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Improving Microbial Balance in Female Genital Tract May Boost Health

Source: Brigham and Women's Hospital
Date: 3/7/2022
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Advances in gene sequencing and computational biology have revolutionized the study of the microbiome over the past decade. But compared with other bodily systems like the gastrointestinal tract and skin, much less attention has been paid to the microbiome of the female genital tract. This is despite its important role in modulating reproductive health.

Raina Fichorova, MD, PhD, is the director of the Laboratory of Genital Tract Biology, the Walter Channing Distinguished Chair in Obstetrics and Gynecology, the inaugural BWH OBGYN vice chair for Research at Brigham and Women’s Hospital, and professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School. She is also a leader in studying host-microbe interactions in the female reproductive tract, including their role in inflammation, resilience to infection and reproduction. Some of her efforts have focused on the development of a novel biotherapeutic treatment, which she has patented and is now working to bring into clinical trials.

“There is an overwhelming body of evidence showing that the resident vaginal microbes are a fundamental part of the fabric of innate immunity in the female genital tract,” Dr. Fichorova says. “They have consequences not only for women’s health, but also for the health and development of their offspring.”

Addressing an Unmet Need in Women’s Health

Central to the work in Dr. Fichorova’s laboratory is the characterization of the microbes that play a role in bacterial vaginal dysbiosis, which is associated with increased inflammation in the genital mucosa, increased susceptibility to sexual transmitted infections and adverse pregnancy outcomes.

Despite available antibiotic treatment, an estimated 21.2 million women of reproductive age in the United States have this condition, including 23% of white women, 51% of Black women and 32% of Latina women. In African countries, where Dr. Fichorova has conducted much of her research, the prevalence among reproductive age women is between 35% and 50%.

“There is an unmet need for better ways to treat this condition, which affects up to half of women of reproductive age in the most vulnerable populations around the globe,” she says. “There are major gaps in the study of this condition and how to address it therapeutically.”

Dr. Fichorova and her team have developed metrics to distinguish good from bad maternal bacteria and to identify microbes that can affect the offspring either directly or through epigenetic changes, due to the presence or absence of inflammation in the uterus and placenta. The investigators discovered that maternal bacteria ascending to the placenta are associated with newborn inflammation and that maternal bacteria are also linked to epigenetic regulation of inflammatory genes in the placental tissue.

“We’ve found that certain types of lactobacilli in the uterus and placenta reduce inflammation at all molecular checkpoints,” Dr. Fichorova says.

Developing a Live Biotherapeutic Treatment

One effort to come from this work is the development of live biotherapeutics, which “have the potential to reduce inflammation and prevent the ascendance of harmful bacteria to the placenta,” according to Dr. Fichorova.

In 2021, Dr. Fichorova and her colleagues at the Brigham were granted a patent for a mixture of strains of lactobacilli that has the potential to correct the microbial balance in the female reproductive tract.

“We have identified and cloned bacterial strains of the human vaginal microbiome obtained from healthy moms who delivered healthy babies at term here at the Brigham,” she says. “These strains synergistically colonize the human vaginal cells, are homeostatic and noninflammatory and have genomes that are fully characterized.”

In addition to the biotherapeutic blend, the patent includes an algorithm to synthesize a unique cocktail of these strains in optimal proportions.

With funding from the National Institutes of Health as well as internal funding from within the Brigham through its “Shark Tank” program, Dr. Fichorova and her colleagues have made progress toward developing vaginal delivery systems for their biotherapeutic. They are also collaborating with the pharmaceutical industry.

“The successful translation of our research concept and implementation of a live biotherapeutic device would contribute to improved reproductive and sexual health and also reduce preterm birth, infant mortality and disability rates associated with a disturbed vaginal microbiome,” she says. “Our research has the potential to benefit at least 500 babies born preterm at the Brigham each year.”

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Role of Neurons in the Tumor Microenvironment that Drive Cancer Growth

Source: Brigham and Women's Hospital
Date: 4/5/2022
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Cancer researchers increasingly are recognizing the role that different cell types within the tumor microenvironment play in advancing disease growth. In recent years, research discoveries in angiogenesis and immunotherapy have led to the approval of drugs that slow the growth and spread of cancer by targeting cells within the tumor microenvironment, validating this approach. Yet the role of neurons and the nervous system has remained largely unexplored.

Humsa Venkatesh, PhD, a cancer biologist in the Department of Neurology at Brigham and Women’s Hospital, is studying the neural regulation of cancer and how nerve cells found within the tumor microenvironment drive malignant growth. Her research has implications for primary brain tumors such as gliomas as well as for other types of cancers both in and outside of the brain.

“My work lays the foundation for a new field focused on the neurobiology of cancers,” Dr. Venkatesh says. “We’ve found that the nervous system plays a fundamental role in tumor growth and that this dependency on neural input is a huge vulnerability for a number of cancers.”

How Brain Cancer Hijacks Normal Growth Mechanisms

Dr. Venkatesh began this area of inquiry as a postdoctoral fellow at Stanford, with a focus on pediatric high-grade gliomas. She hypothesized that since neurons are a large component of the brain tumor microenvironment and neural activity plays such a strong role in development, the cancer cells may similarly rely upon activity for progression.

Using techniques such as optogenetics and single-cell sequencing, she and her colleagues showed that interactions between neurons and glioma cells include activity-dependent secretion of mitogens and, perhaps more importantly, electrochemical communication that occurs via direct neuron-to-glioma synapses.

“It is interesting because cancer cells seem to hijack normal mechanisms of neural signaling,” Dr. Venkatesh says. “Our findings make it clear that these tumor cells physically and functionally integrate into the brain’s normal, healthy neural circuits.”

The work, published in Nature, utilized preclinical models of glioma to further demonstrate that blocking this electrochemical signaling either with drugs or by inducing genetic changes slowed tumor growth.

“This electrical aspect of cancer biology has been completely underappreciated, and it gives us a new strategy to attack these tumors therapeutically,” Dr. Venkatesh says.

This research led to the development of clinical trials of repurposed neuromodulatory drugs for the treatment of some forms of primary brain cancer.

Shifting Focus to Brain Metastasis

Since joining the Brigham, Dr. Venkatesh’s work has expanded to study the role that neurons within the tumor microenvironment play in the progression of metastatic brain cancers.

“We know that a lot of cancers tend to be innervated, including prostate, lung and pancreatic cancers,” she says. “This got me thinking about whether these non-glial derived cancers also respond to neuronal cues.”

Although many cancers have the ability to spread to the brain, they are different from brain cancers in that they do not originate in glial cells. “But what is fascinating is that these metastatic cells upregulate similar neuronal gene expression profiles,” Dr. Venkatesh says.

Currently, Dr. Venkatesh’s research is largely focused on small cell lung cancer. Her team is looking at how these cancer cells have the ability to use signals from neurons in the tumor microenvironment and leverage them to communicate with neighboring cells. This integration and communication appear to be essential for the growth and spread of tumors.

“We know there may be different mechanisms and different neural populations involved,” she says. “But what’s become quite clear is that neuronal communication is a critical component of the tumor microenvironment for a large number of different cancers.”

Uniting Disciplines to Study Cancer Neuroscience

Dr. Venkatesh explains that she came to the Brigham to help grow a new program in cancer neuroscience. She’s looking forward to collaborating with other investigators at the Brigham as well as with colleagues at Massachusetts General Hospital, Harvard Medical School and MIT.

“We’re at a critical juncture where there have been so many advances in technology as well as in interdisciplinary science,” she says. “Neuroscientists, molecular biologists, cancer biologists and others have all worked together to advance this interesting and exciting new field.”

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‘Disease Deconstruction’ Approach Yields Insights on Autoimmune

Source: Brigham and Women's Hospital
Date: 2/15/2022
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Advances over the past two decades in next-generation sequencing and precision medicine have shown that cancer should be defined not only by its location in the body, but also by the specific molecular changes driving each person’s disease. For several years, experts at Brigham and Women’s Hospital have taken a similar, molecular-driven approach to studying the underpinnings of autoinflammatory disease—specifically rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

One of the leaders in this work is Michael B. Brenner, MD, Elizabeth Fay Brigham Professor of Medicine at Harvard Medical School and director of cell and molecular immunology in the Brigham’s Division of Rheumatology, Inflammation, and Immunity. Much of Dr. Brenner’s work decoding the underlying causes of these rheumatic diseases has relied on an approach called “disease deconstruction,” which is grounded in single-cell, discovery-based research.

“Most research is hypothesis-driven—we have an idea that a particular cell or pathway is causing a disease, and we study the tissue to see if it’s altered there,” Dr. Brenner says. “With discovery-based research, we look at everything with no bias or preconception. This allows us to find things that are entirely unexpected.”

Finding Underlying Causes of Rheumatoid Disease

A considerable amount of this work has been done under the umbrella of the Accelerating Medicines Partnership (AMP) RA/SLE Consortium, a multiyear, $50 million initiative funded by the National Institutes of Health (NIH) and the nonprofit Foundation for the NIH, a government-industry partnership. RA, SLE and related autoimmune disorders have been a major focus of the AMP program.

“This area of research was identified by NIH director Francis Collins as one where technology could help make new inroads into understanding complex, heterogeneous diseases,” says Dr. Brenner, who has co-led the AMP RA/SLE program for six years. “The AMP projects were created to come up with new ways to find targets for treating those diseases.”

Looking at “everything” requires analysis of hundreds of patient samples with a range of different technologies. Among these are mass cytometry, which allows researchers to sift through tissues and isolate particular cell types of interest, and single-cell RNA sequencing to identify which genes are transcribed. The goal of this work is to learn more about the mechanisms of disease so they can be more precisely targeted.

For the RA studies, synovial tissue was collected from the joints of people with the disease. For SLE, the investigators focused on kidney tissue, because lupus nephritis is the most serious complication of SLE. In each case, about one-third of samples were collected from patients who were newly diagnosed and treatment-naïve to learn more about the underlying causes of the disease. The other two-thirds of samples were collected from patients who did not respond to available treatments, with the aim of finding new pathways that potentially could be targets of treatment.

Discoveries Suggest New Treatment Approaches

This research has already yielded a series of important studies from Dr. Brenner’s lab. One paper published in Nature in 2020, led by investigators Kevin S. Wei, MD, PhD, Ilya Korsunskiy, PhD, and Soumya Raychaudhuri, MD, PhD, defined the underlying role of NOTCH3 signaling in synovial fibroblasts as central in RA pathology. Another Nature paper published in 2017, led by Deepak A. Rao, MD, PhD, unexpectedly identified a highly expanded population of CD4+ T helper cells that drives B cells and autoantibodies in RA.

A resource paper published in Nature Immunology in 2019 led by Fan Zhang, PhD, and Dr. Raychaudhuri provided an atlas of all the cells making up the inflamed synovium in RA from the first phase of the consortium. Meanwhile, a paper just accepted for publication in Science Immunology led by Daimon Simmons, MD, PhD, defines super-activated macrophages in RA and other autoimmune conditions.

In November 2021, a new AMP project focused on autoimmune and immune-mediated (AIM) diseases and called AMP-AIM was launched. In addition to RA and SLE, it will expand to other diseases, including psoriasis, psoriatic arthritis and Sjögren’s disease. Investigators at the Brigham will continue to play a leading role.

“We’re realizing more and more that although these diseases bear the same name, they are actually very different from patient to patient and fall into molecular and cellular subtypes that now allow us to stratify patients in new ways with therapeutic implications,” Dr. Brenner concludes.

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How Trauma Informed Care Improves The Patient Experience

Source: Brigham and Women's Hospital
Date: 2/24/2022
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Over the past two years, the COVID-19 pandemic and a renewed emphasis on issues surrounding racial justice have brought the need for trauma-informed healthcare into greater focus. Trauma-informed care is based on a framework that recognizes people’s lived experiences can affect how they engage with the healthcare system.

Trauma-informed care programs have been in place for a decade at Brigham and Women’s Hospital but are now expanding across more areas. The emphasis on this type of care has contributed to a greater awareness of societal issues and the development of clinical programs and policies that minimize the chance of retraumatizing patients.

“Many people have experienced traumas of a variety of sorts, even if they don’t have a diagnosis of post-traumatic stress disorder,” says Nomi Levy-Carrick, MD, MPhil, a consultation-liaison psychiatrist in the Department of Psychiatry at the Brigham. “Through training of providers and staff, we can help ensure these patients get healthcare that takes their individual histories into consideration. This need is often amplified for people with chronic illnesses who require ongoing care.”

Guiding Principles for Patient Resilience

As Dr. Levy-Carrick explains, the difference between trauma-focused care and trauma-informed care is an important one. “We are not talking about care that’s focused on the specific trauma content itself,” she says. “Rather, this is care that is mindful about recognizing how a patient’s past experiences, whether individual, interpersonal or community-based, can impact their current engagement in healthcare.”

The Substance Abuse and Mental Health Services Administration within the U.S. Department of Health and Human Services has created six guiding principles for trauma-informed care, which aim to restore feelings of safety and self-worth in patients while promoting healing. These principles are:

  • Safety
  • Trustworthiness and transparency
  • Peer support and mutual self-help
  • Collaboration and mutuality
  • Empowerment voice and choice
  • Cultural, historical and gender issues

“As a consultation-liaison psychiatrist, I work with colleagues across the institution to make sure everyone who has contact with patients is aware of these principles and how to apply them. We see this as a clinical component of overall health equity efforts,” says Dr. Levy-Carrick, who serves as co-chair of the Mass General Brigham Trauma-Informed Care Initiative. This includes not only clinical staff, but also those who handle patient check-ins, scheduling requests and other issues.

Annie Lewis-O’Connor, PhD, NP-BC, MPH, FAAN, is a nurse scientist and the other co-chair of the Trauma-Informed Care Initiative. She also founded and directs the Brigham’s Coordinated Approach to Resiliency & Empowerment (CARE) Clinic, which provides coordination of care for individuals impacted by interpersonal violence and trauma.

“What I love about the trauma-informed care model is that it addresses issues of equity and allows patients to provide input about their preferences and desires,” Dr. Lewis-O’Connor says. “Instead of having a system where you do things ‘to’ or ‘for’ the patient, trauma-informed care means doing ‘with’ the patient. It’s a very different way of delivering healthcare.”

Impact of Care Model Spans Many Departments

From 2018 to 2020, Drs. Levy-Carrick and Lewis-O’Connor were members of an interdisciplinary team that received funding through the Robert Wood Johnson Foundation Clinical Scholars Program to create, implement and evaluate a trauma-informed care model in the Brigham’s Department of Emergency Medicine. The other team members were Samara Grossman, MSW, LICSW, of the Department of Psychiatry; Eve Rittenberg, MD, of the Fish Center for Women’s Health; and Hanni M. Stoklosa, MD, MPH, of the Department of Emergency Medicine.

The emergency department is one area where this care model is so important because trust with patients must be established quickly. “Transparency is a really valuable way of doing that,” Dr. Levy-Carrick says. “Our communications with patients must be very clear. We want to empower them to share information about their history in a way that makes them comfortable.”

Dr. Levy-Carrick has also collaborated with pulmonary and critical care medicine specialists Daniela J. Lamas, MD, and Gerald Lawrence Weinhouse, MD, along with social worker Stacey Salomon, LICSW, to include a trauma-informed framework for the Critical Illness Recovery Program to improve the lives of patients with post-intensive care syndrome.

Dr. Lewis-O’Connor adds that this care model has been invaluable in supporting staff, both in terms of how workers across the Brigham relate to each other and how they have coped with trauma, stress and racism over the past two years.

“For the first time, it’s probably more uncomfortable for the people in the room if we don’t talk about these things,” she says. “There’s been a real shift. People are finding their words and finding safe spaces to talk about their past experiences.”

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Study Reveals How Cancer Cells Hijack Mitochondria From Immune Cells

Source: Brigham and Women's Hospital
Date: 1/25/2022
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By taking the brakes off the immune system and allowing it to attack cancer cells, checkpoint inhibitors have spurred significant advances in the treatment of many people with cancer over the past decade. But for patients who do not respond to these drugs — still the majority of people with cancer — alternative interventions are needed.

A team of investigators from Brigham and Women’s Hospital and MIT is using the power of nanotechnology to develop an entirely new approach for boosting the immune response to cancer. Through the use of field-emission scanning electron microscopy (FESEM), they have learned that cancer cells actually steal mitochondria from T cells — an action that both strengthens the cancer cells and weakens the immune response.

“Nanotechnology is helping us to better understand important basic biological functions,” says Shiladitya Sengupta, MS, PhD, co-director of the Brigham’s Center for Engineered Therapeutics and the study’s senior author. “If we could develop a drug to inhibit this hijacking of mitochondria, it could make immune checkpoint therapy much more effective. That’s what we’re now trying to do.”

Dr. Sengupta and team’s latest study was published in November in Nature Biotechnology.

Observing the Transfer of Mitochondria

To study the interactions between cancer cells and immune cells, Dr. Sengupta’s team co-cultured breast cancer cells with different types of immune cells, including T cells. When they looked at the cells using FESEM, they saw that tube-like filaments were connecting the two types of cells. “The cancer cell sends out these nanotubes, which are almost like tentacles,” he says.

When researchers zoomed in further, they noticed there were small particles along the length of these filaments. Suspecting the particles were mitochondria, they labeled these organelles with a fluorescent green dye that bonds to mitochondrial proteins. They then were able to observe the mitochondria being pulled out of the T cells, traveling the length of the nanotubes and being incorporated into the cancer cells.

Further analysis of the metabolic functions of both the immune cells and the cancer cells confirmed that the shift in mitochondria from one cell to the other was affecting cell function.

Look for Drug Strategies to Protect Immune Response

Next, the researchers tested whether they could intervene and prevent the cancer cells from hijacking mitochondria. In mouse models of breast cancer, they injected a drug that blocks the formation of these filaments. When they combined this agent with immune checkpoint inhibitors, they saw a significant reduction in tumor growth in the mice.

Dr. Sengupta’s team is now working with other investigators to develop next-generation filament-inhibiting agents that are more drug-like and potentially could be developed for evaluation in clinical trials.

“The implication of this work is that if we can prevent the mitochondrial hijacking from happening, essentially preventing the T cell’s batteries from being stolen by the cancer cells, then the immune cell retains the energy to attack the cancer cell,” he explains.

Dr. Sengupta expects this approach could be successful for a number of different solid tumors. “We’ve observed this behavior in lung cancer, breast cancer, melanoma and many other tumor types,” he says. “We believe this could be part of a broad strategy for making immunotherapy more effective.”

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WHAT ARE THE BEST TREATMENT OPTIONS FOR EPILEPSY THAT DOESN’T RESPOND TO MEDICATIONS?

Source: Brigham and Women's Hospital
Date: 2/1/2022
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About one-third of people with epilepsy do not experience adequate control of their seizures with medication alone, making them potential candidates for surgical interventions. But some of these candidates do not qualify for more traditional surgeries due to the location of seizures in the brain, so they need better options.

At Brigham and Women’s Hospital, surgeons and physicians are developing several new treatments that offer the possibility of better seizure control. These therapies require a great deal of diagnostic and surgical expertise along with the latest cutting-edge tools.

“We’re fortunate because we not only have the most advanced technology, but also have an unbelievably dedicated team of experts, including neuroradiologists, neuropsychologists and epileptologists,” says Garth Rees Cosgrove, MD, director of epilepsy and functional neurosurgery at the Brigham. “This ensures that every patient we see receives the best care available.”

Robotic Guidance Improves Seizure Diagnosis

The first step to offering the best care for every patient is a comprehensive evaluation to determine the location of the brain seizures. Among the diagnostic tools available at the Brigham are a 7T MRI scanner, PET scanner, magnetoencephalography scanner and state-of the-art, six-bed EEG monitoring unit (EMU). Patients’ seizure activities are monitored 24 hours a day, which enables the team to hypothesize about where the seizures are coming from.

For patients in whom the seizure locations cannot be identified with regular scalp EEG monitoring in the EMU, phase two evaluations can be done by using a robotic guidance system that implants electrodes into the brain to monitor seizure activity. The Brigham also houses the Advanced Multimodality Image Guided Operating (AMIGO) suite, which holds an array of advanced imaging equipment and interventional surgical systems.

“Patients will see the best outcomes if we can accurately identify where the seizures are coming from and resect or laser ablate those areas,” Dr. Cosgrove says. “Minimally invasive approaches are also available, and this is where the AMIGO suite is so important. While patients are asleep in the MRI scanner, we use guidance systems to very precisely ensure we are in the right location. This approach is more comfortable for the patient, as well as safer and more accurate.”

Neuromodulatory and Laser Surgery Offer Seizure Relief

Open surgical resection may not be an option for patients who have multiple seizure sites in the brain or seizure sites that are within areas that control critical functions. In these cases, laser ablation, which is used when the seizure site is in a part of the brain that would be difficult to resect, and neuromodulation treatments can provide relief from seizure activity.

For patients whose seizures are located within critical areas for movement, language or thinking—and that would cause neurological deficits if destroyed—two neuromodulation approaches are increasingly used at the Brigham: responsive neural stimulation (RNS) and deep brain stimulation (DBS).

With both techniques, a surgeon implants a neurostimulation device in the brain. These specialized devices are programmed to detect and then deliver electric currents that disrupt seizure activity. With RNS, the device can detect and then stimulate the area to abort seizures. This stimulation interrupts the brain’s abnormal electrical activity. With DBS, more constant stimulation is used to reset the brain’s normal activity.

Providing Long-lasting Seizure Control

RNS and DBS have been proven to provide beneficial, long-lasting control of seizures for most patients who receive them.

“When you add a new medication to somebody’s regimen, they tend to do better for a few months, but then the brain finds a way to adapt and the seizures return,” Dr. Cosgrove says. “With these brain stimulation techniques, the results don’t happen immediately, but at the three- to five-year mark, about 75% of patients will have improvement in their seizures.”

For these patients, this can lead to an extraordinary improvement in quality of life. “It’s not a cure, but it makes a big difference for people who otherwise have no options,” Dr. Cosgrove says.

Epilepsy Research and Development

The Brigham’s focus on research will continue to drive the development of new and improved treatments in the future. Among the novel techniques being developed by Brigham investigators are low-intensity and high-intensity focused ultrasound. These noninvasive treatments, which were developed to treat Parkinson’s disease, are now being investigated in clinical trials for patients with epilepsy.

“For adults who have had epilepsy their whole lives and have tried every other kind of treatment, this research has the potential to truly be life-changing,” Dr. Cosgrove says.

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DOES TOTAL KNEE REPLACEMENT OFFER A GOOD VALUE FOR PATIENTS WITH ADVANCED KNEE OSTEOARTHRITIS AND EXTREME OBESITY?

Source: Brigham and Women's Hospital
Date: 5/17/2021
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Total knee replacement (TKR) for the treatment of advanced knee osteoarthritis is an efficacious and cost-effective treatment, even for people with extreme obesity (defined as having a body mass index, or BMI, of 40 or higher). This finding from experts at Brigham and Women’s Hospital was published recently in the Annals of Internal Medicine.

“Total knee replacement is one of the best medical advancements of the 20th century, reducing pain and helping people gain functional status and become more active in their day-to-day lives,” said corresponding author Elena Losina, PhD, co-director of the Brigham’s Orthopaedic and Arthritis Center for Outcomes Research and a founding director of the Policy and Innovation eValuation in Orthopaedic Treatments Center.

“The challenge is that knee osteoarthritis disproportionally affects people who have extreme obesity,” she added. “Many surgeons are hesitant to offer the procedure because of their concerns about complications in this patient population.”

The goal of the study was to help inform physicians, policymakers and patients about the long-term clinical benefits and value of the procedure.

OAPol Computer Model Aids in Analysis

To perform their analysis, investigators used a computer simulation called the Osteoarthritis Policy (OAPol) Model, which was developed by a multicenter team that Dr. Losina leads. The OAPol model has been continuously funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases since 2006.

“The goal of this type of research is to capture all the long- and short-term benefits and the detriments of a specific medical procedure over a timeframe that is meaningful,” Dr. Losina said. “Because a total knee replacement lasts decades in most cases, a computer simulation is a good way to help evaluate this procedure over its long-lasting timeline.”

The analysis looked at the benefits, risks and costs of TKR surgery. The primary benefit noted was pain reduction. The potential risks involved postsurgical complications, including pulmonary embolism, pneumonia, deep vein thrombosis and infection. Investigators also looked at the cost of the procedure and the dollar value of the quality-adjusted life years (QALY) gained. This measure accounts for factors like workdays lost due to pain or other complications of illness.

The analysis found favorable cost-effective ratios of $35,200 per QALY for patients aged 65 and under and $54,100 per QALY for those over age 65. Most patients with extreme obesity develop advanced knee osteoarthritis earlier in their lives and consider surgery earlier compared to patients with similar stages of knee osteoarthriris who don’t have extreme obesity. That is why the researchers conducted analysis for different age groups.

In addition, CMS is the most likely payer for those over age 65, while those younger than 65 are more likely to be covered by commercial insurances. The analysis provided valuable data for both types of payers.

“There are plenty of interventions that cost a lot but provide little benefit. Our study showed that despite being costly, this procedure provides a very good value,” Dr. Losina said. “As a society, it’s important to promote good value care and reduce wastage of health care resources.”

Weighing Benefits and Risks of TKR

Dr. Losina explained that although the rates of surgical and postsurgical complications are higher in people with obesity, because overall complication rates are so low, even a two- or three-fold increase means this operation is still very safe overall.

“But it’s still important to recognize the challenges,” she noted. “Patients with BMIs over 50 may be so heavy that equipment in some operating rooms may not be suitable. Especially in nonacademic settings, if surgeons don’t feel comfortable operating on these patients, they may want to refer these more challenging cases to an academic medical center. Ideally it would be helpful for these patients to try to lose weight, but it may be difficult to achieve without rigorous, structured weight-reduction programs.”

Richard Iorio, MD, chief of the Adult Reconstruction and Total Joint Arthroplasty Service and Vice Chairman for Clinical Effectiveness at the Brigham, said that he “applauds Dr. Losina and her team for their pioneering work concerning the cost-effectiveness of TKA in those with extreme obesity.”

He explained that several patient demographic factors and medical comorbidities may lead to increased episode-of-care costs. When combined, they can lead to complication rates that are orders of magnitude higher. Most of these factors are nonmodifiable, but others can be optimized before surgery, he noted.

“It is unfortunate that hospitals and surgeons are judged by short-term complication rates instead of a 20- to 30-year horizon for determining success or failure,” Dr. Iorio said. “If episode-of-care length is changed to reflect the true survivorship of the operation, we may be able to ultimately prevent problems with access to care for high-risk patients.”

As Dr. Losina concluded, it’s all about improving patients’ lives. “Orthopaedic surgeons want nothing but the best for their patients,” she said. “We hope this study will help to facilitate the availability of this procedure in those who need it.”

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ADVANCING CARE FOR TRAUMATIC SPINE INJURIES

Source: Brigham and Women's Hospital
Date: 8/26/2021
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Treating patients with traumatic spinal cord injuries has significant challenges, in large part because of the potentially severe and life-altering effects these injuries can have. Despite recent progress in finding the best way to treat spinal cord damage, many patients are left with profound disabilities. Additional research, both in the lab and the clinic, is vital.

At Brigham and Women’s Hospital, physicians and scientists are making advances on several fronts. From the time patients with these injuries are brought into the Emergency Department, experts in trauma and critical care medicine collaborate with spine surgeons, neurologists and other specialists to address the most immediate complications and do everything possible to ensure the best long-term outcomes.

“The Brigham has an experienced and efficient ED system, and when a patient comes in with a traumatic spine injury, the first thing we look at is ABC — airway, breathing and circulation,” said Yi Lu, MD, PhD, director of neurological trauma and co-director of the Brigham’s Adult Spinal Deformity and Scoliosis Program. “At the same time, there have been quite a few studies showing that if the spinal cord can be decompressed and stabilized within the first 24 hours, the outcomes are much better.”

Dr. Lu added that even though some of these surgeries are quite complex, the team at the Brigham always strives to bring these patients in to the operating room as quickly as possible to maximize their likelihood of a functional recovery.

Exploring New Interventions to Repair Nerve Damage

Beyond surgery, a number of medical interventions are being explored to improve patient outcomes, including drugs, cell-based therapies and biomaterials and neural scaffolds. Dr. Lu and other Brigham investigators are studying many of these approaches in the lab in cell and animal models.

Corticosteroids were once considered promising for reducing long-term damage, but research revealed these drugs tend to do more harm than good. Similarly, other therapeutic agents, including GM-1 ganglioside and rho kinase inhibitors, have had clinical trials discontinued after failing to show benefit.

Other medical interventions, however, have shown promise and continue to be studied. These include riluzole, a sodium channel inhibitor currently approved to treat ALS, the antibiotic minocycline and granulocyte colony-stimulating factor, all of which are being tested in later-stage clinical trials.

Stem cell-based therapies are also considered a promising avenue for repairing damaged nerve connections. However, more research is needed to determine the best subtype of stem cells and how to use them. Likewise, the use of neuro-spinal scaffolds are being studied as a way to promote neuronal growth. A clinical trial looking at this approach is underway at the Brigham.

In addition to these medical treatments, research is looking at technological interventions such as neuromodulation and brain-computer interfaces. “Spinal cord stimulators combined with extensive physical therapy have shown improvements in functional outcomes,” Dr. Lu said. “Brain-machine interfaces that bypass the injury site may also help patients’ functional outcomes.”

A Team-Based Approach to Care

Dr. Lu said that the Brigham’s expertise extends far beyond treatment of the injury itself. “Many of these patients require extensive and meticulous care in the intensive care unit,” he said. “From head to toe, every single system in the body can be affected by spinal cord injury.”

He credits the Brigham’s nursing team with making sure patients’ needs are addressed. This includes tackling not only blood pressure and breathing problems that can occur as a direct result of injury, but also preventing and treating other longer-term issues that can arise in patients who are paralyzed, such as aspiration pneumonia, bed sores and urinary tract problems like retention.

Dr. Lu noted that physical therapists, including those at Spaulding Rehabilitation Hospital, where the majority of the Brigham’s spinal cord injury patients go after being discharged, also play a vital role. Spaulding Rehabilitation Hospital is a Harvard Medical School-affiliated hospital that’s part of the Mass General Brigham healthcare system (formerly known as Partners HealthCare).

“Physical therapy is a very important part of recovery, if not the most important part,” he said. “Close interaction between our team and the physicians and therapists at Spaulding ensure our patients are well taken care of and have the best recovery possible. We, and our patients, are fortunate to have this relationship.”

New Spine Center: A Multidisciplinary, Integrated Care Model

Brigham and Women’s Spine Center is a new service line committed to high-quality care that is carried throughout each patient experience by a team of renowned experts in spine conditions including Harvard Medical School-appointed neurosurgeons, orthopaedic surgeons, pain medicine specialists, physical medicine and rehabilitation specialists, advanced practitioners and other clinical staff.

Our team of specialists offer a range of personalized treatment options to help patients regain function, such as:

  • Rehabilitation solutions, including physical therapy or occupational therapy
  • Minimally invasive interventional treatments, including injections or medications
  • Surgical treatments including spinal decompression, spinal fusion or spinal reconstruction

Our multidisciplinary team advocates for each patient’s best interest and customizes care recommendations to meet individual goals.

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ROBOTIC THORACIC SURGERY EXTENDS MINIMALLY INVASIVE OPTIONS TO MORE PATIENTS

Source: Brigham and Women's Hospital
Date: 9/2/2021
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Developments in robotic surgery are enabling procedures in minimally invasive thoracic surgery that previously were not feasible. At Brigham and Women’s Hospital, a team that includes thoracic surgeons and pulmonologists along with experts in vascular surgery, anesthesiology and intensive care has facilitated the increased use of these procedures for many different medical conditions.

“Improvements in the technology allow us to perform operations that historically have been managed with only open surgery,” said M. Blair Marshall, MD, of the Division of Thoracic Surgery. “These advances include better articulation of the instrumentation and increased magnification of the cameras.”

“Noninvasive thoracic procedures tend to be very well tolerated by patients,” added Jon O. Wee MD, section chief for esophageal surgery, director of robotics in thoracic surgery and co-director of minimally invasive thoracic surgery. “They have certainly contributed to shorter hospital stays and better patient outcomes, and in many cases have allowed us to offer surgery to patients who would not be able to tolerate open procedures due to comorbidities.”

The procedures that have benefited from the increased use of robotic surgery include lung surgery after immunotherapy, treatment of tracheobronchomalacia (TBM) and bronchoplasty surgery in patients with airway tumors.

Surgery After Neoadjuvant Immunotherapy

Adding checkpoint inhibitors to the oncology armamentarium has created new opportunities for patients with lung cancer to be cured. But when immunotherapy is used as part of a neoadjuvant treatment strategy, it can present surgical complexities that make more traditional video-assisted thoracoscopic surgery (VATS) inaccessible.

“The addition of immunotherapy creates some of the most technically challenging operations,” Dr. Marshall said. “The robust immune response that occurs as the cancer cells die is unpredictable and can lead to scar tissue that acts almost like a glue between the other tissues.”

“Before the current advances in robotics, these are operations that we would never have tried to treat with minimally invasive approaches,” Dr. Wee said. He explained that the Brigham currently has a number of clinical trials that incorporate immunotherapy into neoadjuvant treatment in patients who predominantly have Stage 3 disease.

Robotic Procedures for Tracheobronchomalacia Cases

Cases of TBM are on the rise, due in large part to increasing obesity rates. This condition, characterized by the collapse of the airway, leads to difficulty breathing, chronic infections and coughing. Historically, patients with TBM have had few options beyond open surgery. Yet due to other health problems, most of them are not good candidates for these open procedures, which can be quite complex.

“These procedures are quite difficult with VATS,” Dr. Marshall said. “Robotics gives us another option.”

“This is a very technical operation that requires a lot of technical maneuvering of the airway,” Dr. Wee said. “With the additional dexterity and individualization that the robot provides, we can now offer many patients the benefits of appropriate surgical care by aligning the airway architecture while diminishing the morbidity associated with a big, open incision.”

Reconstructing Airways With Robotics

Traditionally, surgical treatment for both benign and malignant airway tumors has involved removing much of the lung. Bronchoplasty performed with robotic instrumentation allows surgeons to repair and reconstruct the airway while sparing healthy lung tissue.

“Previously, patients would have been committed to a lung resection with a loss of a large portion of the lung in order to address the airway issue,” Dr. Wee said. “Now we can reconstruct the airway so that only the tumor and the disease is removed, while the lung is left intact and the function is preserved.”

“The real advantage of the robotic technology is not so much the surgical removal of the cancer itself, because a lot of this can be done with VATS,” Dr. Marshall said. “The true advantage comes in the reconstruction, which often requires meticulous fine suturing. This can only be mimicked with the robot.”

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TRIALS ADDRESS NEW OPTIONS FOR TRICUSPID VALVE DEFECTS

Source: Brigham and Women's Hospital
Date: 8/4/2021
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The tricuspid valve is often referred to as the “forgotten valve.” That’s because when it begins to malfunction, it usually doesn’t result in the same severity of symptoms as when there are problems with the aortic and mitral valves. Additionally, when it does stop working properly, fewer interventions are available for treatment.

Recently, however, that situation has begun to change. Experts from Brigham and Women’s Hospital are now participating in two multicenter clinical trials studying catheter-based treatments that could restore the function of the tricuspid valve. One trial is looking at valve repair, and the other is focused on valve replacement. Both approaches would provide new options for patients who don’t respond to medical treatment, but who are not good candidates for open-heart surgery, either because their disease is not severe enough to warrant the risks or due to comorbid conditions.

“We’ve seen tremendous success in the aortic space, to the point that now the majority of aortic valve replacements in the United States are done through a catheter-based treatment rather than by surgery,” said Pinak Bipin Shah, MD, director of the Interventional Cardiovascular Disease Training Program and director of the Cardiac Catheterization Laboratory at the Brigham. “There’s also one approved transcatheter device for the treatment of mitral valve regurgitation. Given what we’ve seen in these other areas, there’s now a lot of interest in looking at whether we can treat the tricuspid valves with catheter-based approaches.”

A Focus on Valve Repair and Replacement

One study being offered at the Brigham is the TRILUMINATE Pivotal Trial, which is a prospective, randomized trial that is evaluating an investigational clip device in patients who are experiencing symptoms from severe tricuspid regurgitation. The other study, the TRISCEND II Pivotal Trial, is looking at Evoque, a tricuspid valve replacement system that doesn’t require open-heart surgery. The control in both trials is medical therapy.

“There’s still much to be learned about the optimal time of treatment for these patients, but we probably ought to be intervening on these patients sooner rather than later,” said Tsuyoshi Kaneko, MD, a cardiac surgeon who specializes in endovascular approaches. “At the same time, the invasiveness of open-heart surgery is often more than we feel comfortable offering to patients who may otherwise feel well. Having transcatheter options for the management of these patients will be an important new option.”

“With tricuspid regurgitation, the patient typically doesn’t notice anything unusual. It’s often picked up on an echocardiogram looking for some other process,” Dr. Shah added. “But although it doesn’t cause symptoms right away, we are learning that this can be a very difficult illness to deal with if left untreated. It can result in dysfunction of the right side of the heart and lead to problems including severe fluid retention, shortness of breath and fatigue.”

Evaluating Less-Invasive Treatments for Tricuspid Valve Defects

Like other transcatheter procedures, tricuspid valve repairs and replacements are done under general anesthesia with echo guidance using a transesophageal echocardiogram. The procedures last no more than two hours, and the team thinks they will need even less time as they gain more experience. Patients who have these procedures require only an overnight stay and usually can go back to normal activities within a week.

For patients who have significant tricuspid regurgitation, especially those who are symptomatic, the comprehensive, multidisciplinary Cardiac Valve Center at the Brigham provides evaluations to determine the best course of action for managing disease. Having additional options for those with tricuspid valve defects adds to the scope of what can be offered to patients.

“This treatment is going to be really revolutionary because it is so much less invasive than open-heart surgery,” Dr. Kaneko said. “We will be able to offer treatment earlier in the disease process, allowing for a much more rapid recovery while preventing later complications.”