treatment on the pembrolizumab trial at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London. He said:

"I was first diagnosed with cancer of the larynx back in 2011 but quickly went into remission after having standard treatments. I went back to enjoying my retirement, until I started having symptoms again, like coughing up blood, in January 2014. I thought it was the reoccurrence of the same cancer, but it turned out three or four tumours had spread to my right lung. I was told I had squamous cell carcinomas of the head and neck, which was inoperable and probably incurable.

"The standard treatments of radiotherapy and chemotherapy weren't really doing much for me this time around. My tumours were still getting larger and I was told there wasn't much more the doctors could do.

"I was really lucky to get a place on The Royal Marsden's pembrolizumab trial and started treatment in May 2015. I travelled down from Leicester every three weeks for two years. My tumour was shrinking all the time and I felt a bit better every time I went - it made a huge difference to my life and I was able to return to normality.

"Now I have CT scans every nine weeks, which are still showing stable disease and slight tumour shrinkage each time. It's remarkable how I've responded to the drug and I don't think I'd be here without it."

Up to 17 per cent of children could have symptoms consistent with fetal alcohol spectrum disorder (FASD) according to new research published today (Friday 30 November) in Preventive Medicine.

The UK has the fourth highest level of prenatal alcohol use in the world, but no estimates existed from a population-based study on how many people may have FASD. FASD is a group of lifelong conditions caused by exposure to alcohol in pregnancy that affect learning and behaviour and can cause physical abnormalities.

FASD is considered to be a relatively hidden disability because most individuals with it do not show physical features. It is thought to be under-diagnosed with only one specialist clinic in England.

Researchers from the University of Bristol and Cardiff University worked with clinicians to assess a wide range of information on mothers' drinking in pregnancy and studied the development of 13,495 children from Bristol's Children of the 90s study.

They applied a screening tool and found that up to 79 per cent of children in the sample were exposed to alcohol in pregnancy and that to up to 17 per cent screened positive for symptoms of FASD. A positive FASD screen was defined as problems with at least three different areas of learning or behaviour, with or without physical anomalies (growth deficiency and distinctive facial features, which include a smooth philtrum, thin upper lip and small eye openings).

Dr Cheryl McQuire, researcher in epidemiology and alcohol-related outcomes at the University of Bristol, led the research and said:

"Our results showed that a significant number of children screened positive for features consistent with FASD. The results are based on a screening tool, which is not the same as a formal diagnosis. Nevertheless, the high rates of prenatal alcohol use and FASD-relevant symptoms that we found in our study suggest that FASD is likely to be a significant public health concern in the UK.

"These results are important because without UK estimates of FASD prevalence, awareness will remain low and children, teenagers and adults will continue to find it difficult to seek diagnosis and to access the support they may need.

"Although information on prenatal alcohol use was collected several years ago and guidance on drinking during pregnancy has since changed, rates of prenatal alcohol exposure in the UK have remained high. Recent estimates suggest that three quarters of women drink some alcohol during pregnancy, with one third at binge levels. This suggests that many individuals in our population today could also have symptoms of FASD.

"The most up-to-date guidance states that the safest approach is not to drink alcohol at all if you are pregnant, or if you think you may become pregnant. It is important that people are aware of the risks so that they can make an informed decision about drinking in pregnancy.

"The next steps should include follow-up studies to further clarify the current number of people in the UK with FASD. Some countries, such as the USA, Canada and Italy have used in-school screening and have concluded that up to 10 per cent of children in the general population are affected, with rates as high as 30 per cent among children in care."

Dr Raja Mukherjee runs a diagnostic clinic for FASD at Surrey and Boarders Partnership NHS Foundation Trust and contributed towards the research. He said:

"These are really important results that show there are likely to be many individuals with this disorder already out there who are being missed. There seems to be a disconnect between these findings and what many clinicians often report as a rare condition.

"It shows that it is a disorder that is seemingly hidden in plain sight that we need to pay attention to. Unless we start looking for it we will continue to miss it. If we fail to diagnose it then those affected individuals will continue to be affected by a lack of support and have subsequent impact on them and wider service. These results can be the first step in helping us in the UK to realise it is no longer a condition we can ignore"

Chief Executive of NO-FAS UK Sandra Butcher added:

"This study shines light on a staggeringly widespread and largely avoidable public health crisis. No policy maker who cares about the mental and physical health of the most vulnerable in our society should rest easy until we have in place UK-wide comprehensive action and training on FASD prevention, diagnosis and support that extends across the individual's lifespan. Babies with FASD grow into adults with FASD and more support is needed on every level."

Advice updated in January 2016 from the Chief Medical Officer states that if you are pregnant or think you could become pregnant, the safest approach is not to drink alcohol at all, to keep all risks to your baby to a minimum. It also states that the risk of harm is likely to be low if you have drunk only small amounts of alcohol before you knew you were pregnant or during pregnancy.

The guidance advises that if you find out you are pregnant after you have drunk alcohol during early pregnancy, you should avoid further drinking. It also states that it is unlikely in most cases that your baby has been affected and you are worried about alcohol use during pregnancy to talk to your doctor or midwife.

Women who experience pregnancy loss and do not go on to have children are at greater risk of cardiovascular disease, such as heart disease and stroke, compared with women who have only one or two children, according to new research from the University of Cambridge and the University of North Carolina.

The study, published today in the Journal of Women's Health, also found that women who have five or more children are at an increased risk of cardiovascular disease in later life.

Cardiovascular disease is the leading cause of death among women in every major developed country and most emerging economies. Approximately 28,000 women die from heart attacks each year in the UK. In 2016 alone, 20,000 women died after having a stroke - a higher number that that in men.

During pregnancy, the mother's body experiences changes during pregnancy including weight gain and accumulation of abdominal fat, higher levels of cholesterol, increased insulin resistance, and changes in the structure of the heart. Although most changes that occur during pregnancy are temporary, these changes are known to be risk factors for cardiovascular disease in the general population.

Previous studies have attempted to assess the relationship between pregnancy and childbirth on the one hand and cardiovascular disease on the other. However, due to limitations in these studies - including not taking into account breastfeeding history and grouping together women who had never been pregnant with those who had been pregnant but experienced pregnancy loss - their results have been inconclusive and sometimes contradictory.

In this new study, a team of researchers in the US and the UK analysed data from more than 8,500 White and African-American women, aged 45-64 years, in the US. This included health service data on cardiovascular disease over a thirty year period (1987-2016) and self-reported data on the number of pregnancies and births, and breastfeeding practices.

Within the study population, 138 women reported having experienced pregnancy loss and having no live born children. 3,108 women had one or two live born children, 3,126 had 3-4 live born children, and 1,694 had five or more live born children.

The researchers found that women who experienced pregnancy loss and did not have any live born children were at 64% greater risk of both coronary heart disease and 46% greater risk of heart failure compared to women with one or two children. Women with five or more births had a 38% higher risk of having serious heart attack, regardless of how long they breastfed for.

The team say that there may be several possible reasons for the link between cardiovascular risk and multiple births. Repeated pregnancies could result in long-lasting changes within the body including weight gain, especially around the waist, and increased levels of cholesterol in the blood. Also, the number of children a woman has also encompasses other factors including child-rearing, age at menopause and health conditions. Therefore, the researchers say it is unclear whether the increased risk of heart failure, coronary heart disease and heart attacks reflect the direct impact of repeated pregnancies, or the stressors associated with rearing multiple children, or both.

The increased risk of coronary heart disease and heart failure found in women with prior pregnancies, but no live born children, may reflect the increased risk previously identified after a history of miscarriage. Several mechanisms have been proposed to underlie the relationship between miscarriage and coronary heart disease, including immune disorders, chronic disease and dysfunction of the endothelium (cells that line the interior of blood vessels).

"Conditions such as heart disease and stroke together are the leading cause of death in women in the developed world and it is essential that we understand why this is the case," says Dr Clare Oliver-Williams, a Junior Research Fellow at Homerton College who works at from the Department of Public Health and Primary Care at the University of Cambridge. "Our work suggests that there is a relation between cardiovascular disease risk and both pregnancy loss and having a large number of births.

"This study isn't designed to stress and worry women, especially those who have experienced the distress of pregnancy loss. Instead we want to empower women with knowledge that will help them to reduce their risk.

"Most women know by the age of 40 how many children and pregnancy losses they have had, which is years before most heart attacks and strokes occur. This provides a window of opportunity to make lifestyle changes, such as exercise and diet that can help reduce the risk of cardiovascular disease."

Highlight

Concerning adherence to certain recommended measures of kidney disease care for veterans with diabetes within the Veterans Affairs Health Care System, there is modest facility-level variation for some measures and larger facility-level variation for others.

Washington, DC (November 29, 2018) -- A new study has uncovered variation across facilities in the Veterans Affairs (VA) Health System concerning the delivery of key measures of kidney disease care for veterans with diabetes. The findings, which appear in an upcoming issue of the Clinical Journal of the American Society of Nephrology (CJASN), point to areas where care might be improved and standardized among facilities.

The VA Health System is the largest integrated health care system in the United States, and several programs have been implemented to improve the quality of care delivered through the health system to patients with chronic kidney disease (CKD). To assess the extent to which care for patients with CKD varies across different VA facilities, Sankar Navaneethan, MD, MS, MPH (Baylor College of Medicine) and his colleagues examined information on 281,233 patients with diabetes and concomitant CKD receiving care in 130 facilities across the VA Health Care System in 2013-2014.

Among those with stage 3 CKD, the median proportions of patients receiving guideline-recommended core measures were 37% for urine albumin:creatinine ratio/urine protein:creatinine ratio, 74% for hemoglobin measurement, 66% for angiotensin converting enzyme inhibitor/angiotensin receptor blocker prescriptions, 85% for statin prescriptions, 47% for achieving blood pressure

"Despite the ongoing best efforts to improve the care for veterans with diabetes and kidney disease, adherence to guideline-recommended core measures such as ordering of certain laboratory tests, and scheduling of referrals to kidney specialists in eligible patients remains suboptimal, with modest facility-level variations for some measures and larger facility-level variation for others. It is important to note that these rates are similar, if not better than other health care systems," said Dr. Navaneethan. "Our results point out potential areas where additional efforts and programs could be implemented to address practice level variations noted among VA facilities."

In an accompanying editorial, Tyler Woodell, MD and Dena Rifkin, MD, MS (University of California, San Diego) note that certain measures are likely practiced with appropriate adherence and variability that reflect patient-centered care, but other measures must improve. "Clinical leaders should review this information, identify potential deficiencies, and defend those situations in which seemingly inappropriate care is actually appropriate," they wrote. "We can then propose solutions such as automated opt-out order sets, clinical reminders, or patient- centered integration of competing demands to improve care delivery in pursuit of the 'right rate.'"

ANN ARBOR, Mich. -- Amphetamine and opioid use in pregnancy increased substantially over the last decade in the United States, a new Michigan Medicine-led study finds. And a disproportionate rise occurred in rural counties.

Among pregnant women in all parts of the country, amphetamine-affected births (mostly attributed to methamphetamine) doubled -- from 1.2 per 1,000 hospitalizations in 2008-2009 to 2.4 per 1,000 delivery hospitalizations by 2014-2015, the new research finds.

The rate of opioid use also quadrupled from 1.5 per 1,000 delivery hospitalizations in 2004-2005 to 6.5 per 1,000 delivery hospitalizations in 2014-2015, according to the findings published in the American Journal of Public Health. The study sample included about 47million deliveries occurring in U.S. hospitals over the 12-year-period.

For pregnant women with amphetamine use, the risk of severe maternal morbidity and mortality was 1.6 times the rate identified among moms with opioid use. The incidence of preterm delivery, pre-eclampsia or eclampsia, heart failure or heart attack, and need for a blood transfusion were also higher among deliveries to moms with amphetamine use compared to opioid use.

"We know from our previous research on maternal health disparities that there are disproportionately higher rates of substance affected births in rural communities," says lead author Lindsay Admon, M.D., M.Sc., an obstetrician-gynecologist at University of Michigan Von Voigtlander Women's Hospital and a graduate of the National Clinician Scholar's Program at U-M's Institute for Healthcare Policy and Innovation.

"When we looked at the specific types of substances driving this disparity, we were surprised to find that amphetamine use accounted for such a significant portion," Admon adds, noting that few, if any, studies have examined the incidence of amphetamine use in pregnancy in the last decade.

"Our findings suggest both amphetamine and opioid use are growing public health crises that affect delivery and birth outcomes."

Admon, the study's senior author Tyler Winkelman, M.D., M.Sc., and colleagues also recently examined 1.3 million hospitalizations related to amphetamines in the general adult population, finding that by 2015 amphetamine-related hospitalizations were associated with higher risk for in-hospital mortality and accounted for $2.2 billion dollars in hospital costs.

Geography influences health, recovery

An estimated 82,254 delivery hospitalizations during the decade-long study period included one or more amphetamine use diagnoses and 170,164 included one or more opioid use diagnoses.

By 2014-15, amphetamine use complicated roughly 1 percent of all deliveries in the rural West (11.2 per 1,000 hospital deliveries), which was higher than the incidence of maternal opioid use in most regions. The highest incidence of maternal opioid use was identified in the rural Northeast, complicating nearly 3 percent of all deliveries (28.7 per 1,000 hospital deliveries.)

Higher proportions of patients in both substance use groups were non-Hispanic white, from lower-income communities, and had public insurance compared to other hospital deliveries.

"Early and adequate access to prenatal care for women with substance use has been shown to improve birth outcomes," Admon says. "However, geographic disparities have a major impact on the health and well-being of pregnant women and infants. There are significant barriers to obstetric care access in many rural communities, particularly for women with substance use."

Barriers to treatment

Determining treatment specifically for prenatal amphetamine use is also a challenge.

While there's gold standard medical treatment for maternal opioid use, Admon says, the evidence for amphetamine use disorder treatment among pregnant women is limited. Cessation is associated with improved birth outcomes, but obstetricians could use more guidance on how to promote cessation among their patients.

Federal efforts to curb access to precursor drugs used to make meth in the mid-2000s helped reduce amphetamine use overall, Admon notes. But as new methods were used to make the drug, meth use has again spiked.

Rural areas have the double whammy of greater access to amphetamines but less access to addiction treatment services. Further complicating the matter are laws that criminalize substance use during pregnancy that may discourage women from disclosing the concern to their health provider.

Neonatal intensive care units in rural counties may also not have adequate capacity to care for babies born with neonatal abstinence syndrome, which describe health problems a baby experiences when withdrawing from exposure to narcotics.

"We have seen a significant increase in infants born with symptoms of drug withdrawal," says Winkelman, of Hennepin Healthcare in Minneapolis and graduate of the National Clinician Scholar's Program at U-M's IHPI.

"We need to devote more resources to prevent and treat substance use in pregnancy, especially in low-income and rural communities."

Neonatal abstinence syndrome accounted for $3 billion in hospital costs between 2004 and 2014, according to another study led by Winkelman and colleagues.

More intervention needed

The new U-M-led study follows Admon's previous research, which found that pre-existing, chronic conditions among delivering women have increased substantially and are linked to adverse birth outcomes.

Prior work by Admon and colleagues also examined racial and ethnic disparities in the incidence of behavioral health conditions, including substance use disorders. Substance use were less common among African-American and Hispanic women, but, when present, were associated with a higher risk for adverse birth outcomes compared to non-Hispanic white women.

"It is critical that health providers employ universal screening for substance use early in pregnancy," Admon says. "Optimizing access to prenatal care is a crucial mechanism to connect women with the services they need for their health and their baby's health."

"We need to find better ways to prevent, detect, and treat maternal amphetamine and opioid use. Developing treatment programs that can reach women in the geographic areas most affected by these epidemics is key to improving outcomes for mothers and newborns."

Rockville, Md. (November 29, 2018)--New research suggests that curcumin, a main ingredient in curry, may improve exercise intolerance related to heart failure. The study is published ahead of print in the Journal of Applied Physiology.

Curcumin, a chemical that comes from the turmeric plant, has been used as a traditional Asian medicine for centuries, primarily to treat gastrointestinal ailments and skin wounds. Studies increasingly suggest that the compound may prevent or limit muscle wasting associated with a number of health conditions, including heart failure.

Heart failure affects more than 6 million people living in the U.S. People with heart failure have a reduced function of the left ventricle--the chamber of the heart that pumps blood out to the rest of the body--called reduced ejection fraction. A decreased ability to exercise (exercise intolerance) is another significant characteristic of heart failure. Previous research has found that higher than normal levels of oxidative stress--an imbalance of two different kinds of molecules that can result in cell damage--contribute to exercise intolerance in people with heart failure. Heart failure is also associated with lower than normal expression of antioxidant enzymes in the muscles, but the reason for this is unclear. Antioxidant enzymes both prevent and repair damage from oxidative stress. Boosting enzyme levels may improve exercise performance in people in heart failure.

Researchers from the University of Nebraska Medical Center theorized that a reduction in the normal signaling of Nrf2, a protein that regulates the expression of antioxidant enzymes, may play a role in the impaired expression of antioxidant enzymes. They examined the effects of curcumin, which is known to promote activation of Nrf2, on a mouse model of heart failure with reduced ejection fraction. One group of mice with heart failure received daily doses of curcumin for 12 weeks, and another group did not receive treatment. The heart failure groups were compared to a control group of healthy mice that received curcumin and an untreated control group.

The research team measured the exercise capacity of all the mice before and after curcumin treatment. The researchers also examined muscle fiber samples to assess enzyme expression levels. They found that expression of Nrf2 increased and levels of antioxidant enzymes improved in the animals with heart failure that were given curcumin. In addition, both groups that received curcumin--even the animals without heart failure--had improved exercise capacity when compared with the untreated groups, suggesting the effects of curcumin on skeletal muscle is not exclusive to heart failure.

"These data suggest that activation of Nrf2 in skeletal muscle may represent a novel therapeutic strategy to improve ... quality of life" in people with heart failure with reduced ejection fraction, the researchers wrote.

It can take up to a year for some bowel cancer patients in the UK to start treatment, according to international research co-ordinated by Cancer Research UK and published in BMJ Open* today.

Researchers found that it took a year or more from first spotting a symptom to beginning treatment for 10% of patients in England, Northern Ireland and Wales.

A team from the International Cancer Benchmarking Partnership (ICBP) - a collaboration between countries with similar healthcare systems and high-quality data - tracked each step people with bowel cancer went through before treatment. They examined questionnaires, completed by 2,866 international patients and their doctors, as well as medical records of patients diagnosed between 2013 and 2015.

They found that men and women in Wales took the longest to contact their doctor once they had noticed a health concern or symptom (49 days on average**).

Once cancer had been diagnosed patients in Wales then waited the longest (39 days on average) before starting chemotherapy, radiotherapy or having surgery - more than double the length of time for patients in Denmark and Victoria, Australia (14 days).

Overall, patients in Wales had the longest time than any of the other areas in the study between noticing a change and beginning treatment (168 days on average).

This compared to 145 days in England, 138 days in Northern Ireland and 120 days in Scotland. Denmark performed the best with the process taking 77 days on average.

Between the countries there was also a big difference in the time it took for patients to be diagnosed, once they had sought help. Patients in Denmark and Victoria most commonly waited 27 and 28 days respectively to receive a bowel cancer diagnosis, compared to patients in Manitoba in Canada who waited 76 days.

In the UK, patients in Wales and Northern Ireland waited longer to receive their diagnosis (on average 60 and 64 days respectively) than patients in Scotland (38 days) and England (48 days). ***

By comparing healthcare systems in similar countries, the ICBP can help identify important differences to inspire improvements in diagnosing cancer across the world and help save more lives.

Waiting longer to begin treatment can increase patient anxiety and may also impact on the success of treatment.

Sara Hiom, Cancer Research UK's director of early diagnosis, said: "This work shows that the UK has a major task ahead to improve how promptly bowel cancer patients receive treatment.

"There is much we can learn from other countries, from addressing barriers to encourage people to visit the GP if they notice unusual changes to ensuring they have the swiftest possible path from referral to diagnosis and treatment.

"It's also essential we have enough staff and capacity to perform and report tests promptly and deliver treatment without delay. Diagnosing bowel cancer relies on trained endoscopists and pathologists and there have long been shortages of these vital health professionals across the UK.

"Increasing the necessary workforce so that patients can get the care they need, when they need it will ensure a less stressful and worrying time for patients and their families, as well as extending lives and ultimately saving NHS spending on costly treatments. Without this investment in the NHS, the Prime Minister's commendable ambition to improve early diagnosis will not be realised."

Professor David Weller, lead author based at the University of Edinburgh, said: "The significant variation between participating countries in the time it took for patients to begin treatment shows there is real potential to speed up this process.

"Further research is needed to understand these differences and build on what is working well in other countries to give patients in the UK the best possible care."

Please contact the BJC press office for the full paper or with any other questions on 0203 469 8300, out of hours, 07050 264 059 or bjcpress@cancer.org.uk. Scientists can be directly contacted regarding media interviews using the contact details provided.

Please reference the British Journal of Cancer in any media activity.

Paper: Dasatinib Sensitizes Triple Negative Breast Cancer Cells to Chemotherapy by Targeting Breast Cancer Stem Cells
Corresponding author: Dr. Jean-Jacques Lebrun
Telephone: 514.934 1934 Ext 34846
E-mail: JJ.Lebrun@mcgill.ca
Author summary: Triple negative breast cancers (TNBCs) have very poor patient survival outcomes and are responsible for most breast cancer-related deaths. Although showing an initial response to presurgical chemotherapy, most of these tumours are recurrent, develop resistance to chemotherapy treatments and spread to distant organs (metastasis), ultimately increasing the death toll by this type of tumours. In fact, less than 30% of patients with metastatic and chemo-resistant TNBC survive after 5 years, highlighting the fact that resistance to chemotherapy remains one of the biggest challenge for breast cancer patient's management. In our study, we tested different drugs for their efficacy to eliminate a population of cancer cells that are responsible for chemotherapy resistance driving tumour recurrence and metastasis. We found a specific drug, called dasatinib, to efficiently suppress the aggressive features of these cancer cells and re-sensitize chemo-resistant TNBCs to chemotherapy. Moreover, our study provides evidence for the use of a combination of dasatinib with chemotherapeutic agents in treating chemo-resistant and metastatic breast cancers. These results provide a rationale to expand on these findings and to test this combination treatment in clinical trials using large cohorts of metastatic breast cancer patients with TNBCs.
Post embargo link: https://doi.org/10.1038/s41416-018-0287-3
DOI: s41416-018-0287-3

Paper: Increased risk of second cancers at sites associated with HPV after a prior HPV-associated malignancy, a systematic review and meta-analysis
Corresponding author: Dr Duncan Gilbert
E-mail: duncan.gilbert@ucl.ac.uk
Author summary: Human papilloma viruses (HPV) cause 5% of cancers worldwide. HPV can cause cancer of the cervix, anus, vulva, vagina and penis and some tonsil and tongue cancers. These cancers can be successfully treated either with surgery or a combination of chemotherapy and radiotherapy if more advanced. These treatments cure many patients. Patients cured of one HPV linked cancer may be at a higher risk of developing a second cancer. We searched for, and analysed, all previous reports and combined these results to estimate that increased risk. Overall, we found patients were at a higher risk of getting a second cancer at any of these sites. The increase in risk ranges from around twice as likely to get cervix cancer after a cancer of the tonsil or tongue, to being 14 times as likely to get anal cancer after being treated for a vulvo-vaginal cancer. Although these relative risks are high the absolute risk remains low. We hope this information can help guide work to detect these cancers early (e.g. through follow up and screening) or, in the future, prevent them.
Post embargo link: https://doi.org/10.1038/s41416-018-0273-9
DOI: s41416-018-0273-9

Ben-Gurion University Cyber Security Researcher to Present Medical Equipment Hacking and Defensive Solutions to the Radiological Society of North America

CHICAGO...November 27, 2018 - As internet connectivity of medical imaging equipment in hospitals increases the potential for malicious cyberattacks, Ben-Gurion University of the Negev (BGU) researcher Tom Mahler will present his team's approach to solutions using artificial intelligence (AI) at the Radiological Society of North America (RSNA) Annual Meeting on November 27 at 3:00 p.m. in Chicago.

The internet has been beneficial for health care--radiology included--improving access in remote areas, allowing for faster and better diagnoses, and vastly improving the management and transfer of medical records and images. Medical imaging devices such as X-ray, mammography, MRI, and CT machines play a crucial role in diagnosis and treatment. But as these devices are typically connected to hospital networks, they can be potentially susceptible to sophisticated cyberattacks, including ransomware attacks that can disable the machines.

During his presentation, "CTrl-Alt-Radiate?" Tom Mahler, BGU Ph.D. candidate and researcher in Cyber@BGU, demonstrated how a hacker might bypass security mechanisms of a CT machine in order to manipulate its behavior. Because CT uses ionizing radiation, changes to dose could negatively affect image quality, or--in extreme cases--pose harm to the patient. Hacking a system is the first step in determining vulnerabilities and creating solutions.

"In the current phase of our research, we focus on developing an anomaly detection system using advanced AI methods to train the system with actual commands recorded from actual equipment," says Mahler. "Our system will monitor scan protocols to detect whether outgoing commands are malicious before they are executed and will alert or possibly stop if it detects an issue."

While other solutions have focused on securing the entire hospital network, the goal of this device-focused approach is to be the last line of defense for medical imaging devices to prevent as many attacks as possible.

The BGU model learns to recognize typical imaging scan protocols and to predict if a new, unseen command is legitimate or not. If an attacker sends a malicious command to the device, the system will detect it and alert the operator before the command is executed. Mahler notes that the system is not yet finished, but that the results are a significant milestone on the path to securing medical imaging devices.

"The medical information device development process, from concept to market, takes three to seven years. Cyber threats can change significantly over that period, which leave medical imaging devices highly vulnerable," Mahler says. "If health care manufacturers and hospitals take a proactive approach, we can prevent such attacks from happening in the first place."

The next step in this process is to collect more scans from different devices and sites to create a more accurate model.

RSNA is an association of over 54,000 radiologists, radiation oncologists, medical physicists, and related scientists that promotes excellence in patient care and health care delivery through education, research and technologic innovation.

CHICAGO - Two new studies being presented this week at the annual meeting of the Radiological Society of North America (RSNA) address the potential risk of cyberattacks in medical imaging.

The Internet has been highly beneficial to health care--radiology included--improving access in remote areas, allowing for faster and better diagnoses, and vastly improving the management and transfer of medical records and images. However, increased connectivity can lead to increased vulnerability to outside interference.

Researchers and cybersecurity experts have begun to examine ways to mitigate the risk of cyberattacks in medical imaging before they become a real danger.

Medical imaging devices, such as X-ray, mammography, MRI and CT machines, play a crucial role in diagnosis and treatment. As these devices are typically connected to hospital networks, they can be potentially susceptible to sophisticated cyberattacks, including ransomware attacks that can disable the machines. Due to their critical role in the emergency room, CT devices may face the greatest risk of cyberattack.

In a study presented today, researchers from Ben-Gurion University of the Negev in Beer-Sheva, Israel, identified areas of vulnerability and ways to increase security in CT equipment. They demonstrated how a hacker might bypass security mechanisms of a CT machine in order to manipulate its behavior. Because CT uses ionizing radiation, changes to dose could negatively affect image quality, or--in extreme cases--pose harm to the patient.

"In the current phase of our research, we focus on developing solutions to prevent such attacks in order to protect medical devices," said Tom Mahler, Ph.D. candidate and teaching assistant at Ben-Gurion University of the Negev. "Our solution monitors the outgoing commands from the device before they are executed, and will alert--and possibly halt--if it detects anomalies."

For anomaly detection, the researchers developed a system using various advanced machine learning and deep learning methods, with training data consisting of actual commands recorded from real devices. The model learns to recognize normal commands and to predict if a new, unseen command is legitimate or not. If an attacker sends a malicious command to the device, the system will detect it and alert the operator before the command is executed.

"In cybersecurity, it is best to take the 'onion' model of protection and build the protection in layers," Mahler said. "Previous efforts in this area have focused on securing the hospital network. Our solution is device-oriented, and our goal is to be the last line of defense for medical imaging devices."

He added that it is also important to note that although these types of attacks are theoretically possible, there is no indication that they ever actually occurred.

"If health care manufacturers and hospitals will take a proactive approach, we could prevent such attacks from happening in the first place," he said.

A second study, to be presented tomorrow, looked at the potential to tamper with mammogram results.

The researchers trained a cycle-consistent generative adversarial network (CycleGAN), a type of artificial intelligence application, on 680 mammographic images from 334 patients, to convert images showing cancer to healthy ones and to do the same, in reverse, for the normal control images. They wanted to determine if a CycleGAN could insert or remove cancer-specific features into mammograms in a realistic fashion.

"As doctors, it is our moral duty to first protect our patients from harm," said Anton S. Becker, M.D., radiology resident at University Hospital Zurich and ETH Zurich, in Switzerland. "For example, as radiologists we are used to protecting patients from unnecessary radiation. When neural networks or other algorithms inevitably find their way into our clinical routine, we will need to learn how to protect our patients from any unwanted side effects of those as well."

The images were presented to three radiologists, who reviewed the images and indicated whether they thought the images were genuine or modified. None of the radiologists could reliably distinguish between the two.

"Neural networks, such as CycleGAN, are not only able to learn what breast cancer looks like," Dr. Becker said, "we have now shown that they can insert these learned characteristics into mammograms of healthy patients or remove cancerous lesions from the image and replace them with normal looking tissue."

Dr. Becker anticipates that this type of attack won't be feasible for at least five years and said patients shouldn't be concerned right now. Still, he hopes to draw the attention of the medical community, and hardware and software vendors, so that they may make the necessary adjustments to address this issue while it is still theoretical.

Dr. Becker said that artificial intelligence, in general, will greatly enrich radiology, offering faster diagnoses and other advantages. He added that there are positive aspects to these findings as well.

"Neural networks can teach us more about the image characteristics of certain cancers, making us better doctors."

UC San Francisco scientists have figured out why some lung cancers become drug-resistant after initially responding to targeted therapies. In the process, they devised a new two-pronged approach that yields an effective treatment for these cancers in the laboratory and holds tremendous promise for the future of precision medicine, they said. The findings are detailed in a study published Nov. 26 in the journal Nature Medicine.

Cancer Outsmarts Precision Therapy

Certain lung cancers are characterized by mutations in a protein called EGFR. Normally, EGFR acts as the 'on/off' switch in a complex molecular circuit that tells the cell when it appropriate to grow and divide (on), and when it's not (off). Though the circuit generally knows when to shut itself off, the mutant forms of EGFR found in lung cancer are stuck in the 'on' position. This leads to abnormal cell proliferation and transforms healthy tissue into cancer.

Though scientists have developed designer drugs that target mutant EGFR and activate the tumor's self-destruct machinery, these curative effects rarely endure. Even after three successive generations of increasingly potent precision therapies that specifically target the mutant protein, the results are always the same: up to 18 months of remission followed by relapse. And when the tumor returns, it's drug resistant and more aggressive than ever.

"The promise of precision medicine is that it allows doctors to treat patients using drugs that target a patient's unique form of cancer. But for all the hype, precision medicine often fails to live up to its potential. It's an unfortunate clinical reality that needs to be solved," said Sourav Bandyopadhyay, PhD, UCSF associate professor of bioengineering and therapeutic sciences and senior author of the new study.

Bandyopadhyay says that the reason there's a gap separating precision therapy's promise and its actual efficacy is because tumors are clever. They're able to rewire their internal circuitry and devise new strategies to promote their own survival, even after initially succumbing to the shock of targeted therapy. Though researchers have shown that these drugs continue to inhibit EGFR activity after tumors become resistant, the self-rewiring means that the tumor is no longer reliant on the mutant protein for its continued survival. Bandyopadhyay wanted to know why.

Aurora Emerges as Cancer's 'Achilles Heel'

To identify drivers of drug resistance, the researchers took multiple cancer cell lines with mutated EGFR and treated them in the culture dish with either osimertinib or rociletinib, third-generation drugs that target the mutant protein. Osimertinib is FDA approved for the treatment of EGFR-mutated non-small cell lung cancer. Though the cancer cells appeared to die off after the drugs were administered, they reemerged just six weeks later resistant to both.

After the cancer cells stopped responding to EGFR drugs, the researchers tested 94 additional drugs to see if any could reverse the acquired resistance. They discovered that drugs targeting a protein called Aurora Kinase A, when combined with osimertinib or rociletinib, killed the cancer cells once and for all.

Similar results were observed when the researchers transplanted drug-resistant tumors from lung cancer patients into live mice. Though the tumors continued to grow when the mice were treated with EGFR drugs alone, the two-pronged approach in which both proteins were targeted simultaneously caused the tumors to shrink with no observed toxicity to the mice.

"Aurora kinase was never before associated with drug resistance in cancer. It's a fundamentally new pathway for resistance to emerge," said Bandyopadhyay, who's also a member of the UCSF Helen Diller Family Comprehensive Cancer Center.

Aurora Helps Cancer Escape Death

The researchers found that Aurora doesn't drive tumor growth on its own. That's why a treatment regimen targeting only Aurora failed to thwart the cancer's progress. What Aurora provides is a way for malignancies to escape death.

Osimertinib and rociletinib work by shutting off mutant EGFR. This not only slows the cancer's growth, it also triggers its self-destruct circuitry, causing tumors to wither away and die. That is, until the tumor rewires itself and activates Aurora.

Aurora serves as cancer's escape hatch. Acting independently of EGFR, Aurora silences the cell's suicide circuits, regardless of what EGFR is telling these circuits to do, thus ensuring the cancer's continued survival. By targeting Aurora and mutant EGFR in tandem, the researchers effectively sealed the cancers fate by sealing shut its lone escape hatch.

A Clinically Significant Discovery

Not only did the researchers discover a new way to target drug-resistant tumors, they also identified a biomarker that could tell clinicians whether the lung cancer they're treating would be susceptible to combined therapies that target both EGFR and Aurora.

The researchers found elevated levels of a protein called TPX2 in biopsies of advanced stage, drug-resistant lung cancers taken from multiple patients. They believe that TPX2, which is known to activate Aurora kinase, may help clinicians identify when a patient's tumor will succumb to combined targeted therapies.

The next step, says Bandyopadhyay, is to work towards getting their two-pronged approach and the TPX2 biomarker approved for clinical trials.

"As more and more patients are progressing on third-generation EGFR inhibitors, our work delineates a new mechanism of resistance that appears to occur in the majority of patients and is targetable using existing Aurora kinase inhibitors. We hope this work re-invigorates pharma interest in cell cycle inhibitors such as Aurora kinase inhibitors. We believe that this class of molecules has incredible power when combined with other targeted therapies, which is not how they have been tested historically. We hope that our results catalyze the initiation of new trials so that patients with mutant EGFR may reap the benefits of our combined approach."

DURHAM, N.C. - A study including health data for more than 500,000 children in the U.S. suggests obesity might be to blame for about a quarter (23 to 27 percent) of asthma in children who are obese.

This could mean about 10 percent of all kids ages 2 to 17 with asthma -- almost 1 million children in the U.S. -- might have avoided the illness by maintaining a healthy weight, according to researchers at Duke University and collaborators with the National Pediatric Learning Health System (PEDSnet). The findings will be published Nov. 26 by the journal Pediatrics.

"Asthma is the No. 1 chronic disease in children and some of the causes such as genetics and viral infections during childhood are things we can't prevent," said Jason E. Lang, M.D., associate professor of pediatrics at Duke and the study's lead author. "Obesity may be the only risk factor for childhood asthma that could be preventable. This is another piece of evidence that keeping kids active and at a healthy weight is important."

For the retrospective study, researchers analyzed data for 507,496 children from more than 19 million doctor's visits at six major children's health centers.

The data were entered into a clinical research data network called PEDSnet between 2009 and 2015.

Those classified as having asthma had been diagnosed at two or more doctor's appointments and had also received a prescription, such as an inhaler. Tests of their lung function also confirmed they had the disease.

Children classified as obese -- those with a body-mass index (BMI) in the 95th percentile or above for their age and sex -- had a 30-percent increased risk of developing asthma than peers of a healthy weight. Asthma did not affect just those with obesity. Children who were overweight but not obese (BMI in the 85-94th percentile) also had a 17-percent increased asthma risk compared to healthy-weight peers.

The researchers calculated asthma risk using several models and adjusted for risk factors such as sex, age, socioeconomic status and allergies. The results remained similar.

The study has several limitations, Lang said, including that the data were collected during doctor's visits and not in a controlled clinical research setting. Lang said more experiments are needed to prove overweight and obesity directly cause changes that lead to asthma because scientists don't completely understand how or why this would occur.

Scientists have explored hypotheses including potential differences in how children's lungs and airways develop when they are overweight, and inflammatory changes in the body due to obesity, Lang said.

Still, these findings and others, such as how asthma often improves with weight loss, suggests obesity plays a key role or is directly to blame, Lang said.

"I think it's reasonable to be concerned that it's a causal relationship," Lang said. "It appears becoming overweight or obese as a child significantly increases your risk of developing asthma, and it's a significant increase, directing attention again to the importance of preventing obesity at an early age."