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Using Motion-Capture Technology to Advance Ergonomic Studies of Ureteroscopy

Source: Brigham and Women's Hospital - On a Mission
Date: 01/22/2020
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Ureteroscopy is one of the most common procedures performed by urologists. Yet little is known about what optimizes the procedure’s success, especially in terms of how the urologist holds the ureteroscope and which hand and arm movements are most effective.

A study published in the Journal of Urology in 2018 looking at common gestures that surgeons used in performing robotic radical prostatectomy inspired Brigham and Women’s Hospital urologist Daniel Arthur Wollin, MD, to conduct similar research analyzing the ergonomics of ureteroscopy.

“You sometimes hear a particular person described as being a really good urological endoscopist, but it’s unclear what makes someone good at doing these procedures,” he said. “We don’t know whether it’s speed, consistency, form, economy of motion or particular tricks that they’ve taught themselves or picked up from others. We wanted to take a closer look.”

Using Technology to Monitor Movement

Dr. Wollin decided to use ureteroscopy simulators that are currently available for training purposes to study particular movements and how they correlate to various metrics of procedure success. He did this by labeling volunteers with tracking dots (the same kind that are employed in motion-capture animation) to monitor movements of the torso, head, pelvis, hands and wrists during simulated procedures.

He recruited 12 urologists to participate, six men and six women. Half were residents and half were attendings or fellows. Some had completed endourologic fellowships.

The participants completed 13 different timed tasks for the removal of kidney stones, and their movements were correlated with their procedure times and other measures of success.

“We know there’s a wide variety of skill levels in ureteroscopy. There are certain things that will take one urologist hours, and another person can do it in 20 minutes,” he said. “Many of these skills build up over time, but they may also be dependent on tricks that people are shown during their training. One of our goals is to determine whether there are ‘right’ ways to do certain procedures and, if so, how those things can be taught.”

Looking More Deeply at Cause and Effect

Dr. Wollin explained that it’s too early to make recommendations based on his studies. But he did offer a few observations. For example, the less a urologist moved their head and body around while performing a complex task, the faster they completed it. This correlation was not seen with simple tasks.

“People may have been moving around more because they were having trouble and needed to shift their bodies around and try a lot of different things,” he said. “Or they may have just been people who move around more in general, and those movements led to slower task times. We can’t yet differentiate between the two. But we can say that people who move less tended to do better.”

Dr. Wollin noted that companies that make ureteroscopes could be interested in his research. “This device was designed 30 or 40 years ago, and given the technology we have today, it’s unlikely it would be designed in the same way now,” he said. “We would like to be able to gather more data and conduct this research on a larger scale, maybe at a national or international conference. Theoretically, you could map everyone’s style while operating the scope and use that information to take a more in-depth look at how it connects to clinical outcomes.”

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Bridge Clinic Connects People Struggling with Addiction to Much-Needed Services

Source: Brigham and Women's Hospital - On a Mission
Date: 01/16/2020
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The opioid epidemic in the United States is entering its third decade, and Brigham and Women’s Hospital has had a longstanding commitment to deliver care to those facing addiction to opioids as well as alcohol and other drugs. The Brigham’s Bridge Clinic, established in 2018, is the latest program aimed at reducing barriers to treatment. The clinic provides urgent, on-demand care while also helping patients transition to other, longer-term programs.

“If you look around the country, the vast majority of people who have substance-use disorders are not receiving any treatment whatsoever—about 90 percent are unable to access care,” said Joji Suzuki, MD, director of the Division of Addiction Psychiatry in the Brigham’s Department of Psychiatry. “This is in contrast to conditions like diabetes or heart disease, where most people are receiving treatment.”

Over the past decade, the Brigham has undertaken many efforts to expand access to substance use-disorder treatment for people who need it. These include launching a comprehensive outpatient clinic, establishing addiction treatment programs in primary care settings and assisting hospital teams in managing patients with substance-use disorders hospitalized for acute medical reasons.

“What we began to realize pretty quickly is that when we offer treatment for substance-use disorders to hospitalized patients who have come to the Brigham for another condition, they’re very willing to start addiction treatment,” Dr. Suzuki said. “But addiction treatment is relatively scarce, and patients often needed to wait weeks or even months to begin treatment. This was the primary motivation for the creation of the Bridge Clinic.”

A Walk-In Clinic With Several Paths of Referral

The Bridge Clinic, which is open during regular daytime hours as well as Tuesday evenings, is designed as a walk-in clinic. Although patients are asked to make appointments, it is set up to offer care whenever people show up. One reason the clinic can operate this way is that it is funded primarily by philanthropic support, rather than a fee-for-service model. Plans call for the clinic to expand its evening hours and open on weekends in the future.

“Our goal is to be flexible and to keep access as open as possible. This really flies in the face of how most hospitals have done addiction treatment in the past and all the barriers that have existed,” Dr. Suzuki said. “People are used to being given a list of phone numbers to call and then sent on their way. We are focused on retaining them in our clinic until we can help them get somewhere else.”

Patients are referred to the Bridge Clinic in many different ways. They may come through the emergency department, inpatient units, an outpatient clinic or one of the Brigham’s outpatient addiction programs.

A distinguishing feature of the Bridge Clinic is that it provides basic medical and psychiatric care in addition to addiction treatment. “The clinic includes primary care physicians, addiction psychiatrists, a nurse practitioner, a women’s health specialist, a peer recovery coach and a resource specialist,” Dr. Suzuki said. “We also have the ability to manage infectious disease complications, such as HIV, hepatitis C and bacterial infections, which are somewhat common in this population.”

The clinic staff also features recovery coaches who are in recovery themselves and help motivate and inspire patients.

Early Success in a Challenging Patient Population

Dr. Suzuki said that in the first year of the program, close to 200 patients were referred to the Bridge Clinic, and just under 90 percent showed up. The team is continuing to collect patient outcomes and plans to report on these soon, but the early signs indicate the program has been very successful in bridging patients to community programs for longer-term treatment.

“We’ve been very surprised at how good these outcomes are because this is a very challenging population to treat,” he concluded. “Many are homeless, and many have other medical comorbidities. The staff has done a tremendous amount of work to retain patients and to bridge them to other programs. I’m very proud of what we’ve accomplished so far.”

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Clinical and Basic Research from the Brigham Highlighted at Annual ACR Meeting

Source: Brigham and Women's Hospital - On a Mission
Date: 01/17/2020
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This November, members of Brigham and Women’s Hospital’s Division of Rheumatology, Inflammation and Immunity presented several groundbreaking studies at the American College of Rheumatology’s (ACR’s) annual meeting in Atlanta.

Among the work presented was clinical research examining avoidable health problems in Medicaid recipients with lupus and basic research focusing on single-cell analysis of immune cells from various autoimmune disease tissues.

Preventive Care in Low-Income Lupus Patients

The lupus study was led by investigator and clinician Candace H. Feldman, MD, MPH, ScD. She and her colleagues used billing claims data for Medicaid beneficiaries to look at vaccine-preventable illnesses for which lupus patients end up in the emergency room or hospital. They found a significant burden of acute care use for these conditions that could be prevented with vaccines.

Many lupus patients have difficulty accessing outpatient care, where most preventive services are provided. Obstacles include transportation problems, an inability to miss work due to financial constraints and a lack of childcare. Dr. Feldman noted that she and colleagues focused on conditions that would be potentially avoidable or whose harm or adverse events would be lessened through sustained access to high-quality outpatient care.

According to Dr. Feldman, studies have shown that lupus patients tend to have low rates for several vaccines, including human papillomavirus (HPV), influenza and pneumococcal disease. “Also, compared with the general population, people with lupus are more susceptible to infections both from the disease itself and from the medications that suppress their immune system and are more likely to have severe complications if they develop these infections,” she added.

One reason vaccines may be overlooked, Dr. Feldman explained, is that patients with complicated illnesses usually have a number of other things to discuss during clinic visits. She pointed out that a few studies, mostly case reports, have suggested that vaccines may be unsafe for people with autoimmune diseases like lupus, but stressed that larger studies have refuted these findings and confirmed that these non-live vaccines are both safe and efficacious for most patients with lupus.

“Another issue is that many people with lupus, especially younger patients, tend to get much of their primary care from rheumatologists. Yet rheumatologists may not be thinking about whether their patients need these vaccines or stock them in their clinics or be equipped to provide preventive care like pap tests,” Dr. Feldman said. “It’s important that rheumatologists be aware of these issues and talk to their patients about vaccinations and other forms of preventive care.”

Immune Cell Subtypes Across Many Inflammatory Diseases

The single-cell analysis study included an in-depth examination of immune cells from people with immune dysfunction, such as rheumatoid arthritis, lupus nephritis, ulcerative colitis, Crohn’s disease and interstitial lung disease. All samples were from human tissues and compared to tissues of the same type taken from noninflammatory or health samples.

“Traditional bulk RNA sequencing provides average quantifications of gene expression across different populations of cells. Recent advances of single-cell technologies have provided single-cell transcriptomics to unbiasedly uncover diverse immune cell populations from disease tissues,” said Fan Zhang, PhD, a computational biologist at the Brigham, Harvard Medical School and the Broad Institute of Harvard and MIT, who presented the work at ACR. “Single-cell analysis gives us a much higher resolution and allows us to quantify many finer immune subtypes and their contributions to disease pathogenesis in each individual sample.”

The data used in this study came from several publicly available datasets, including the single-cell data generated by the Accelerating Medicines Partnership RA/SLE consortium, which is funded by the National Institutes of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases and several pharmaceutical companies.

“Many researchers have done immunogenomics research with a focus on only a preselected cell type and one immune dysfunction disease,” Dr. Zhang said. “Something that was unique about our study was that we compared multiple immune cells from similar inflammatory diseases from different tissues and organs. Thus, there was obviously a computational challenge that required a lot of multidata integration as well as an understanding of immunology and rheumatology.”

The investigators identified 21 diverse cell-type populations across multiple tissue sources, including distinct subpopulations of myeloid cells, T cells, B cells and plasma cells.

“Our research showed what these diseases have in common and also what’s different about them,” Dr. Zhang said. “They suggested new approaches for common therapeutic drugs based on the shared inflammatory immune cells, which may be effective for a number of different autoimmune diseases. I think integration of computational biology and immunogenomics with the field of rheumatic diseases is promising and will generate new insights for drug discovery.”

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Brigham and Women’s Hospital Rheumatologists Shine at ACR’S Annual Meeting

Source: Brigham and Women's Hospital - On a Mission
Date: 01/22/2020
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The Division of Rheumatology, Inflammation and Immunity at Brigham and Women’s Hospital was well-represented among the presenters, moderators and award recipients at the American College of Rheumatology’s (ACR’s) annual meeting, held in November in Atlanta.

The division had 117 accepted research abstracts, 39 oral presentations, 78 posters and 24 invited presenters and moderators.

“This is a meeting where rheumatologists and scientists from all over the globe come together to share ideas and make connections,” said Daniel Solomon, MD, MPH, chief of the Section of Clinical Sciences in the Division of Rheumatology, Inflammation and Immunity. “For a single institution to contribute such a considerable proportion of research at a single meeting is noteworthy.”

Experts from the Brigham presented significant research in disease areas such as lupus, vasculitis, psoriatic arthritis and ankylosing spondylitis, according to Dr. Solomon. Another important topic at the meeting was immunophenotyping for patients with rheumatic diseases. This effort aims to guide treatment decision-making and eventually develop more personalized therapies for different subsets of patients based on the subtypes of immune cells driving their disease.

A Number of Honors

Recently, two members of the division have taken on major leadership roles within the ACR. Ellen M. Gravallese, MD, who became chief of the Brigham’s Division of Rheumatology, Inflammation and Immunity in November, officially took up the mantle as the 83rd president of the ACR. Her term will run from November 2019 to November 2020. Meanwhile, Dr. Solomon was named editor-in-chief of Arthritis & Rheumatology, the major journal in American rheumatology.

At this year’s ACR annual meeting, members of the division were presented with several awards and appointed to leadership positions during the annual meeting, including:

Sarah Kim Chen, MD, MPH, received a Distinguished Fellow Award. Dr. Chen’s research focuses on the use of prescription opioids among patients with rheumatic diseases compared to people with other diseases, including hypertension.

Jonathan Scott Coblyn, MD, and Simon M. Helfgott, MD, were appointed ACR Masters. This prestigious designation honors members who have made outstanding contributions to the field of rheumatology through scholarly achievement and/or service to their patients, students and profession. Dr. Coblyn, whose research focuses primarily on rheumatoid arthritis, is director of clinical rheumatology and director of the Center for Arthritis and Joint Diseases. Dr. Helfgott’s research focuses on the medical treatment of rheumatoid arthritis and other inflammatory disorders.

Candace H. Feldman, MD, MPH, ScD, received the Mary Betty Stevens, MD, Young Investigator Prize for her research on systemic lupus erythematosus (SLE). Dr. Feldman is a clinician and epidemiologist who studies health care disparities, particularly in people with SLE. Read about her work here.

Maura Daly Iversen, MPH, DPT, ScD, received a Lifetime Achievement Award from the Association of Rheumatology Professionals, a division of the ACR. Dr. Iversen is a behavioral scientist and epidemiologist whose research focuses on clinical and translational trials of exercise to manage arthritis symptoms and reduce cardiovascular risk.

Katherine P. Liao, MD, MPH, received the Henry Kunkel Young Investigator Award, which recognizes physician-scientists aged 45 or younger who have made outstanding contributions to basic or clinical research in the field of rheumatology. Her lab is developing bioinformatics methods to study rheumatoid arthritis and the clinical and genetic factors that lead to outcomes such as cardiovascular disease and severe joint damage.

Beyond the awards given out at the ACR meeting, Sonali Parekh Desai, MD, MPH, also of the Division of Rheumatology, Inflammation and Immunity, was given the Donabedian Award in Quality and Safety from the American Public Health Association on November 5. Dr. Desai, medical director for ambulatory patient safety at the Brigham, is leading work to reduce diagnostic errors through an ambulatory safety net program focused on missed and delayed diagnosis of cancer.

“The Division of Rheumatology, Inflammation and Immunity continues to be one of the top-ranked programs in the United States,” Dr. Solomon said. “The members of the division demonstrate outstanding leadership throughout all aspects of the field, including clinical care, research, publishing and teaching.”

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Care Model Has a Critical Impact on Patient Care in Psychiatry

Source: Brigham and Women's Hospital - On a Mission
Date: 01/30/2020
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For over 20 years, the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) model has offered improved care for patients in need of psychiatric care in the primary care setting. At Brigham and Women’s Hospital, a collaborative care paradigm modeled on IMPACT is in the final stages of being rolled out to primary care practices throughout the system.

“This approach can also be valuable because it can facilitate more frequent clinical contacts with an interdisciplinary team around the assessment of a treatment response,” said Jane L. Erb, MD, psychiatric director, behavioral health integration into primary care. “We know that when PCPs have the proper tools, this practice can work well for many patients, like those with mild cases of depression or anxiety. At the same time, when a patient has greater needs, it’s important to have a system in place to ensure they get the specialized care they need.”

David S. Kroll, MD, associate vice chair for program development in the Department of Psychiatry, noted that depression is the leading cause of disability in the United States and suicide is the 10th leading cause of death. Even in a large metropolitan area like Greater Boston, however, patients can struggle to access psychiatric care services.

“The IMPACT model organizes the management of depression screening and referrals into a more systematic approach,” Dr. Kroll said. “Patients who just need first-line treatments can get them right away through primary care, while those who don’t respond or have more complex problems can be prioritized for referral to a psychiatry clinic.”

Making Depression Screening Central to Care

At the Brigham, depression screening has become a central part of care, in the same way that patients are screened for conditions like cardiovascular disease or diabetes. Questionnaires to screen for depression are given to patients to fill out in the waiting room, and PCPs can follow up with anyone who screens positive during their appointment.

Primary care offices have depression care specialists on staff to guide patients and later check in with them about issues like prescription fulfillment, side effects and the effectiveness of medications and counseling. At the Brigham, social workers collaborate with support specialists who proactively help patients with this treatment as well as other health conditions like diabetes and high blood pressure.

“The goal of this program is to administer first-line treatments to patients with straightforward cases of depression. This applies to the majority of the cases we see,” Dr. Kroll said. “First-line care may be medication or psychotherapy, or a combination of the two. This system works well because patients don’t have to wait to get an appointment with a psychiatrist who will ultimately give them the same treatment.”

Comprehensive Care for Complicated Health Issues

Dr. Erb noted that because many of the Brigham’s patients have complicated health issues requiring multiple medications, a primary care doctor should be taking the lead in managing all the prescriptions.

“The PCPs have a consulting psychiatrist to advise them on specific medications,” she said. “But because so many classes of drugs and conditions have side effects that affect patients psychologically or can interact with one another, it’s important to have someone with a comprehensive view who can put all the pieces together.”

According to Dr. Kroll, this approach can also be valuable because most patients see their PCPs more frequently than they would see a psychiatrist. As a result, if the treatment is not working or adjustments need to be made, the problem will be recognized sooner.

“The backbone of collaborative care is a treatment approach called measurement-based care,” Dr. Kroll explained. “This is a systematic way for us to map out each patient’s trajectory. It gives us a very good view of how they’re doing. The Brigham is bringing this kind of care into our routine practice throughout psychiatry.”

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How the Brigham Meets the Psychiatric Needs of Patients in the Emergency Department

Source: Brigham and Women's Hospital - On a Mission
Date: 01/29/2020
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For many people, their first interaction with Brigham and Women’s Hospital is through the Emergency Department (ED). Usually, they are in a desperate state. As such, the ED is a critical place for patients who need acute psychiatric care.

At the EDs at Brigham and Women’s Hospital’s main campus in Boston’s Longwood/Harvard Medical School neighborhood and at the Brigham and Women’s Faulkner Hospital (BWFH) campus in Boston’s Jamaica Plain neighborhood, psychiatric care is woven into the fabric of emergency observation, diagnosis and care.

“Many other hospitals have a separate psychiatry emergency room, often called Psychiatric Emergency Services,” said Sejal B. Shah, MD, director of the Brigham’s Division of Medical Psychiatry. “But we work in conjunction with the ED to care for the patients. Any time someone comes into the ED and those caring for them think psychiatry could be helpful, someone from our psychiatry consultation service is called in. This may be a fellow, a resident or an attending, who then makes recommendations for psychiatric care to the ED clinicians.” This model keeps the patients under the direct care of the emergency department and avoids a feeling of separate mental health care and lack of emergency physician and nurse “ownership,” while providing close, expert specialty consultation and management.

Psychiatric Consults Lead to a Range of Care Approaches

A psychiatry consult may be needed for any number of reasons. A patient may come in after a suicide attempt or drug overdose. They may exhibit signs of psychosis. Or they may be experiencing delirium or hallucinations due to a medical illness like heart disease or a neurocognitive disorder.

For patients who ultimately are admitted to the hospital for their medical condition, members of the psychiatry consultation team continue to follow them on the medical and surgical floors. The Brigham psychiatry service is the most consulted service in the hospital, and has won awards from among all the services, year after year. For other patients, psychiatry consultants may recommend an inpatient psychiatric unit or outpatient intensive care, also called a partial hospitalization program. Consulting psychiatrists work collaboratively with team members across the ED and the rest of the hospital, including social workers, who may meet with family members or help patients access needed services.

“Many of the patients we treat are brought in because they’re experiencing some kind of psychiatric crisis,” said Naomi A. Schmelzer, MD, MPH, director of medical psychiatry at BWFH’s campus. “Many people lack access to the services they need, so the emergency room becomes their safety net when they’re in crisis.” She added that these patients may come in on their own or may be brought in by a concerned family member or another caregiver.

Getting Patients the Level of Care They Need

According to Dr. Shah, behavioral health issues represent about 8 percent of total ED visits nationally.

“BWFH’s campus is located near many nursing homes and group homes,” Dr. Shah noted. “When people who live in these facilities have a medical problem, whether it’s related to their psychiatric illness or not, they are often brought there.”

Dr. Schmelzer emphasized that the emergency medicine physicians at both hospitals are supportive of patients’ psychiatric needs and work to reduce any stigma patients may feel. “We collaborate well with them.” she said. “At BWFH, many of the ED patients are there for psychiatric reasons. The Psychiatry Consultation-Liaison service and the ED have instituted daily interdisciplinary rounds to review the care of all psychiatric patients in the ED.”

However, Dr. Shah cautioned, the best place to treat psychiatric illnesses is not in the ED.

“Our job is to stabilize patients and then help to figure out where they can get the level of care they need,” she said. “But as part of that, we may go ahead and start patients on an antidepressant or antipsychotic while they’re still in the emergency room. Or we make sure they get medication for substance withdrawal, if that’s what’s needed.”

“The emergency room doctors are our partners in making sure that these patients are treated appropriately and don’t fall through the cracks,” Dr. Shah concluded.

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Researchers Find that Vitamin B6 Contributes to Survival of Acute Myeloid Leukemia Cells

Source: Memorial Sloan Kettering - On Cancer
Date: 01/13/2020
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Tumors require many building blocks to support the cell division needed to grow and spread. For that reason, an important approach in the development of new drugs is to look for ways to target the metabolism of cancer cells. A class of metabolism-influencing drugs called IDH inhibitors is already being used to treat some cases of acute myeloid leukemia (AML).

Researchers from the Sloan Kettering Institute and Cold Spring Harbor Laboratory (CSHL) recently discovered a surprising contributor to AML cell metabolism: an active form of vitamin B6, also known as pyridoxal 5’-phosphate. The findings were published January 13 in Cancer Cell.

“This research suggested for the first time that the vitamin B6 pathway might be important for sustaining cancer,” says co-corresponding author Scott Lowe, Chair of the Cancer Biology and Genetics Program at SKI. “We already knew that vitamin B6 served as a regulator for a whole series of enzymes that are needed to make the building blocks required for cell growth and proliferation.”

Homing in on the Vitamin B6 Pathway

The study involved a collaboration between Chi-Chao Chen, then a PhD student in the Lowe laboratory, and Lingbo Zhang, a CSHL Fellow, who searched for molecular vulnerabilities that could be targeted in AML cells while sparing normal cells. They used the gene-editing tool CRISPR to upset different genes in these cells and study the effects. One gene that rose to the top of the list of important players was PDXK.

The PDXK gene directs the production of proteins that produce PLP, the active form of vitamin B6. Previous research had established that PLP can be blocked with isoniazid, an antibiotic used to treat tuberculosis (TB) infections. In TB, isoniazid works by attacking enzymes produced by the Mycobacterium tuberculosis bacterium. In cell cultures and mouse models of AML, it curbed the function of PLP, which in turn inhibited the growth of cancer cells.

“When we further studied the vitamin B6 pathway, we uncovered the role of another protein having similar AML selectivity, called BCL2,” Dr. Chen said. “It turns out there is already a drug that blocks BCL2, called venetoclax (Venclexta®), which is approved to treat AML and other blood cancers. However, that drug works not by affecting metabolism, but by promoting cell death.”

Effects on Fast-Growing Cells

Dr. Lowe and his colleagues still aren’t sure why AML cells are so sensitive to drugs that block PLP. “It’s a bit of a puzzle, and something we still need to determine,” he says. “It could be that because these cells grow so fast, they’re just more vulnerable to the effects on this pathway than other types of cells.”

Though vitamin B6 is found in many foods including meat, fish, dairy products, and some fruits and vegetables, Dr. Lowe doesn’t think that people with leukemia need to be concerned about consuming these foods. He notes, “Although our study provides evidence that AML needs this vitamin to proliferate, there isn’t any indication that consuming it causes or facilitates cancer. Vitamin B6 is important for many functions in the body and eliminating it completely would cause serious harm.”

Looking for Combination Approaches

Research on vitamin B6 and leukemia is still in early stages, but it’s something Dr. Lowe and his team intend to pursue. “We don’t have any plans to start giving isoniazid to people with leukemia because we don’t think it’s sufficiently potent for this treatment. But isoniazid demonstrates that it’s possible to develop drugs that target this pathway,” Dr. Lowe says.

His group plans to work with the Tri-Institutional Therapeutics Discovery Institute of MSK, the Rockefeller University, and Weill Cornell Medicine to develop this approach. He expects that one likely tactic will involve combining a PLP inhibitor with venetoclax.

“Although vitamin B6 hasn’t previously been implicated in cancer, there have been studies linking other vitamins, including vitamin C and vitamin D,” Dr. Lowe concludes. “These latest findings further emphasize the importance of studying vitamin signaling pathways in cancer.”

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Study Reveals a New Way That Stress and Aging Lead to Alzheimer’s

Source: Memorial Sloan Kettering - On Cancer
Date: 01/16/2020
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The body is presented with stressors throughout life. These stressors include genetic and environmental challenges that accumulate over time and damage cells, circuits, and organs. This can lead to a wide variety of maladies, including cancer and age-related brain disorders.

Sloan Kettering Institute scientist Gabriela Chiosis and her colleagues study the effects of stressors on proteins and the networks they make up in cells. In a new study published in Nature Communications, her team discovered how stress rewires key connections in the brain. These changes lead to malfunctions associated with Alzheimer’s disease. In addition, they demonstrated how a drug that’s currently being tested in clinical trials for Alzheimer’s, called PU-AD, may correct faulty wiring and preserve brain functions. In lab mice, the drug rewired circuitry within the hippocampus, the part of the brain associated with memory. The result was improved memory without any side effects.

“This study is the culmination of years of research in my lab,” Dr. Chiosis says. “It’s a paradigm-shifting way to think about Alzheimer’s.”

Identifying Common Factors in Cancer Biology and Alzheimer’s Disease for Therapeutics

In 2016, Dr. Chiosis led a study showing that in cancer cells, proteins called chaperones band together in response to stressors associated with cancer and form faulty networks. She named this faulty network of chaperones the epichaperome.

As their name implies, chaperone proteins take care of our cells. They help proteins get made and ensure that cellular activities are coordinated properly. The epichaperome, on the other hand, changes how proteins interact with one another. It causes them to improperly organize inside cells and accelerates the course of disease.

An experimental drug developed at MSK called PU-H71 targets these faulty epichaperomes when they form in cancer. Dr. Chiosis’s 2016 study found that the effectiveness of PU-H71 on tumors depends on how many chaperones have banded into epichaperomes: The more the chaperones have switched to become epichaperomes, the more effective PU-H71 was.

Looking for Epichaperomes in Alzheimer’s Disease

In the new study, Dr. Chiosis and her team analyzed brain tissue from people with Alzheimer’s disease. They compared these to tissues from people of the same age without Alzheimer’s. Higher numbers of chaperones banded into epichaperomes in brain tissue from people with Alzheimer’s compared with healthy brain tissue. These findings were validated in multiple mouse and cellular models of Alzheimer’s disease.

Alzheimer’s is a progressive neurodegenerative disease with complex causes. Many stressors can contribute to it, including diabetes, stroke, high blood pressure, and traumatic brain injury. Genetic risk factors and other age-related changes can also damage brain circuitry over decades. “We decided to look at whether this complex matrix of stressors that change the brain is related to epichaperome formation,” Dr. Chiosis says.

This turned out to be the case. Her team found that in the Alzheimer’s brain tissue, epichaperomes assisted the incorrect organization of many proteins required for normal brain function, including memory and higher-order executive function. Faulty disorganization of memory-related proteins seemed to cascade into defective communication between neurons. That disruption ultimately led to brain dysfunction.

“These changes were similar to network failures seen in electrical or mechanical components that eventually lead to system failure and shutdown,” explains Dr. Chiosis, a member of SKI’s Chemical Biology Program. “The epichaperome acts like a scaffold that allows the misconnectivity of proteins, and in turn, neuronal circuits collapse and underlie age-related cognitive dysfunction.”

Based on their discoveries, Dr. Chiosis and her colleagues, including neuroscientists at Weill Cornell Medicine, the New York University School of Medicine, and the Nathan Kline Institute for Psychiatric Research, developed a term to describe this phenomenon: protein connectivity–based dysfunction (PCBD). “Many people who study Alzheimer’s are thinking about circuits in the brain. But there’s no clear understanding of how stressors due to aging and the environment change the way proteins interact,” she says. “Our research demonstrates that epichaperome formation rewires brain circuitry in Alzheimer’s by enabling proteins to misconnect, leading to downstream PCBD and cognitive decline.”

Validating Findings in Animal Models of Disease

Armed with this knowledge about epichaperomes, Dr. Chiosis and her team treated a mouse model of Alzheimer’s with PU-AD. Like PU-H71 in cancer, PU-AD uncouples the faulty protein networks created by epichaperomes. They found that PU-AD corrected how proteins interacted in the mice. The drug was able to fix signaling problems between neurons. The treated brains resembled those of normal mice.

Further research showed that after Alzheimer’s mice were given PU-AD, they performed much better in tests that evaluate memory function. They also survived longer than mice given a placebo. This indicates that the drug treatment was safe and effective.

The first clinical trial of PU-AD launched in 2019 to confirm in healthy volunteers that the drug is safe. PU-H71 is already in clinical trials for lymphoma, breast cancer, and other cancers. That drug appears to be safe, and researchers are optimistic that the same will hold true for PU-AD. PET imaging versions of both drugs are also being studied in clinical trials as a way to track changes in cells and PCBD in living patients, with the hope that the drug treatment reverses damage in real time.

Summing up the findings in such diverse disorders as cancer and Alzheimer’s disease, Dr. Chiosis says, “Epichaperomes are disease hallmarks that we are just beginning to understand. The idea that we might be able to target this whole network with drugs and treat such complex diseases as cancer and Alzheimer’s is pretty remarkable.”

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Unique Genetic Change Found in Rare Ovarian Tumor Could Spare Patients from Unnecessary Treatment

Source: Memorial Sloan Kettering - On Cancer
Date: 01/27/2020
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As research has revealed more about the genomics of cancer, it’s changed the way that doctors think about the disease. There is not a single type of breast tumor or colon tumor, for example, but many variations of each kind of cancer. The differences are in tumors’ appearance under a microscope, their molecular signatures, and distinct changes that drive their growth.

This variety is also found with ovarian tumors. There are many types, and not all behave or respond to treatment in the same way. For a rare ovarian tumor called sclerosing stromal tumor (SST), the situation is even more complicated. SST is not a cancer but a benign tumor that can be misdiagnosed as cancer.

“If a woman with SST is misdiagnosed as having ovarian cancer, she would likely be given more-aggressive treatments that she wouldn’t need,” says Britta Weigelt, a Memorial Sloan Kettering research scientist and senior author of a study published January 2 in Nature Communications. “Although these tumors can cause a lot of pain and other symptoms, they can be successfully treated with surgery alone because they do not spread.”

The Rarest of Rare Tumors

In the study, the investigators reported that they had identified a unique molecular change in SSTs. This allows for the accurate diagnosis of this tumor. They also say that some of the biological insights learned may be applicable to other kinds of tumors.

SSTs make up about 5% of an already rare type of ovarian tumor called sex cord-stromal tumor. Most of these tumors, which can also grow in the testes, are cancerous. Despite how uncommon SSTs are, the researchers from MSK and their colleagues at Massachusetts General Hospital in Boston, as well as collaborators from outside the United States, were able to obtain 26 samples that were confirmed to be this type of tumor. “This was, by a wide margin, the largest collection of these tumors ever studied with genetic approaches,” says Sarah Kim, the first author of the study and a fellow in Dr. Weigelt’s lab. “I completed four years of residency, and I never saw a single patient with it. There’s a lack of familiarity with SST in the medical community.”

Of Ovarian Tumors and Hedgehogs

The type of change that drives SST is called a fusion gene. Fusion genes occur when part of a chromosome breaks off and attaches to another part of a chromosome, linking two genes that are not normally linked. Fusion genes are found most commonly in pediatric tumors, especially sarcomas and blood cancers. Similarly, SST also affects younger women — usually in their 20s or 30s.

In SST, one of the genes involved in the fusion is called FHL2. The other gene is called GLI2. FHL2 is a gene that’s naturally expressed at high levels in ovarian tissue. When it fuses to GLI2, it drives the production of a tumor-causing protein.

In the Nature Communications study, 21 of the 26 samples tested had GLI2 fusion genes. The investigators reviewed data for more than 9,000 tumors in a large database and didn’t find any other instances of a FHL2-GLI2 fusion gene, confirming that this fusion is unique to SST.

Further research uncovered that the protein created from the fusion is involved in the Sonic hedgehog pathway. This signaling pathway is important for embryonic development. It has also been implicated in cancer, especially certain brain tumors and basal cell skin cancers. When the researchers tested drugs that target the Sonic hedgehog pathway in SST cell models in a dish, the cells responded, confirming that this pathway was driving cell growth.

“We started this project because SST is a clinical conundrum,” Dr. Kim says. “These findings will make things easier for both doctors and patients, by making it simpler to identify this rare tumor.”

“This study also provides new biological clues about Sonic hedgehog and its role in cancer,” Dr. Weigelt says. “We hope that it may help in the understanding of other tumors that pose diagnostic and clinical challenges.”

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A Decade of Progress in Cancer Care, and What’s Next

Source: Memorial Sloan Kettering - On Cancer
Date: 02/04/2020
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In January, the American Cancer Society reported that the rate of cancer deaths in the United States had fallen 2.2% from 2016 to 2017. This was the largest single-year decline in cancer mortality ever reported.

Many factors have contributed to the continuing decline in cancer deaths. The reduction in the number of people who smoke is chief among them. But advances in diagnosis and treatment, especially those made during the past ten years, have also played a significant role. Experts anticipate that, with further advances in research, cancer survival will continue to improve over the next decade and beyond.

In an interview, Larry Norton, a medical oncologist and Senior Vice President at Memorial Sloan Kettering, talked about some of the biggest achievements in cancer care made between 2010 and 2019, and what he hopes to see next.

Immunotherapy

By any estimate, immunotherapy has been the past decade’s most noteworthy advance in cancer medicine. It was one of the earliest attempts regarding the nonsurgical treatment of cancer. Making it effective, though, has taken more than 100 years, coming into its own only in the 2010s.

The field dramatically accelerated in 2011 with the US Food and Drug Administration’s approval of ipilimumab (Yervoy®) for melanoma. This drug, in a class called immune checkpoint inhibitors, was based on research conducted by immunologist James Allison and developed in clinical trials with the help of MSK physician-scientists. Dr. Allison, who led the Sloan Kettering Institute’s Immunology Program from 2002 to 2012, won a Nobel Prize in 2018 for this pioneering work. Several other checkpoint inhibitor drugs followed. What these therapies have in common is that they take the brakes off the immune system, enabling it to destroy cancer.

“In addition to melanoma, these are some of the first new drugs to really have an impact on lung cancer,” Dr. Norton says. “They also have become very important for treating bladder cancer and other cancers.”

Chimeric antigen receptor (CAR) T cell therapy was another big leap forward in immunotherapy. In this approach, pioneered by MSK’s Michel Sadelain, scientists genetically engineer a patient’s own immune cells to make a new protein that can latch on to cancer. This turns those altered cells into powerful cancer fighters.

What’s Next?

Researchers are looking for ways to make immunotherapy drugs effective in more people and for more types of cancer. One approach that’s promising is using cancer vaccines and viruses to activate tumor cells and make them more visible to the immune system. These treatments are likely to be combined with checkpoint drugs and CAR T.

Targeted Therapies

Targeted therapies came into their own in the late 1990s and early 2000s, with the approval of drugs like trastuzumab (Herceptin®) and imatinib (Gleevec®). But in the 2010s, they became part of standard treatment for many more cancers. Dozens of new drugs were approved for both solid tumors and blood cancers. These therapies are designed to exploit weaknesses found primarily in cancer cells while sparing healthy tissue.

Thanks to studies called basket trials, researchers have learned that the same drug may work against many types of cancer if the tumors have the same genetic changes. One of the most striking examples of this pan-cancer approach is larotrectinib (Vitrakvi®), which the FDA approved in 2018.

Advances in targeted therapy for blood cancers, especially chronic lymphocytic leukemia, acute myeloid leukemia, and acute lymphocytic leukemia, have led to a number of drug approvals. These drugs have fewer side effects than traditional chemotherapy. Because of that, they can be given to people who are unable to tolerate more intense treatment because of their age or other health problems.

What’s Next?

Researchers are learning more about how tumors develop resistance to targeted drugs. In addition, they’re studying the role of tumor heterogeneity, which allows some tumor cells to escape the effect of these drugs.

According to Dr. Norton, another exciting area of research is tackling the noncancerous cells that surround tumors, called the tumor microenvironment. “Some of these cells stimulate cancer growth, and we can also go after them with drugs,” he says. “To paraphrase a Zen koan: Targeting only the tumor is like trying to clap with one hand. You may have to hit both sides of the equation to really make a difference.”

Molecular Diagnostics

With the development of tests like MSK-IMPACT™, launched in 2014, and MSK-ACCESS, launched in 2019, doctors now have the ability to look for hundreds of cancer-causing mutations across of range of tumor types with a single test. As of the end of January 2020, more than 50,000 tumors from more than 43,000 patients have been analyzed with MSK-IMPACT. More recently, MSK-ACCESS has enabled doctors to study tumors using a blood test called a liquid biopsy rather than having to do a more complicated tissue biopsy.

What’s Next?

Molecular diagnostics looks for a number of changes in cells. These might include chromosomal gains and losses, changes in gene copy numbers, structural rearrangements, and broader mutational signatures. Analysis of messenger RNA (the genetic material that carries information from DNA to a cell’s protein-making machinery) is becoming an important diagnostic tool, too.

Unlike other genetic tests, MSK-IMPACT and MSK-ACCESS look for mutations in a person’s normal tissue for comparison. This bonus analysis is revealing new clues about which cancers are inherited.

Diagnostic tests that include normal tissue are also uncovering more details about clonal hematopoiesis (CH). This age-related condition leads to an increased number of white blood cells that carry cancer-causing mutations. CH is not cancer, but people who have it have an increased risk of cancer. “We’re learning more and more about the role that CH cells play in relation to many kinds of cancer, not just blood cancers,” Dr. Norton says.

Screening and Early Detection

In the 2010s, large studies confirmed the benefits of many screening tests, such as colonoscopies for colon and rectal cancer and low-dose CT scans for people at an increased risk of lung cancer because of their smoking history. There have been a number of advances in mammograms and other types of breast screening as well. For example, MRIs can be used to classify a woman’s risk of developing breast cancer.

What’s Next?

Dr. Norton says that the personalization of cancer screening will play a big role over the next decade. “Not everyone needs to have the same level of monitoring,” he notes.

MSK’s Precision Interception and Prevention program combines the principles of precision medicine with research on prevention and early detection. The goal of this approach is to prevent cancer from occurring or stop it at the earliest stages, when it’s easier to treat.

Surgery

Over the past ten years, minimally invasive and robotic surgeries have become standard for more and more cancers. For many cancer types, studies have confirmed that these surgeries are just as effective as open surgeries at controlling disease but with less pain and quicker recovery. 

“Many of these surgical techniques have been advanced at MSK’s Josie Robertson Surgery Center,” Dr. Norton says. The center, which opened in 2016, enables surgeons to perform outpatient procedures in a state-of-the-art setting. More than half of the 20,000 surgeries done at MSK every year are now done on an outpatient basis.

What’s Next?

Although surgery will continue to be an important part of cancer care, Dr. Norton says that continuing advances in other treatments will enable some people to avoid surgery entirely. “For some people with breast cancer, drug therapies and radiation are becoming so effective that we might want to do research looking at whether they might not need surgery or will need only minimally invasive surgery,” he says.

Radiation Therapy

In radiation therapy, one of the important tenets over the past decade has been “less is more.” Advances like intensity-modulated radiation therapy and image-guided radiation therapy use computer programs and advanced imaging to deliver stronger doses of radiation while sparing healthy tissue. Oftentimes, fewer radiation treatments are needed to achieve the same benefits. There have also been advances in identifying which tumors can be effectively controlled with less radiation overall, which reduces side effects.

What’s Next?

In 2019, the New York Proton Center opened in East Harlem. The center aims to provide treatment and to conduct clinical trials comparing proton therapy to other types of radiation. Proton therapy is already in use, especially for head and neck cancers and pediatric tumors. Experts expect it to become more widely used in the 2020s.

Pediatric Cancer

Survivorship rates for pediatric cancers continued to improve in the 2010s. About 80% of children with cancer can now be cured with available treatments. For the remaining 20%, there has been an increased focus on personalized medicine.

All children treated at MSK Kids receive testing with MSK-IMPACT. And clinical trials developed by MSK’s Early Drug Development Service can now include children as young as 12. For children with very rare mutations, protocols for single-patient use (SPU) can provide lifesaving treatment.

What’s Next?

Initiatives like MSK’s Pediatric Translational Medicine Program and the Expanded Genomics Program aim to make personalized medicine an option for more children with cancer. And when investigators conduct SPUs, they collect data to learn how and why certain drugs work or don’t. These findings can lead to future trials.

Supportive Care and the Patient Experience

Research reported in 2017 confirmed that systematic monitoring of patient-reported symptoms during chemotherapy improves survival outcomes. Patient input and the patient experience are now incorporated into the design of clinical trials. These measures empower patients to actively report their symptoms. Doctors and nurses are then able to intervene early, ultimately improving patients’ quality of life as well as survival rates.

What’s Next?

Investigators at MSK are continuing to focus on the influence of nutrition, integrative medicine, and exercise in improving patients’ well-being during and after treatment — as well as their cancer outcomes. Digital health and telemedicine are another exciting frontier in cancer management and research, Dr. Norton says. Clinical trials already underway aim to look for measurable benefits from these interventions.

Many of the advances in cancer treatment and diagnosis seen over the past ten years are possible thanks to funding from donors, Dr. Norton explains. “You can make progress with philanthropic support that you can’t accomplish any other way,” he says. “It gives researchers freedom to be creative in a way that no other type of funding makes possible.”